I want someone to write answers for the question in detail for each chapter.

All questions be answered in detail!!!

Chapter 5

1. What areas/structures in the body produce reproductive hormones?

2. How does the tonic and surge centers differ regarding GnRH regulation?

3. What is the function(s) of gonadotropins? How do they regulate reproduction? 

Chapter 6

1. What are some environmental and social conditions that impact the onset of puberty in females? Are there differences among species?

2. What initiates the onset of puberty in the male?

3. What are some metabolic factors the that affect GnRH neurons?

4. What prevents ovulation in the prepubertal female?

5. What are three criteria that define puberty in the female?

6. Describe the endocrine profile of the postpubertal male.

7. What is an alpha-fetoprotein? How does it regulate the defeminization of the brain?

Chapter 7

1. In detail, what are the differences between the estrous and menstrual cycles, including length? What is the starting point for each? How do the follicular and luteal phases differ for each?

2. What is the difference between estrous and estrus?

3. What is superfecundation?

4. What is anestrus? What are some causative factors?

5. What is a silent estrus?

6. How does suckling regulate LH?

7. What are the types of estrous cycles as described by annual estradiol profiles?

8. How do the estrous cycles of the queen and dog differ from that of ruminants?

9. What is apparent anestrus?

10. For the ruminant, know the hormonal profiles for each estrous cycle stage.

11. What are the primary structure(s) on the ovary during the follicular phase and luteal phase? What hormone is/are secreted by this/these structures?

12. What is a long-day breeder? How does this differ from a short-day breeder?

13. What is the difference between monoestrus and polyestrus? Please give examples of each.

The Puerperium & Lactation
Parturition
Fetal Attachment & Gestation
Early Embryogenesis &
Maternal Recognition of Pregnancy
Ovulation & Fertilization
Cyclicity
Tract Function
Puberty
Prenatal
Development
… ” ( \
‘ ‘
Spermatogenesis
Tract Function
Pub erty
Prenatal
Development
Take Home Message
Hormones m·e secreted by endocrine glands or nerves. They enter tlte blood and cause
cells in target tissues containing specific receptors to secrete new products or new hormones.
Hormones and their products are necessm y for successful reproduction. Protein hormones
act via plasma membrane receptors am/ exert effects in the cytoplasm of the target cell. Ste-
roid hormones act through nuclear receptors that regulate transcription factors that cause
gene expression t’slow responses”, days to weeks) in target cells. Steroid hormones also
act through plasma m embrane receptors that cause “rapid responses” (minutes to hours) in
target tissues. Both types of hormones cause changes in tlzeftmction oftlze target cells.
Reproduction is regu lated by a remarkable
interplay between the nervous system and the en-
docr-ine system. These two systems interact in a
consistent display of teamwork to initiate, coordinate
and regul ate all reproductive f unctions. In order
to understand and appreciate the role of these two
systems, we must fi rst focus on the contro l that each
system exerts independently.
Neural control requires:
• simple neural reflexes or
• neuroendocrine reflexes
The fimdamental responsibility ofthe nervous
system is to translate or transduce external stimuli
into neural signals that bring about a change in the re-
productive organs and tissues. The primary pathways
of nervous involvement are a simple neura l reflex and
a neuroendocrine reflex. The fimctiona l components
of these two pathways are sensory neurons (afferent
neurons taking neural signals toward the spinal cord),
the spinal cord, efferent neurons (nerves leaving the
sp inal cord and traveling to the target tissue) and
target tissues (See Figure 5-1). Target tissues are
those organs that respond to a specific set of stimuli
or hormone.
The bas ic difference between the si mp le
neural reflex and the neuroendocrine reflex is the
type of de livery system each u ses . For example,
a simple neural reflex employs nerves that release
their neurotransmitters (messengers) directly onto
the target tissue. In other words, the target tissue is
directly innervated by a neuron and responds to a
neurotransmitter. In contrast, a neuroendocrine reflex
requires that a neurohormone (a substance released
by a neuron) e nter the blood and act on a remote target
tissue. Neurons releasing neurohonnones are also
called neurosecretory cells . D irect innervation of
the target tissue does not exist in the neuroendocrine
reflex. Instead, the neurohormone in the blood is the
messenger between the neurosecretory cell and the
target tissue. Both of these neural pathways are il-
lustrated in Figure 5-1 .
Neural Reflexes and Neuroendocrine rn
Reflexes Cause Rapid Changes
in Target Tissues
In a simple neural reflex, afferent sensory
neurons synapse directly w ith interneurons in the
spinal cord (See Figure 5-l ). These interneurons
synapse with efferent neurons that travel directly to
the target tissue. The target tissue responds to the
neurotransmitter released by the efferent neuron. A
neurotran smitter is a substance of small molecular
weight that is released from the tenninals of nerves
that causes other nerves to fire or causes contraction
of smooth muscle that swTounds portions of the re-
productive tract (See Figure 5-l ). An example of a
simple neural reflex in reproduction is ejaculation. A
stim ulus originating in the glans penis is recogn ized
by se nsory neurons. Signals are then transmitted
to the spinal cord where they synapse with efferent
neurons that cause a series of muscu lar contractions
resulting in expulsion of semen. A detailed pathway
of this neural event will be presented in Chapter II.
Another examp le of a simple neural reflex that im-
pacts the reproductive system involves temperature
sensitive neurons located in the scrotum ( described
in Chapter 3). When scrotal temperature decreases,
sensory neurons in the scrotum recognize this decrease
and send sensory signals to the spinal cord. Efferent
nerves travel to the tunica dartos in the scrotum and
release neurotransmitters that initiate contTaction that
elevates the testicles to bring them closer to the body,
thus warming them.
The neuroendocrine reflex (See Figure 5-l )
is quite similar to a simple neural reflex. This type
of reflex also starts with sensory neurons. They syn-
apse with interneurons in the sp inal cord. Efferent
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The Puerperium & Lactation
Parturition
Fetal Attachment & Gestation
Early Embryogenesis &
Maternal Recognition of Pregnancy
Ovulation & Fertilization
Cyclicity
Tract Function
Puberty
Prenatal
Development
… ” ( \
‘ ‘
Spermatogenesis
Tract Function
Pub erty
Prenatal
Development
Take Home Message
Hormones m·e secreted by endocrine glands or nerves. They enter tlte blood and cause
cells in target tissues containing specific receptors to secrete new products or new hormones.
Hormones and their products are necessm y for successful reproduction. Protein hormones
act via plasma membrane receptors am/ exert effects in the cytoplasm of the target cell. Ste-
roid hormones act through nuclear receptors that regulate transcription factors that cause
gene expression t’slow responses”, days to weeks) in target cells. Steroid hormones also
act through plasma m embrane receptors that cause “rapid responses” (minutes to hours) in
target tissues. Both types of hormones cause changes in tlzeftmction oftlze target cells.
Reproduction is regu lated by a remarkable
interplay between the nervous system and the en-
docr-ine system. These two systems interact in a
consistent display of teamwork to initiate, coordinate
and regul ate all reproductive f unctions. In order
to understand and appreciate the role of these two
systems, we must fi rst focus on the contro l that each
system exerts independently.
Neural control requires:
• simple neural reflexes or
• neuroendocrine reflexes
The fimdamental responsibility ofthe nervous
system is to translate or transduce external stimuli
into neural signals that bring about a change in the re-
productive organs and tissues. The primary pathways
of nervous involvement are a simple neura l reflex and
a neuroendocrine reflex. The fimctiona l components
of these two pathways are sensory neurons (afferent
neurons taking neural signals toward the spinal cord),
the spinal cord, efferent neurons (nerves leaving the
sp inal cord and traveling to the target tissue) and
target tissues (See Figure 5-1). Target tissues are
those organs that respond to a specific set of stimuli
or hormone.
The bas ic difference between the si mp le
neural reflex and the neuroendocrine reflex is the
type of de livery system each u ses . For example,
a simple neural reflex employs nerves that release
their neurotransmitters (messengers) directly onto
the target tissue. In other words, the target tissue is
directly innervated by a neuron and responds to a
neurotransmitter. In contrast, a neuroendocrine reflex
requires that a neurohormone (a substance released
by a neuron) e nter the blood and act on a remote target
tissue. Neurons releasing neurohonnones are also
called neurosecretory cells . D irect innervation of
the target tissue does not exist in the neuroendocrine
reflex. Instead, the neurohormone in the blood is the
messenger between the neurosecretory cell and the
target tissue. Both of these neural pathways are il-
lustrated in Figure 5-1 .
Neural Reflexes and Neuroendocrine rn
Reflexes Cause Rapid Changes
in Target Tissues
In a simple neural reflex, afferent sensory
neurons synapse directly w ith interneurons in the
spinal cord (See Figure 5-l ). These interneurons
synapse with efferent neurons that travel directly to
the target tissue. The target tissue responds to the
neurotransmitter released by the efferent neuron. A
neurotran smitter is a substance of small molecular
weight that is released from the tenninals of nerves
that causes other nerves to fire or causes contraction
of smooth muscle that swTounds portions of the re-
productive tract (See Figure 5-l ). An example of a
simple neural reflex in reproduction is ejaculation. A
stim ulus originating in the glans penis is recogn ized
by se nsory neurons. Signals are then transmitted
to the spinal cord where they synapse with efferent
neurons that cause a series of muscu lar contractions
resulting in expulsion of semen. A detailed pathway
of this neural event will be presented in Chapter II.
Another examp le of a simple neural reflex that im-
pacts the reproductive system involves temperature
sensitive neurons located in the scrotum ( described
in Chapter 3). When scrotal temperature decreases,
sensory neurons in the scrotum recognize this decrease
and send sensory signals to the spinal cord. Efferent
nerves travel to the tunica dartos in the scrotum and
release neurotransmitters that initiate contTaction that
elevates the testicles to bring them closer to the body,
thus warming them.
The neuroendocrine reflex (See Figure 5-l )
is quite similar to a simple neural reflex. This type
of reflex also starts with sensory neurons. They syn-
apse with interneurons in the sp inal cord. Efferent
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] rn
1 02 Nerves, Hormones and Target Tissues
Figure 5-1. Neural and Neuroendocrine Reflexes
I Stimulus I
thermal, tactile, visual
Afferent
neurons
• Muscles for sexual behavior
and ejaculation
• Muscles for scrotal tone
• Scrotal sweat glands
Hypothalamus
j ‘I _ ___…
FSH Anterior
LH lobe
Oxyr c
epididymis
( “b target tissue )
Sperm movement into
ductus deferens
Mammary gland
( target tissue )
Milk ejection
Sensory nerves, responding to a
stimulus, synapse with interneurons
(I) in the spinal cord. Efferent
neurons travel directly to the target
tissue to cause a response.
Sensory nerves synapse with interneurons (I) in the sp in al cord.
Efferent neurons travel to the hypothalamus where hypothalamic
neurons release neurohormones. These neurohormones enter
the blood and activate target tissues, such as the anterior lobe
of the pituitary, mammary g land or the epididymis.
neurons traveling from the spinal cord synapse with
other neurons in the hypothalamus. The hypothalamic
neurons release small molecular weight materials
from their tenninals. These materials are referred to
as neurohormones because they are released into the
blood rather than directly onto the target tissue. Neu-
rohonnones released into capillaries travel to a target
tissue elsewhere in the body. The classic example of
a neuroendocrine reflex is the suckling reflex. When
suckling occurs, sensory nerves in the teat or nipple
of the lactating female detect the tactile stimulus.
These sensory signals travel to the spinal cord and
then to the hypothalamus where they synapse with
other nerves. The hypothalamic neurons then depo-
larize (“fire”) , causing release of oxytocin directly
fi·om nerve tenninals located in the posterior lobe of
the pituitary. Oxytocin is stored as a neurosecretory
material in the nerve terminals of the posterior lobe
of the pituitary. When these neurosecretory cells
“fire,” oxytocin is released, enters the blood, travels
to the target tissue (in this case, myoepithelial ce lls
of the mammary gland) (See Chapter 15) and causes
these cells to contract, resulting in milk ejection from
the mammary a lveoli. In addition, other forms of
stimuli, such as v isual or auditory, can cause milk
ejection if the animal is preconditioned to respond
to these stimuli. For example, the sight or sound of
the newborn may elicit a simi lar response without
direct mammary stimulation. Also, many dairy cows
entering the milking parlor receive visual or auditory
stimuli prior to actual mammmy stimulation by either
the sight or sounds of the equipment and begin to ex-
perience milk ejection prior to entering the parlor.
Nerves, Hormones and Target Tissues 1 03
The hypothalamus is the neural
control center for reproductive
hormones.
Figure 5-2. Anatomy of the Typical Mammalian Hypothalamus and Pituitary
Sph enoid Bo ne
Saggital view
The hypothalamus is a specialized ventral
portion of the bra in consisting of groups of
nerve cell bodies called hypothalamic nuclei
that appear as lobules in the figure. The surge
center, the tonic center and the paraventricular
nucleus (PVN) have direct influence on repro-
duction. The anterior and posterior lobes of the
pituitary are positioned in a depression of the
sphenoid bone called the sella turcica.
Sphenoid Bone
Frontal view
This view illustrates the relationship of the
paraventricular nucleus (PVN), the surge cen-
ter and the tonic center to the third ventricle
and pituitary. The vertical line in the left panel
represents th e plane of section shown in the
right panel. Notice that the third ventricle (a
brain cavity) separates the lateral portions of
the hypothalamus. AL =Anterior Lobe of the
Pituitary, PL = Posterior Lobe of the Pituitary,
OC = Optic Chiasm.
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] rn
1 02 Nerves, Hormones and Target Tissues
Figure 5-1. Neural and Neuroendocrine Reflexes
I Stimulus I
thermal, tactile, visual
Afferent
neurons
• Muscles for sexual behavior
and ejaculation
• Muscles for scrotal tone
• Scrotal sweat glands
Hypothalamus
j ‘I _ ___…
FSH Anterior
LH lobe
Oxyr c
epididymis
( “b target tissue )
Sperm movement into
ductus deferens
Mammary gland
( target tissue )
Milk ejection
Sensory nerves, responding to a
stimulus, synapse with interneurons
(I) in the spinal cord. Efferent
neurons travel directly to the target
tissue to cause a response.
Sensory nerves synapse with interneurons (I) in the sp in al cord.
Efferent neurons travel to the hypothalamus where hypothalamic
neurons release neurohormones. These neurohormones enter
the blood and activate target tissues, such as the anterior lobe
of the pituitary, mammary g land or the epididymis.
neurons traveling from the spinal cord synapse with
other neurons in the hypothalamus. The hypothalamic
neurons release small molecular weight materials
from their tenninals. These materials are referred to
as neurohormones because they are released into the
blood rather than directly onto the target tissue. Neu-
rohonnones released into capillaries travel to a target
tissue elsewhere in the body. The classic example of
a neuroendocrine reflex is the suckling reflex. When
suckling occurs, sensory nerves in the teat or nipple
of the lactating female detect the tactile stimulus.
These sensory signals travel to the spinal cord and
then to the hypothalamus where they synapse with
other nerves. The hypothalamic neurons then depo-
larize (“fire”) , causing release of oxytocin directly
fi·om nerve tenninals located in the posterior lobe of
the pituitary. Oxytocin is stored as a neurosecretory
material in the nerve terminals of the posterior lobe
of the pituitary. When these neurosecretory cells
“fire,” oxytocin is released, enters the blood, travels
to the target tissue (in this case, myoepithelial ce lls
of the mammary gland) (See Chapter 15) and causes
these cells to contract, resulting in milk ejection from
the mammary a lveoli. In addition, other forms of
stimuli, such as v isual or auditory, can cause milk
ejection if the animal is preconditioned to respond
to these stimuli. For example, the sight or sound of
the newborn may elicit a simi lar response without
direct mammary stimulation. Also, many dairy cows
entering the milking parlor receive visual or auditory
stimuli prior to actual mammmy stimulation by either
the sight or sounds of the equipment and begin to ex-
perience milk ejection prior to entering the parlor.
Nerves, Hormones and Target Tissues 1 03
The hypothalamus is the neural
control center for reproductive
hormones.
Figure 5-2. Anatomy of the Typical Mammalian Hypothalamus and Pituitary
Sph enoid Bo ne
Saggital view
The hypothalamus is a specialized ventral
portion of the bra in consisting of groups of
nerve cell bodies called hypothalamic nuclei
that appear as lobules in the figure. The surge
center, the tonic center and the paraventricular
nucleus (PVN) have direct influence on repro-
duction. The anterior and posterior lobes of the
pituitary are positioned in a depression of the
sphenoid bone called the sella turcica.
Sphenoid Bone
Frontal view
This view illustrates the relationship of the
paraventricular nucleus (PVN), the surge cen-
ter and the tonic center to the third ventricle
and pituitary. The vertical line in the left panel
represents th e plane of section shown in the
right panel. Notice that the third ventricle (a
brain cavity) separates the lateral portions of
the hypothalamus. AL =Anterior Lobe of the
Pituitary, PL = Posterior Lobe of the Pituitary,
OC = Optic Chiasm.
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1 04 Nerves, Hormones and Target Tissues
Figure 5-3. Ventricular System of the Brain
Lateral view Anterior view
Lateral and anterior views of the ventricular system of the brain . The ventricles LV = Lateral Ventricles
are blue-shaded “bags” and appear here as if the brain were transparent. The TV = Third Ventricle
ventricular system is filled with cerebrospinal fluid that continuously circulates FV = Fourth Ventricle
through the ventricles and into the subarachnoid spaces of the central nervous CC = Central Canal
system. The hypothalamus (hatched area) surrounds the third ventricle. P =Pituitary
The hypothalamus is a complex portion of
the brain consisting of clusters of nerve cell bodies.
The clusters, or groups of nerve cell bodies are called
hypothalamic nuclei, each of which has a specific
name. For example, groups of hypothalamic nuclei
that influence reproduction are named the surge center
and the tonic center (See Figure 5-2).
Neurons in these regions secrete gonado-
tropin releasing hormone (GnRH). Neurons in the
para ventricular nucleus (PVN) secrete oxytocin. The
hypothalamic nuclei surround a small cavity known as
the third ventricle, found in the center of the brain (See
Figure 5-3). It is important to understand that each
hypothalamic nucleus has a different function and is
stimulated by different sets of conditions.
The hypothalamo-hypopyseal portal
sytem allows minute quantities of
releasing hormones to act on the ante-
rior pituitmy before they are diluted
by the general circulation.
Axons from the cell bodies of the surge and
tonic centers extend into the p ih1itary stalk region
where the nerve endings (tenninal boutons) terminate
on a sophisticated and highly specialized capillary
network. T his capi llary network is referre d to as
the hypothalamo-hypophyseal portal system (See
Figure 5-4). The tenninal boutons of the hypotha-
Nerves, Hormones and Target Tissues 105
Figure 5-4. The Hypothalamo-Hypophyseal Portal System
MHA= Medial
Hyp ophyseal
Artery
PPP = Primary
Portal Plexus
PV = Portal Vessels
SHA =Su perior
Hypophyseal
Artery
SPP = Secondary
Portal
Plexus
The photograph at the right is a scanning
electron micrograph of th e hypoth alamo-
hypophyseal portal system after vascular
injection with latex (Mercox). It was pro-
vided with permission by Dr. H. Duvernay,
Faculte de Medecine et de Pharmacie de
Besancon, Laboratoire d’Anatomie, Place
St. Jacques , 25030 Besancon , France.
Axons from neuro ns in t he
surge center and the tonic center
extend to the stalk reg ion where
the ir en dings te rmi nate upon
blood vessels of the hypothala-
mo-hypophyseal portal system.
This portal system consists of:
the superi or hypoph yseal ar-
tery; the primary portal plexus,
(where t he surge center and
tonic center neurons term inate);
the medial hypophyseal artery
that supplies part of the anterior
lobe of the pituitary (AL); the por-
tal vessels that transport blood
containing releasing hormones;
and the secondary portal plex us
that delivers blood (and releas-
ing hormones) to the ce lls of th e
anterior lobe.
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1 04 Nerves, Hormones and Target Tissues
Figure 5-3. Ventricular System of the Brain
Lateral view Anterior view
Lateral and anterior views of the ventricular system of the brain . The ventricles LV = Lateral Ventricles
are blue-shaded “bags” and appear here as if the brain were transparent. The TV = Third Ventricle
ventricular system is filled with cerebrospinal fluid that continuously circulates FV = Fourth Ventricle
through the ventricles and into the subarachnoid spaces of the central nervous CC = Central Canal
system. The hypothalamus (hatched area) surrounds the third ventricle. P =Pituitary
The hypothalamus is a complex portion of
the brain consisting of clusters of nerve cell bodies.
The clusters, or groups of nerve cell bodies are called
hypothalamic nuclei, each of which has a specific
name. For example, groups of hypothalamic nuclei
that influence reproduction are named the surge center
and the tonic center (See Figure 5-2).
Neurons in these regions secrete gonado-
tropin releasing hormone (GnRH). Neurons in the
para ventricular nucleus (PVN) secrete oxytocin. The
hypothalamic nuclei surround a small cavity known as
the third ventricle, found in the center of the brain (See
Figure 5-3). It is important to understand that each
hypothalamic nucleus has a different function and is
stimulated by different sets of conditions.
The hypothalamo-hypopyseal portal
sytem allows minute quantities of
releasing hormones to act on the ante-
rior pituitmy before they are diluted
by the general circulation.
Axons from the cell bodies of the surge and
tonic centers extend into the p ih1itary stalk region
where the nerve endings (tenninal boutons) terminate
on a sophisticated and highly specialized capillary
network. T his capi llary network is referre d to as
the hypothalamo-hypophyseal portal system (See
Figure 5-4). The tenninal boutons of the hypotha-
Nerves, Hormones and Target Tissues 105
Figure 5-4. The Hypothalamo-Hypophyseal Portal System
MHA= Medial
Hyp ophyseal
Artery
PPP = Primary
Portal Plexus
PV = Portal Vessels
SHA =Su perior
Hypophyseal
Artery
SPP = Secondary
Portal
Plexus
The photograph at the right is a scanning
electron micrograph of th e hypoth alamo-
hypophyseal portal system after vascular
injection with latex (Mercox). It was pro-
vided with permission by Dr. H. Duvernay,
Faculte de Medecine et de Pharmacie de
Besancon, Laboratoire d’Anatomie, Place
St. Jacques , 25030 Besancon , France.
Axons from neuro ns in t he
surge center and the tonic center
extend to the stalk reg ion where
the ir en dings te rmi nate upon
blood vessels of the hypothala-
mo-hypophyseal portal system.
This portal system consists of:
the superi or hypoph yseal ar-
tery; the primary portal plexus,
(where t he surge center and
tonic center neurons term inate);
the medial hypophyseal artery
that supplies part of the anterior
lobe of the pituitary (AL); the por-
tal vessels that transport blood
containing releasing hormones;
and the secondary portal plex us
that delivers blood (and releas-
ing hormones) to the ce lls of th e
anterior lobe.
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1 06 Nerves, Hormones and Target Tissues
Iamie neurons release neuropeptides that enter the
specialized capillary system at the stalk of the pituitary.
Blood enters the capillary system from the superior
hypophyseal artery that divides into small arterial
capillaries at the level of the pituitary stalk. This pmtal
system enables extremely small quantities (picograms)
of releasing hormones to be secreted into the capillary
plexus (primary portal plexus) of the pituitary stalk.
Releasing hormones are then transfened immediately
to a second capillary plexus in the anterior lobe of the
pituitary where they cause pituitary cells to release
other honnones. The hypothalamo-hypophyseal portal
system is important because it allows minute quantities
of releasing hormones to act directly on the cells of the
anterior lobe of the pituitary before the GnRH becomes
diluted by the systemic circulation.
The posterior lobe of the pituitmy does
not have a portal system.
Neurohormones are deposited directly
into capillaries in the posterior lobe of
the pituitary.
The posterior lobe of the pituitmy is organized
quite differently from the anterior lobe (See Figure
5-5). Neurons from certain hypothalamic nuclei extend
directly into the posterior lobe of the pituitary where
the neurohormone is released into a simple arterio-
venous capillary plexus. For example, cell bodies in
the paraventricular nucleus synthesize oxytocin that
is transported down the axon to the tem1inals in the
posterior lobe. If the neuron is stimulated, oxytocin is
released into the blood.
Endocrine Control is Generally Slower, but
Longer Lasting than Neural Control
In contrast to neural regulation, the endocrine
system relies on hormones to cause responses. A hor-
mone is a substance produced by a gland that acts on a
remote tissue (target tissue) to bring about a change in
the target tissue. These changes involve alterations in
metabolism, synthetic activity and secretmy activity.
Extremely small quantities of a honnone can
cause dramatic physiologic responses. Honnones act
at blood levels ranging from nanograms ( 1 0-9) to pi co-
grams ( 1 0- 12) per ml ofblood (See Table 5-1). The ability
to measure extremely small quantities of hormones has
brought about an explosion of knowledge regarding the
quantities, patterns of secretions and roles of hom1ones
as they relate to reproductive processes.
Table 5-1 . Ill ustration of exponents, decimal
places and common weight designations used in de-
scribing quantities of substances. The shaded area
indicates the range of hormone we ights per milliliter of
blood that cause physiologic responses_
Exponent
1.0
10″1 .1
10″2 .01
10-3 .oo1
10″4 .000, 1
10-s .000,0 I
10·6 .ooo,oo1
1 o-7 .ooo,ooo, 1
10″8 .000,000,01
10·9 .ooo,ooo,oo1
1 o- 10 .ooo,ooo,ooo, 1
IQ-II .000,000,000,01
10″12 .000,000,000,001
Name
gram
milligram
microgram
nanogram
picogram
Hormones are characterized as having rela-
tively short half-lives. Honnonal half-life is defined
as the time required for one-half of a hom1one to disap-
pear from the blood or from the body. Short half-lives
are important because once the hormone is secreted
and released into the blood and causes a response, it
is degraded so that further responses do not occur. It
should be emphasized, however, when hormones are
continually produced (such as progesterone during
pregnancy), their action continues for as long as the
hormone is present. Compared to neural control, hor-
monal control is slower and has durations of m inutes,
hours or even days.
Positive and Negative Feedback
are the Major “Controllers”
of Reproductive Hormones
Now that you understand the basic anatomy
and neural regulation of the reproductive system,
the fundamental mechanisms controlling secretion
of reproductive hormones must be described. These
mechanisms are referred to as positive feedback and
negative feedback The principles of positive and
negative feedback control is one of the most important
concepts to understand. Almost all reproductive ftmc-
tions are controlled by these two mechanisms.
Negative feedback= suppression of
GnRll neurons
Positive feedback= stimulation of
GnRllneurons
Positive and negative f eedback control the
secretion of GnRI-1 that in-turn control s the secretion
of the gonadotropins FSH and LH. For the purpose
of the discussion here, we will use progesterone that
causes strong negative feedback at the hypotha lamic
level. Progesterone strongly inh ibits GnRH neurons
and therefore when progesterone is high, GnRH neu-
Nerves, Hormones and Target Tissues 1 07
rons secrete only basal levels of GnRI-1. Such basal
secretion while allowing for some follicular develop-
ment will not allow sufficient folli cular development
for the secretion of high levels of estradiol. Therefore ,
fe males under the influenc e of progesterone (midcycle
or pregnant) do not cycle fo r the period of time that
progesterone is high.
L FSH & LH=
Incomplete follicular development
Figure 5-5. Relationship Between the Paraventricular Nucleus and the
Posterior Lobe of the Pituitary
Axons from neurons originating in
the hypothalamus (PVN ) extend
into the posterior lobe of the pituitary
where they release their neuroho r-
mones into a capillary plexus.
AL = Anterior Lobe of the
Pituitary
OC = Optic Chiasm
PL = Posterior Lobe of the
P ituita ry
PVN = Paraventricular Nucl eus
From cai tid artery
To target
tissue
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1 06 Nerves, Hormones and Target Tissues
Iamie neurons release neuropeptides that enter the
specialized capillary system at the stalk of the pituitary.
Blood enters the capillary system from the superior
hypophyseal artery that divides into small arterial
capillaries at the level of the pituitary stalk. This pmtal
system enables extremely small quantities (picograms)
of releasing hormones to be secreted into the capillary
plexus (primary portal plexus) of the pituitary stalk.
Releasing hormones are then transfened immediately
to a second capillary plexus in the anterior lobe of the
pituitary where they cause pituitary cells to release
other honnones. The hypothalamo-hypophyseal portal
system is important because it allows minute quantities
of releasing hormones to act directly on the cells of the
anterior lobe of the pituitary before the GnRH becomes
diluted by the systemic circulation.
The posterior lobe of the pituitmy does
not have a portal system.
Neurohormones are deposited directly
into capillaries in the posterior lobe of
the pituitary.
The posterior lobe of the pituitmy is organized
quite differently from the anterior lobe (See Figure
5-5). Neurons from certain hypothalamic nuclei extend
directly into the posterior lobe of the pituitary where
the neurohormone is released into a simple arterio-
venous capillary plexus. For example, cell bodies in
the paraventricular nucleus synthesize oxytocin that
is transported down the axon to the tem1inals in the
posterior lobe. If the neuron is stimulated, oxytocin is
released into the blood.
Endocrine Control is Generally Slower, but
Longer Lasting than Neural Control
In contrast to neural regulation, the endocrine
system relies on hormones to cause responses. A hor-
mone is a substance produced by a gland that acts on a
remote tissue (target tissue) to bring about a change in
the target tissue. These changes involve alterations in
metabolism, synthetic activity and secretmy activity.
Extremely small quantities of a honnone can
cause dramatic physiologic responses. Honnones act
at blood levels ranging from nanograms ( 1 0-9) to pi co-
grams ( 1 0- 12) per ml ofblood (See Table 5-1). The ability
to measure extremely small quantities of hormones has
brought about an explosion of knowledge regarding the
quantities, patterns of secretions and roles of hom1ones
as they relate to reproductive processes.
Table 5-1 . Ill ustration of exponents, decimal
places and common weight designations used in de-
scribing quantities of substances. The shaded area
indicates the range of hormone we ights per milliliter of
blood that cause physiologic responses_
Exponent
1.0
10″1 .1
10″2 .01
10-3 .oo1
10″4 .000, 1
10-s .000,0 I
10·6 .ooo,oo1
1 o-7 .ooo,ooo, 1
10″8 .000,000,01
10·9 .ooo,ooo,oo1
1 o- 10 .ooo,ooo,ooo, 1
IQ-II .000,000,000,01
10″12 .000,000,000,001
Name
gram
milligram
microgram
nanogram
picogram
Hormones are characterized as having rela-
tively short half-lives. Honnonal half-life is defined
as the time required for one-half of a hom1one to disap-
pear from the blood or from the body. Short half-lives
are important because once the hormone is secreted
and released into the blood and causes a response, it
is degraded so that further responses do not occur. It
should be emphasized, however, when hormones are
continually produced (such as progesterone during
pregnancy), their action continues for as long as the
hormone is present. Compared to neural control, hor-
monal control is slower and has durations of m inutes,
hours or even days.
Positive and Negative Feedback
are the Major “Controllers”
of Reproductive Hormones
Now that you understand the basic anatomy
and neural regulation of the reproductive system,
the fundamental mechanisms controlling secretion
of reproductive hormones must be described. These
mechanisms are referred to as positive feedback and
negative feedback The principles of positive and
negative feedback control is one of the most important
concepts to understand. Almost all reproductive ftmc-
tions are controlled by these two mechanisms.
Negative feedback= suppression of
GnRll neurons
Positive feedback= stimulation of
GnRllneurons
Positive and negative f eedback control the
secretion of GnRI-1 that in-turn control s the secretion
of the gonadotropins FSH and LH. For the purpose
of the discussion here, we will use progesterone that
causes strong negative feedback at the hypotha lamic
level. Progesterone strongly inh ibits GnRH neurons
and therefore when progesterone is high, GnRH neu-
Nerves, Hormones and Target Tissues 1 07
rons secrete only basal levels of GnRI-1. Such basal
secretion while allowing for some follicular develop-
ment will not allow sufficient folli cular development
for the secretion of high levels of estradiol. Therefore ,
fe males under the influenc e of progesterone (midcycle
or pregnant) do not cycle fo r the period of time that
progesterone is high.
L FSH & LH=
Incomplete follicular development
Figure 5-5. Relationship Between the Paraventricular Nucleus and the
Posterior Lobe of the Pituitary
Axons from neurons originating in
the hypothalamus (PVN ) extend
into the posterior lobe of the pituitary
where they release their neuroho r-
mones into a capillary plexus.
AL = Anterior Lobe of the
Pituitary
OC = Optic Chiasm
PL = Posterior Lobe of the
P ituita ry
PVN = Paraventricular Nucl eus
From cai tid artery
To target
tissue
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108 Nerves, Hormones and Target Tissues
In direct contrast to negative feedback, posi-
tive fe edback activates the GnRH neurons in the hy-
pothalamus. The female contains a surge center that
is responsible for secreting large quantities of GnRH
that induce ovulation. The surge center will not re-
lease large quantities of GnRH until there is positive
feedback by estradiol. For example, when estradiol
reaches a certain high level (a threshold level) , the
surge center will be positively stimulated and will
release large quantities ofGnRH that cause the release
of large quantities of LH that stimulate ovulation.
LH surge=
Ovulation
It is important to recognize that positive feed-
back and negative feedback are independent controls
within the animal that exert two distinctly different
outcomes. Reproductive endocrinologists think that
the hypothalamus has different sensitivities to posi-
tive and negative feedback of gonadal steroids. For
example, the tonic center in both the male and female
is believed to respond mostly to negative feedback.
While progesterone in the female exerts a strong
negative feedback on both the surge and the tonic
centers, it mostly exerts its effect on the tonic center.
In other words, the tonic center is quite sensitive to
negative feedback . In contrast, the surge center
responds mostly to positive feedback of estradiol.
Therefore, the surge center is very sensitive to positive
feedback. The reasons that these two components of
the hypothalamus differ with regard to their sensitivi-
ties to positive and negative feedback is the subject of
current research. Researchers are attempting to define
how these different subsets of neurons are regulated
by two different controls.
During the past decade, a new class of neu-
ropeptides has emerged as the possible ” gatekeepers”
for GnRH release. These neuropeptides are called
kisspeptins and are secreted by hypothalamic neurons
in the periventricular, preoptic and arcuate nuclei.
Kisspeptin neurons send dendritic aborizations into
hypothalamic nuclei where GnRH cell bodies are
abundant. This is anatomical evidence that kisspeptin
appears to act directly on GnRH neurons to stimulate
GnRH secretion. Kisspeptin is now recognized as an
important regulator of sexual differentiation of the
brain, the timing of puberty (See Chapter 6) and adult
regulation of gonadotropin secretion by gonadal ste-
roids, especially as it relates to seasonal breeding (See
Chapter 7). The emergence of new knowledge about
the mechanism of action of kisspeptin indicates that
positive and negative feedback by gonadal steriods
may act on kisspeptin neurons that in h 1m mediate
GnRH secretion by GnRH neurons .
Reproductive hormones:
• act in minute quantities
• have short half-lives
• bind to specific receptors
• regulate intracellular
biochemical reactions
In order for a hormone to cause a response , it
must first interact specifi cally with the target tissue.
The cells of the target tissue must have receptors that
bind the hormone. Binding of the honnone with its
specific receptor initiates a series of intracellular bio-
chemical reactions.
Hormonal regulation of a bioc hemical re-
action is generally tied to secretory activity of the
target cell. When exposed to a hormone, the target
cell synthesizes s ubstances that are not secreted un-
less the hormone is present. For example, estradiol
(secreted by the ovary), causes the cells of the cervix
to secrete mucus. This change is caused by a series
of biochemical or synthetic pathways within the cells
of the cervix. The steps in these proc esses will be
detailed later in this chapter.
Hormones can be classified by:
• source
• mode of action
• biochemical classification
Reproductive hormones can be classified ac-
cording to their source of origin, their primary mode
of action and their biochem ical classification. Table
5-2 summarizes hormonal c lassification by source,
by target tissue and by their primary acti ons. Details
about these horn1ones will be presented in subsequent
chapters where their fu nctions will be s pecifically
described in the female and in the male.
Tissue Origin Constitutes One Method of
Hormonal Classification
Hypothalamic hormones are produced by
neurons in the hypothalamus. One of their ro les is to
cause the re lease of other hom1ones from the anter ior
lobe of the piruitary. T he primary releasing horn1one
of reproduction is gonadotropin releasing hormone
(GnRH). Neuropeptides of hypothalamic origin are
Figure 5-6. Amino Acid
Sequence of GnRH
NH 2
very small m olecules generally consisting ofless than
twenty a mi no ac ids. T hese small peptides are synthe-
sized and released from neurons in the hypothalamus.
The most important neuropeptide goveming reproduc-
tion is GnRI-I. The am ino acid sequence fo r G nRH, a
decapeptide, is shown in Figure 5-6. The mo lecular
weight of GnRH is only I, 183.
Pituitary hormones are re leased into the
blood fi·om the anterior and posterior lobes of the pi-
tuitmy. The primary reproductive hormones from the
anterior lobe are follicle stimulating hormone (FSH),
luteinizing hormone (LH ) and prolactin . Oxytocin
is the prima ry reproductive hormone synthesized by
nerves in the hypothalamus, stored and released from
the posterior lobe.
Gonadal hormon es orig inate from the
gonads and a ffect fu nction of the hypo tha lamus,
anterior lobe of the p ituitary and tissues of the re-
productive tract. Gonadal honn ones also initiate the
development of secondary sex characteristics th at
cause “maleness” or “femaleness.” In the female,
the ovary secretes estrogens, progesterone, inhibin,
some testosterone, oxytocin and relaxin. In the male,
the testes secrete testosterone and other androgens,
inhibin and estrogens .
Hormones are also secreted by the uterus
and the placenta. T hese are responsib le for governing
cyclicity and maintena nce of pregnancy. An example
of a uterine horn1one is prostaglandin F 2a (PGF2a).
Placental hom10nes include progesterone, estrogens,
equine chorionic gonadotropin (eCG) and human
chorionic gonadotropin (hCG).
Research by reproductive p hysiologists at
Auburn University and Rutgers Un ivers ity suggests
that the mammary gland may also serve as a source
of biologically active factors important fo r neonatal
development. These researchers define d delivery of
bioactive factors from mother to offspring as a spe-
cific consequence of nursing and the consumption
of colostrum (first milk) as ” lactocrine signaling”.
Lactocrine signaling differs from endocrine signal-
ing in that m ilk-borne bioactive factors, provided by
virtue of lactation, are transported in colostrum/ milk
(not blood) and absorbed into the neonatal circu lation
Nerves, Hormones and Target Tissues 1 09
where they act on target tissues. L actocrine transmis-
sion of relaxin and its effects on development of the
neonatal female reproductive tract is an example of
this mechanism.
Rep1·oductive hormones originate from the:
• hypothalamus
• pituitary
• gonads
• uterus
• placenta
M ode of Action is Another M ethod
of H ormonal Classification
Neurohormones are synthesized by neurons
and are released directly into the bl ood so that they
can cause a response in target tissues elsewhere in
the body. A neurohormone can act on any number of
tissues provided that the tissue has cellular receptors
for the neurohormone. An example is oxytocin that
is synthesized by hypothalamic neurons, stored and
released by the posterior lobe of the pitu itary.
Releasing hormones are also synthesized
by neurons in the hypothalamus and cause release of
other hormones from the anterior lobe of the pituitary.
They can a lso be classified as neurohormones because
they are synthesized and released by neurons . An ex-
ample is gonadotropin releasing hom1one (GnRH) that
controls the release ofFS H and Ll-1 from the anterior
lobe of the pituitary.
Gonado tropin s are hom10nes synthesized
and secreted by specialized cells in the anterior lobe
of the pituitary gland called gonadotropes. The suffix
” tropin” means having an affinity fo r or to nourish.
Thus, these hormones have a stimulatory infl uence
on the gonads (the ovary and the testis). Gonado-
tropins are follicle stimulating hormone (FSH) and
luteinizing hormone (LH). Lutein izing hormone is
responsible for causing ovulation and sti mu lating the
corpus luteum (CL) to secrete progesterone. Luteiniz-
ing hormone causes testosterone secretion in the male.
Follicle stimulating hom1one causes follicular growth
in the ovary of the fema le. It stimulates Sertoli cells
in the male and is probably a “key player” in govern-
ing spermatogenesis.
Sexual promoters (estrogens, progesterone,
testosterone) are secreted by the gonads of both the
male and the fe ma le to stimulate the reproductive
tract, to regulate the function of the hyp othalamus
and the anterior lobe of the piruitary and to regulate
V
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108 Nerves, Hormones and Target Tissues
In direct contrast to negative feedback, posi-
tive fe edback activates the GnRH neurons in the hy-
pothalamus. The female contains a surge center that
is responsible for secreting large quantities of GnRH
that induce ovulation. The surge center will not re-
lease large quantities of GnRH until there is positive
feedback by estradiol. For example, when estradiol
reaches a certain high level (a threshold level) , the
surge center will be positively stimulated and will
release large quantities ofGnRH that cause the release
of large quantities of LH that stimulate ovulation.
LH surge=
Ovulation
It is important to recognize that positive feed-
back and negative feedback are independent controls
within the animal that exert two distinctly different
outcomes. Reproductive endocrinologists think that
the hypothalamus has different sensitivities to posi-
tive and negative feedback of gonadal steroids. For
example, the tonic center in both the male and female
is believed to respond mostly to negative feedback.
While progesterone in the female exerts a strong
negative feedback on both the surge and the tonic
centers, it mostly exerts its effect on the tonic center.
In other words, the tonic center is quite sensitive to
negative feedback . In contrast, the surge center
responds mostly to positive feedback of estradiol.
Therefore, the surge center is very sensitive to positive
feedback. The reasons that these two components of
the hypothalamus differ with regard to their sensitivi-
ties to positive and negative feedback is the subject of
current research. Researchers are attempting to define
how these different subsets of neurons are regulated
by two different controls.
During the past decade, a new class of neu-
ropeptides has emerged as the possible ” gatekeepers”
for GnRH release. These neuropeptides are called
kisspeptins and are secreted by hypothalamic neurons
in the periventricular, preoptic and arcuate nuclei.
Kisspeptin neurons send dendritic aborizations into
hypothalamic nuclei where GnRH cell bodies are
abundant. This is anatomical evidence that kisspeptin
appears to act directly on GnRH neurons to stimulate
GnRH secretion. Kisspeptin is now recognized as an
important regulator of sexual differentiation of the
brain, the timing of puberty (See Chapter 6) and adult
regulation of gonadotropin secretion by gonadal ste-
roids, especially as it relates to seasonal breeding (See
Chapter 7). The emergence of new knowledge about
the mechanism of action of kisspeptin indicates that
positive and negative feedback by gonadal steriods
may act on kisspeptin neurons that in h 1m mediate
GnRH secretion by GnRH neurons .
Reproductive hormones:
• act in minute quantities
• have short half-lives
• bind to specific receptors
• regulate intracellular
biochemical reactions
In order for a hormone to cause a response , it
must first interact specifi cally with the target tissue.
The cells of the target tissue must have receptors that
bind the hormone. Binding of the honnone with its
specific receptor initiates a series of intracellular bio-
chemical reactions.
Hormonal regulation of a bioc hemical re-
action is generally tied to secretory activity of the
target cell. When exposed to a hormone, the target
cell synthesizes s ubstances that are not secreted un-
less the hormone is present. For example, estradiol
(secreted by the ovary), causes the cells of the cervix
to secrete mucus. This change is caused by a series
of biochemical or synthetic pathways within the cells
of the cervix. The steps in these proc esses will be
detailed later in this chapter.
Hormones can be classified by:
• source
• mode of action
• biochemical classification
Reproductive hormones can be classified ac-
cording to their source of origin, their primary mode
of action and their biochem ical classification. Table
5-2 summarizes hormonal c lassification by source,
by target tissue and by their primary acti ons. Details
about these horn1ones will be presented in subsequent
chapters where their fu nctions will be s pecifically
described in the female and in the male.
Tissue Origin Constitutes One Method of
Hormonal Classification
Hypothalamic hormones are produced by
neurons in the hypothalamus. One of their ro les is to
cause the re lease of other hom1ones from the anter ior
lobe of the piruitary. T he primary releasing horn1one
of reproduction is gonadotropin releasing hormone
(GnRH). Neuropeptides of hypothalamic origin are
Figure 5-6. Amino Acid
Sequence of GnRH
NH 2
very small m olecules generally consisting ofless than
twenty a mi no ac ids. T hese small peptides are synthe-
sized and released from neurons in the hypothalamus.
The most important neuropeptide goveming reproduc-
tion is GnRI-I. The am ino acid sequence fo r G nRH, a
decapeptide, is shown in Figure 5-6. The mo lecular
weight of GnRH is only I, 183.
Pituitary hormones are re leased into the
blood fi·om the anterior and posterior lobes of the pi-
tuitmy. The primary reproductive hormones from the
anterior lobe are follicle stimulating hormone (FSH),
luteinizing hormone (LH ) and prolactin . Oxytocin
is the prima ry reproductive hormone synthesized by
nerves in the hypothalamus, stored and released from
the posterior lobe.
Gonadal hormon es orig inate from the
gonads and a ffect fu nction of the hypo tha lamus,
anterior lobe of the p ituitary and tissues of the re-
productive tract. Gonadal honn ones also initiate the
development of secondary sex characteristics th at
cause “maleness” or “femaleness.” In the female,
the ovary secretes estrogens, progesterone, inhibin,
some testosterone, oxytocin and relaxin. In the male,
the testes secrete testosterone and other androgens,
inhibin and estrogens .
Hormones are also secreted by the uterus
and the placenta. T hese are responsib le for governing
cyclicity and maintena nce of pregnancy. An example
of a uterine horn1one is prostaglandin F 2a (PGF2a).
Placental hom10nes include progesterone, estrogens,
equine chorionic gonadotropin (eCG) and human
chorionic gonadotropin (hCG).
Research by reproductive p hysiologists at
Auburn University and Rutgers Un ivers ity suggests
that the mammary gland may also serve as a source
of biologically active factors important fo r neonatal
development. These researchers define d delivery of
bioactive factors from mother to offspring as a spe-
cific consequence of nursing and the consumption
of colostrum (first milk) as ” lactocrine signaling”.
Lactocrine signaling differs from endocrine signal-
ing in that m ilk-borne bioactive factors, provided by
virtue of lactation, are transported in colostrum/ milk
(not blood) and absorbed into the neonatal circu lation
Nerves, Hormones and Target Tissues 1 09
where they act on target tissues. L actocrine transmis-
sion of relaxin and its effects on development of the
neonatal female reproductive tract is an example of
this mechanism.
Rep1·oductive hormones originate from the:
• hypothalamus
• pituitary
• gonads
• uterus
• placenta
M ode of Action is Another M ethod
of H ormonal Classification
Neurohormones are synthesized by neurons
and are released directly into the bl ood so that they
can cause a response in target tissues elsewhere in
the body. A neurohormone can act on any number of
tissues provided that the tissue has cellular receptors
for the neurohormone. An example is oxytocin that
is synthesized by hypothalamic neurons, stored and
released by the posterior lobe of the pitu itary.
Releasing hormones are also synthesized
by neurons in the hypothalamus and cause release of
other hormones from the anterior lobe of the pituitary.
They can a lso be classified as neurohormones because
they are synthesized and released by neurons . An ex-
ample is gonadotropin releasing hom1one (GnRH) that
controls the release ofFS H and Ll-1 from the anterior
lobe of the pituitary.
Gonado tropin s are hom10nes synthesized
and secreted by specialized cells in the anterior lobe
of the pituitary gland called gonadotropes. The suffix
” tropin” means having an affinity fo r or to nourish.
Thus, these hormones have a stimulatory infl uence
on the gonads (the ovary and the testis). Gonado-
tropins are follicle stimulating hormone (FSH) and
luteinizing hormone (LH). Lutein izing hormone is
responsible for causing ovulation and sti mu lating the
corpus luteum (CL) to secrete progesterone. Luteiniz-
ing hormone causes testosterone secretion in the male.
Follicle stimulating hom1one causes follicular growth
in the ovary of the fema le. It stimulates Sertoli cells
in the male and is probably a “key player” in govern-
ing spermatogenesis.
Sexual promoters (estrogens, progesterone,
testosterone) are secreted by the gonads of both the
male and the fe ma le to stimulate the reproductive
tract, to regulate the function of the hyp othalamus
and the anterior lobe of the piruitary and to regulate
V
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11 O Nerves, Hormones and Target Tissues
reproductive behavior. These hormones also cause
the development of secondary sex characteristics.
The sexual promoters are the driving force for all
reproductive function.
Human chorionic gonadotropin (hCG) and
equine chorionic gonadotropin (eCG) are secreted
by the early embryo (conceptus). These placental
hormones cause stimulation of the maternal ovary.
Pregnancy maintenance hormones are in
high concentrations during times of pregnancy. They
are responsible for maintenance of pregnancy (e.g.,
progesterone) and, in some cases, assisting the female
in her lactation ability. Placental lactogen promotes
development of the mammmy gland of the dam and
is therefore lactogenic.
General metabolic hormones promote
metabolic well-being. Such honnones are thyroxin
from the thyroid gland, the adrenal corticoids from
the adrenal cortex and growth hormone (somatotro-
pin) from the anterior lobe of the pituitary. Thyroxin
regulates metabolic rate of the animal. The adrenal
corticoids perform a host of functions ranging from
mineral metabolism to regulation of inflammatory
responses. Growth hom1one helps regulate growth,
lactation and protein metabolism. These general
metabolic honnones are all necessary for optimum
reproduction. However, they are considered to exert
an indirect rather than a direct effect on reproductive
fi.mction.
Luteolytic hormones cause destmction of the
corpus luteum. The suffix “lytic” is a derivative of the
word lysis. Lysis means decomposition, disintegration
or dissolution. Luteolytic hormones, therefore, cause
the corpus luteum to stop functioning. The major lu-
teolytic hormone is prostaglandin F2a (PGF2a)· As
you shall see in Chapter 9, PGF2a causes a decrease in
secretion of progesterone by the corpus luteum.
Reproductive hormones can cause:
• release of other hormones
(releasing hormones)
• stimulation of the gonads
(gonadotropins)
• sexual promotion (steroids)
• pregnancy maintenance
•luteolysis (destruction ofthe CL)
Hormonal Biochemical Structure
Constitutes Another Classification Method
Peptides are relatively small molecules with
only a few amino acids joined by peptide bonds. The
most important reproductive peptide is GnRH shown
in Figure 5-6.
Prolactin is an example of a protein hom1one
that consists of a single polypeptide chain of 198
amino acids and is not glycosylated.
Relaxin is a two-chain nonglycosylated poly-
peptide. It consists of an alpha (a ) chain and a beta
CP) chain. These polypeptide chains are connected
by two disulfide crosslinks. The primary source of
relaxin is the corpus luteum of pregnancy. There is
supporting evidence that relaxin is synthesized by the
placenta as well.
Glycoproteins are polypeptide honnones that
contain carbohydrate moieties and range in mo lecular
weight from several hundred to 70,000. Some glyco-
protein hom1ones are composed of two side-by-side
polypeptide chains that have carbohydrates attached
to each chain. These polypeptide chains have been
designated as the a and P subunits (See Figure 5-7).
The anterior lobe of the pituitary synthesizes and se-
cretes glycoprotein hormones that all have the same
a subunit but different subunits. The a subunit for
FSH, LH and thyroid stimulating hom1one (TSH) are
identical within species. However, the p subunit is
unique to each individual hom1one and gives each of
these glycoprotein hormones a high degree of speci-
ficity and function. Individual a and B subunits of
these molecules have no biological activity. If an a
subunit of one honnone is combined with the P subunit
of another honnone, the activity will be determined
by the hormone that contributed the subunit. The a
and B subunits are held together with hydrogen bonds
and van der Waals forces and thus are not covalently
attached (See Figure 5-7).
Inhibin is another glycoprotein hormone
that contains an a and one of two subunits
(designated p A or p B). This honnone appears to have
the same physiologic activity regardless of which P
subunit is present. lnhibin suppresses FSH secretion
fi·om the anterior lobe of the pituitary.
Researchers have identified a protein from
follicular fluid that consists of two p subunits called
activin. Activin causes release of FSH in pituitary
cells in culture and therefore has the opposite effect
of inhibin in-vitro.
Follistatin, a glycoprotein, was originally
isolated from ovarian follicular fluid. It inhibited FSH
secretion from pihtitary cells in culhtre. However,
compared to inhibin, it has low physiologic activity.
Follistatin binds to activin and limits widespread ac-
tions of activin.
Nerves, Hormones and Target Tissues 111
Figure 5-7. Generic Illustration of a Glycoprotein Hormone
The a and subun its are
held together no n-co va –
lently by hydrogen bonding
and van der Waals forces
(dotted lines).
COOH
Subunit – u nique fo r each hormo ne COOH
Carbohydrate (CHO ) moieties are
shown in boxes and are covalently
bonded to the a and B subunit.
Dispersed along each subunit of the hormone
are carbohydrate mo ieties that are thought to protect
the molecule from short-term degradation that might
occur during transport in the blood and interstitial
compartments to target tissues. The quantity of car-
bohydrate moieties on the surface of the protein is
thought to detem1ine the duration of the hormone ‘s
half-life. In other words, the higher the degree of
glycosylation (number of carbohydrate moi eties), the
longer the half-life of the honn one. Recent research
findings indicate that a single glycoprotein honnone
may have as many as 6 to 8 subtypes in which the
degree ofglycosylation varies significantly. G lycopro-
tein hormones can be degraded easily by proteolytic
enzymes in the digestive tract. Therefore, they are
not effective when given orally.
Biochemical classifications include:
• peptides
• glycoproteins
• steroids
• prostaglandins
Steroid hormones have a common molecular
nucleus called the cyclopentanoperhydropbenan-
tbrene nucleus. The molecule is composed of four
rings designated A, B, C and D . Each carbon in the
ring has a number, as shown in Figure 5-8.
Stero ids are synthesized from cholesterol
through a series of complex pathways involving many
enzymatic conversions . Figure 5- 9 ill ustr ates the
major biochemical transfonnations that occ ur in the
gonadal steroid synthetic pathway. Stero id molecules
are sexual promoters and cause profound changes in
both the male and female reproductive tract and will
be discussed in later chapters.
Figure 5-B. Standardized
Labeling of the Steroid
Molecule
21 22
23
‘——-< 25 24 A , B, C and D designate specific rings. Numbers designate specific carbons. 26 27 V et B oo ks .ir 11 O Nerves, Hormones and Target Tissues reproductive behavior. These hormones also cause the development of secondary sex characteristics. The sexual promoters are the driving force for all reproductive function. Human chorionic gonadotropin (hCG) and equine chorionic gonadotropin (eCG) are secreted by the early embryo (conceptus). These placental hormones cause stimulation of the maternal ovary. Pregnancy maintenance hormones are in high concentrations during times of pregnancy. They are responsible for maintenance of pregnancy (e.g., progesterone) and, in some cases, assisting the female in her lactation ability. Placental lactogen promotes development of the mammmy gland of the dam and is therefore lactogenic. General metabolic hormones promote metabolic well-being. Such honnones are thyroxin from the thyroid gland, the adrenal corticoids from the adrenal cortex and growth hormone (somatotro- pin) from the anterior lobe of the pituitary. Thyroxin regulates metabolic rate of the animal. The adrenal corticoids perform a host of functions ranging from mineral metabolism to regulation of inflammatory responses. Growth hom1one helps regulate growth, lactation and protein metabolism. These general metabolic honnones are all necessary for optimum reproduction. However, they are considered to exert an indirect rather than a direct effect on reproductive fi.mction. Luteolytic hormones cause destmction of the corpus luteum. The suffix "lytic" is a derivative of the word lysis. Lysis means decomposition, disintegration or dissolution. Luteolytic hormones, therefore, cause the corpus luteum to stop functioning. The major lu- teolytic hormone is prostaglandin F2a (PGF2a)· As you shall see in Chapter 9, PGF2a causes a decrease in secretion of progesterone by the corpus luteum. Reproductive hormones can cause: • release of other hormones (releasing hormones) • stimulation of the gonads (gonadotropins) • sexual promotion (steroids) • pregnancy maintenance •luteolysis (destruction ofthe CL) Hormonal Biochemical Structure Constitutes Another Classification Method Peptides are relatively small molecules with only a few amino acids joined by peptide bonds. The most important reproductive peptide is GnRH shown in Figure 5-6. Prolactin is an example of a protein hom1one that consists of a single polypeptide chain of 198 amino acids and is not glycosylated. Relaxin is a two-chain nonglycosylated poly- peptide. It consists of an alpha (a ) chain and a beta CP) chain. These polypeptide chains are connected by two disulfide crosslinks. The primary source of relaxin is the corpus luteum of pregnancy. There is supporting evidence that relaxin is synthesized by the placenta as well. Glycoproteins are polypeptide honnones that contain carbohydrate moieties and range in mo lecular weight from several hundred to 70,000. Some glyco- protein hom1ones are composed of two side-by-side polypeptide chains that have carbohydrates attached to each chain. These polypeptide chains have been designated as the a and P subunits (See Figure 5-7). The anterior lobe of the pituitary synthesizes and se- cretes glycoprotein hormones that all have the same a subunit but different subunits. The a subunit for FSH, LH and thyroid stimulating hom1one (TSH) are identical within species. However, the p subunit is unique to each individual hom1one and gives each of these glycoprotein hormones a high degree of speci- ficity and function. Individual a and B subunits of these molecules have no biological activity. If an a subunit of one honnone is combined with the P subunit of another honnone, the activity will be determined by the hormone that contributed the subunit. The a and B subunits are held together with hydrogen bonds and van der Waals forces and thus are not covalently attached (See Figure 5-7). Inhibin is another glycoprotein hormone that contains an a and one of two subunits (designated p A or p B). This honnone appears to have the same physiologic activity regardless of which P subunit is present. lnhibin suppresses FSH secretion fi·om the anterior lobe of the pituitary. Researchers have identified a protein from follicular fluid that consists of two p subunits called activin. Activin causes release of FSH in pituitary cells in culture and therefore has the opposite effect of inhibin in-vitro. Follistatin, a glycoprotein, was originally isolated from ovarian follicular fluid. It inhibited FSH secretion from pihtitary cells in culhtre. However, compared to inhibin, it has low physiologic activity. Follistatin binds to activin and limits widespread ac- tions of activin. Nerves, Hormones and Target Tissues 111 Figure 5-7. Generic Illustration of a Glycoprotein Hormone The a and subun its are held together no n-co va - lently by hydrogen bonding and van der Waals forces (dotted lines). COOH Subunit - u nique fo r each hormo ne COOH Carbohydrate (CHO ) moieties are shown in boxes and are covalently bonded to the a and B subunit. Dispersed along each subunit of the hormone are carbohydrate mo ieties that are thought to protect the molecule from short-term degradation that might occur during transport in the blood and interstitial compartments to target tissues. The quantity of car- bohydrate moieties on the surface of the protein is thought to detem1ine the duration of the hormone 's half-life. In other words, the higher the degree of glycosylation (number of carbohydrate moi eties), the longer the half-life of the honn one. Recent research findings indicate that a single glycoprotein honnone may have as many as 6 to 8 subtypes in which the degree ofglycosylation varies significantly. G lycopro- tein hormones can be degraded easily by proteolytic enzymes in the digestive tract. Therefore, they are not effective when given orally. Biochemical classifications include: • peptides • glycoproteins • steroids • prostaglandins Steroid hormones have a common molecular nucleus called the cyclopentanoperhydropbenan- tbrene nucleus. The molecule is composed of four rings designated A, B, C and D . Each carbon in the ring has a number, as shown in Figure 5-8. Stero ids are synthesized from cholesterol through a series of complex pathways involving many enzymatic conversions . Figure 5- 9 ill ustr ates the major biochemical transfonnations that occ ur in the gonadal steroid synthetic pathway. Stero id molecules are sexual promoters and cause profound changes in both the male and female reproductive tract and will be discussed in later chapters. Figure 5-B. Standardized Labeling of the Steroid Molecule 21 22 23 '-------< 25 24 A , B, C and D designate specific rings. Numbers designate specific carbons. 26 27 V et B oo ks .ir 112 Nerves, Hormones and Target Tissues OH OH 0 0 OH Figure 5-9. Gonadal Steroid Synthetic Pathway CH3 I Cholesterol (27 carbons) C=O Enzymatic conversion CH3 Pregnenolone (21 carbons) I C=O Enzymatic conversion OH OH ( 21 carbons) Enzymatic conversion Testosterone ( 19 carbons) Enzymatic conversion (I 8 carbons) Prostaglandins were first discovered in semi- nal plasma of mammalian semen and were thought to originate from the prostate gland. Thus, these compounds were named prostaglandins. The seminal vesicles are now known to secrete more prostaglandin than the prostate, at least in the ram. Prostaglandins Figure 5-10. Structure of PGF2a and PGEz (The dashed lines represent bonds that extend into the plane of the page) Prostaglandin F2a (PGF2a) OH OH I I I OH COOH Prostaglandin E2 (PGE2) 0 I I I OH OH COOH are among the most ubiquitous and physi ologically active substances in the body. They are lipids con- sisting of 20-carbon unsaturated hydroxy fatty acids that are derived from arachidonic acid. There are at least six biochemical prostaglandins and numerous metabolites that have an extremely wide range of physiologic activity. For example, prostaglandin E1 (PGE2) lowers blood pressure, while prostaglandin F2a (PGF2u) increases blood pressure. Prostaglandins also stimulate uterine smooth muscle, influence lipid metabolism and mediate inflammation. As fa r as the reproductive system is concerned, the two most important prostaglandins are PGF2a and PGE2 (See Figure 5-l 0). Ovulation is controlled, at least in part, by PGF2u and PGE2. The discovery that PGF2u caused luteolysis (destruction ofthe corpus luteum) in the female opened a new world of application for the control of the estrous cycle. Use of prostaglandins as a tool for reproductive management is now routine and some of these strate- gies will be discussed in Chapter 9. Prostaglandins are rapidly degraded in the blood. In fact, almost Nerves, Hormones and Target Tissues 113 Figure 5-11. Target Tissues Bind Hormones, Other Tissues Do Not Hormones (green spheres) are secreted by cells of the endocrine gland and are re- leased into the blood. The blood delivers the hormone to the ta rget tissues. Endocrine Gland (secretes ho rmo ne • @) Target Tiss u e (specific recep t ors) tissues contain rece ptors (yellow) that specifically bmd the hormone. Nontarget tissues also have receptors (orange) but for other hormone s. The specific hormone shown here (green) will not bind to the orange receptors. Therefore, the tissue will not respond. 8 + @ = @ > Res ponse by
T T Ta rget Cell
Receptor
Bo un d
Hormone
) No
Resp onse
all ofPGF2u is removed from blood during one pass
through the pulmonary circulation (30 seconds). Thus,
PGF2u has an extremely short half-l ife (seconds).
Pheromones are Another Class of
Substances that Cause Remote Effects
In addition to molecules that are transported
by blood, another class of materials exists that d irectly
influences reproductive processes. These materials
are called pheromones. Pheromones are substances
to the outside of the body. They are generally
volatile and are detected by the olfactory system (and
perhaps the vomeronasal organ) by members of the
same species. Pheromones cause specific behavioral
or physiologic responses by the percipient. Phero-
known to influence the onset of puberty,
the tdentrfication offemales in estrus by the males and
other behavioral traits.
Endocrine glands are composed of many cells
that synthesize and secrete specific honnones. These
hmmone molecules enter the blood and are transported
to every cell in the body. In spite of the fact that every
cell in the body is exposed to the hormone, only certain
cells with specific receptors are capable of responding
to the hormone. Ti ssues contain ing these cells are
called target tissues. For example, if a hormone’s
responsibi lity is to cause the cervix to synthesize
mucus, other organs such as the liver, the kidney or
the pancreas will not secrete mucus in response to
the honnone.
No Bin ding
Hormone action requires the presence
of specific receptors on target cells.
Target tissues are distinguished fro m other
tissues because the ir cells contain spec ific molecules
that bind a specific hormone. These specific molecules
located in the cells of target tissues are known as hor-
mone receptors (See Figure 5-11 ) . Receptors have
a specific affinity (degree of attraction) for a specific
honnone and thus bind it. Once the receptor in the
target tissue has bound the hormone, the target tissue
begins to perfonn a new ftmction. Often, the target
Figure 5-12. Hypothetical
Model of the LH Receptor
Extrace ll ular
domain
Intrace llu lar
domain
V
et
B
oo
ks
.ir

112 Nerves, Hormones and Target Tissues
OH
OH
0
0
OH
Figure 5-9. Gonadal Steroid
Synthetic Pathway
CH3
I
Cholesterol
(27 carbons)
C=O Enzymatic
conversion
CH3
Pregnenolone
(21 carbons)
I
C=O Enzymatic
conversion
OH
OH
( 21 carbons)
Enzymatic
conversion
Testosterone
( 19 carbons)
Enzymatic
conversion
(I 8 carbons)
Prostaglandins were first discovered in semi-
nal plasma of mammalian semen and were thought
to originate from the prostate gland. Thus, these
compounds were named prostaglandins. The seminal
vesicles are now known to secrete more prostaglandin
than the prostate, at least in the ram. Prostaglandins
Figure 5-10. Structure of PGF2a
and PGEz
(The dashed lines represent bonds that
extend into the plane of the page)
Prostaglandin F2a (PGF2a)
OH
OH
I
I
I
OH
COOH
Prostaglandin E2 (PGE2)
0
I
I
I
OH OH
COOH
are among the most ubiquitous and physi ologically
active substances in the body. They are lipids con-
sisting of 20-carbon unsaturated hydroxy fatty acids
that are derived from arachidonic acid. There are at
least six biochemical prostaglandins and numerous
metabolites that have an extremely wide range of
physiologic activity. For example, prostaglandin E1
(PGE2) lowers blood pressure, while prostaglandin
F2a (PGF2u) increases blood pressure. Prostaglandins
also stimulate uterine smooth muscle, influence lipid
metabolism and mediate inflammation. As fa r as
the reproductive system is concerned, the two most
important prostaglandins are PGF2a and PGE2 (See
Figure 5-l 0). Ovulation is controlled, at least in part,
by PGF2u and PGE2.
The discovery that PGF2u caused luteolysis
(destruction ofthe corpus luteum) in the female opened
a new world of application for the control of the estrous
cycle. Use of prostaglandins as a tool for reproductive
management is now routine and some of these strate-
gies will be discussed in Chapter 9. Prostaglandins
are rapidly degraded in the blood. In fact, almost
Nerves, Hormones and Target Tissues 113
Figure 5-11. Target Tissues Bind Hormones, Other Tissues Do Not
Hormones (green spheres)
are secreted by cells of the
endocrine gland and are re-
leased into the blood. The
blood delivers the hormone to
the ta rget tissues.
Endocrine Gland
(secretes ho rmo ne • @)
Target Tiss u e
(specific recep t ors)
tissues contain rece ptors (yellow) that specifically
bmd the hormone. Nontarget tissues also have receptors
(orange) but for other hormone s. The specific hormone
shown here (green) will not bind to the orange receptors.
Therefore, the tissue will not respond.
8 + @ = @ > Res ponse by
T T Ta rget Cell
Receptor
Bo un d
Hormone
) No
Resp onse
all ofPGF2u is removed from blood during one pass
through the pulmonary circulation (30 seconds). Thus,
PGF2u has an extremely short half-l ife (seconds).
Pheromones are Another Class of
Substances that Cause Remote Effects
In addition to molecules that are transported
by blood, another class of materials exists that d irectly
influences reproductive processes. These materials
are called pheromones. Pheromones are substances
to the outside of the body. They are generally
volatile and are detected by the olfactory system (and
perhaps the vomeronasal organ) by members of the
same species. Pheromones cause specific behavioral
or physiologic responses by the percipient. Phero-
known to influence the onset of puberty,
the tdentrfication offemales in estrus by the males and
other behavioral traits.
Endocrine glands are composed of many cells
that synthesize and secrete specific honnones. These
hmmone molecules enter the blood and are transported
to every cell in the body. In spite of the fact that every
cell in the body is exposed to the hormone, only certain
cells with specific receptors are capable of responding
to the hormone. Ti ssues contain ing these cells are
called target tissues. For example, if a hormone’s
responsibi lity is to cause the cervix to synthesize
mucus, other organs such as the liver, the kidney or
the pancreas will not secrete mucus in response to
the honnone.
No Bin ding
Hormone action requires the presence
of specific receptors on target cells.
Target tissues are distinguished fro m other
tissues because the ir cells contain spec ific molecules
that bind a specific hormone. These specific molecules
located in the cells of target tissues are known as hor-
mone receptors (See Figure 5-11 ) . Receptors have
a specific affinity (degree of attraction) for a specific
honnone and thus bind it. Once the receptor in the
target tissue has bound the hormone, the target tissue
begins to perfonn a new ftmction. Often, the target
Figure 5-12. Hypothetical
Model of the LH Receptor
Extrace ll ular
domain
Intrace llu lar
domain
V
et
B
oo
ks
.ir

114 Nerves, Hormones and Target Tissues
tissue secretes another hormone that acts upon another
tissue elsewhere in the body.
Protein hormones bind to plasma
membrane receptors.
Receptors for protein hormones are an inte-
gral part of the plasma membrane of the target cell.
They contain tlu·ee distinct regions. These regions are
referred to as receptor domains. The configuration of
the LH receptor consists of an extracellular domain,
a transmembrane domain and an intracellular do-
main (See Figure 5-12).
The extracellular domain has a specific site
that binds the specific hormone. When this site is
occupied, the transmembrane domain changes its
configuration and activates other membrane proteins
known as G-proteins . The number of transmembrane
“loops” may vary as a function of receptor type. The
function of the intracellular domain of the receptor
is not clear.
Steps of Action for Protein Hot·mones
Step 1 – Hormone-Receptor Binding. The
hormone diff1.1ses from the blood into the interstitial
compartment and b inds to a me mbrane receptor
that is specific for the hormone. The binding oc-
curs on the surface of the target ce lls (See Figure
5-13). In general, receptors to the gonadotrop ins
are sparsely di stributed on the surface of the target
cells . In fact, onl y 2,000 to 20,00 0 LH or FSH
receptors are present per follicle cell . Hormone-
receptor binding is thought to be bro ught about
by a specific geometric configuration of the receptor
Figure 5-13. Protein Hormone Mechanisms of Action
(Circled numbers in the figure are steps of action described in the text)
®
Hormone
(Primary messenger)
Blood
Protein hormones activate pro-
tein kinases via cAMP. Cyclic
AMP activates the regulatory
subunit (R) that, in turn, ac-
tivates the catalytic subunit
(C) of the enzyme resulting in
activation of other enzymes
by phosphorylation. This al-
lows the construction of new
proteins (including enzymes)
for reproduction.
New protein
products for
reproduction
Cytoplasm
0
New protein
synthesis
Kinases
that ” fits” the geom etric configuration of the honnone.
The hormone receptor binding is much like fitting two
adj acent pieces of a puzzle together. The affinity of the
hormone-receptor binding varies among hormones.
Step 2 -Adenyl ate Cyclase Activation. T he
horm one-receptor complex activates a membrane
bound enzy me known as aden ylat e c y clase and
membrane b ound G-proteins. When the honn one
rec eptor complex is fo nned, the G-protein is trans-
formed in a way th at activates adenylate cyclas e
(See Figure 5-13 ). The active fonn of this enzyme
converts ATP to cyclic AMP (cAMP) within the cy-
toplasm of the cell. Cyclic AMP has been tenned the
“second messenger” in the pathway because cAMP
must be present before fur ther “downstream” events
can oc cur. T he primary messenger is the honnone
itself.
Step 3- Protein Kinase Activation. Cyclic
AMP activates a family of control enzymes located
in the cytoplasm called protein kinases. These pro-
tein kinases are responsible fo r activating enzymes in
the cytoplasm that convert substrates into products.
Protein kinase s consist of a regulatory and a catalytic
subunit. The regulatory subunit binds cAMP and this
binding causes activation of the catalytic subunit that
initiates the conversion of existing substrates to new
products.
Step 4 – Synthesis of New Products. The
products made by the cell are genera lly secreted and
these secretory products have sp ecific functions that
enhance reproductive processes. For example, the
gonadotropins (FSH and LH) bind to fo llicle cells in
the ovary that results in the synthesis of a new prod-
uct, estradiol. When steroids are synthesize d, they
are not actively secreted, but simp ly diffuse through
the plasma membrane into the interstitia l spaces and
into the blood.
Steroid hormones have two types
of receptors.
Until recently, it was thought that steroid hor-
mones acted exclusively thr ough nuclear receptors to
produce a response in target cells. Research has shown
that in addition to nuclear receptors, steroid honn ones
also bind to membrane receptors oftar·get cells. There
is a functional difference between membrane receptor
binding and nuclear receptor binding. N uclear recep-
tor binding caus es “slow” responses (hours to days)
that require transcriptional involvement, fo llowed by
product synthesis and secretion by the target cell. For
example, a target tissue for estradiol in the female is
the cervix . When estrad iol binds to nuclear receptors
in the cervical cells, it promotes the synthesis and
secretion of cervical mucus. This process requires
several days.
Nerves, Hormones and Target Tissues 115
Steroid hormone binding to membrane recep-
tors typica lly results in “fast” responses (seconds to
minutes). The myometrium has membrane estradiol
receptors. When estrogens bind to these receptors they
cause permeabilitity changes in the calcium channels
in myometrial smooth muscle, caus ing increased mo-
ti lity (contraction) of the myometrium. As illustrated
in Figure 5-14, it is thought that the steroid hormone
target cells contain both membrane-bound receptors
and nuclear receptors.
S t eps of Action for Steroid Hormones :
M embrane Recept ors ( ” Fast Response”)
Although several variations in the biochemical path-
ways followi ng binding to membrane receptors are
known, fo r this purpose we wi ll use the pathway as
described for protein hormones (See Figure 5-1 4).
Step 1- Steroid Binding to Membrane Receptor·s
Step 2- Adenylate C yclase Activation
Step 3- Protein Kinase Activation
Step 4- Changes in Ca++- channel permeability
Steps of Action for Steroid Hormones:
N uclear Receptors (“Slow Response”)
Step 1 – Steroid Transport. Steroid hor-
mones are transported in the blood by a complex
system. Steroids are not water soluble and therefore
cannot be transported as free molecules. Therefore,
they must attach to molecules that are water solub le.
Stero ids bind to a variety of plasma proteins in a
nonspecific manner althroug h some steroids have
spec ific carrier protein s. These transport proteins
carry steroids in the blood and interstitial flu id to the
cell membranes of all cells. The binding of stero ids to
plasma proteins tends to extend the ir ha lf-life .
Step 2 – Mo v ement Throu2h the Cell
Membrane and Cytoplasm. When the ster oid-
carrier protein complex travels into the interstitium
and comes in contact w ith target cells, the stero id
disassociates from the carrier pro tein and diffuses
thr ough the pl asma membrane because they are lipid
solubile (See Figure 5- 14 ). After the steroid m olecule
enters the cell, it diffuses through the cytop lasm and
into the nucleus.
Step 3 – Bindin2 of Steroid to Nuclear· Re-
ceptor. If the cell is a target cell, the steroid binds to
a spec ific nuclear receptor. The steroid-receptor bind-
ing is similar to protein-receptor binding in that the
steroid must “fit” the receptor. The steroid-receptor
complex is referred to as a transcription factor and
initiates DNA- direc ted messenger RNA synthesis
(transcr iption).
V
et
B
oo
ks
.ir

114 Nerves, Hormones and Target Tissues
tissue secretes another hormone that acts upon another
tissue elsewhere in the body.
Protein hormones bind to plasma
membrane receptors.
Receptors for protein hormones are an inte-
gral part of the plasma membrane of the target cell.
They contain tlu·ee distinct regions. These regions are
referred to as receptor domains. The configuration of
the LH receptor consists of an extracellular domain,
a transmembrane domain and an intracellular do-
main (See Figure 5-12).
The extracellular domain has a specific site
that binds the specific hormone. When this site is
occupied, the transmembrane domain changes its
configuration and activates other membrane proteins
known as G-proteins . The number of transmembrane
“loops” may vary as a function of receptor type. The
function of the intracellular domain of the receptor
is not clear.
Steps of Action for Protein Hot·mones
Step 1 – Hormone-Receptor Binding. The
hormone diff1.1ses from the blood into the interstitial
compartment and b inds to a me mbrane receptor
that is specific for the hormone. The binding oc-
curs on the surface of the target ce lls (See Figure
5-13). In general, receptors to the gonadotrop ins
are sparsely di stributed on the surface of the target
cells . In fact, onl y 2,000 to 20,00 0 LH or FSH
receptors are present per follicle cell . Hormone-
receptor binding is thought to be bro ught about
by a specific geometric configuration of the receptor
Figure 5-13. Protein Hormone Mechanisms of Action
(Circled numbers in the figure are steps of action described in the text)
®
Hormone
(Primary messenger)
Blood
Protein hormones activate pro-
tein kinases via cAMP. Cyclic
AMP activates the regulatory
subunit (R) that, in turn, ac-
tivates the catalytic subunit
(C) of the enzyme resulting in
activation of other enzymes
by phosphorylation. This al-
lows the construction of new
proteins (including enzymes)
for reproduction.
New protein
products for
reproduction
Cytoplasm
0
New protein
synthesis
Kinases
that ” fits” the geom etric configuration of the honnone.
The hormone receptor binding is much like fitting two
adj acent pieces of a puzzle together. The affinity of the
hormone-receptor binding varies among hormones.
Step 2 -Adenyl ate Cyclase Activation. T he
horm one-receptor complex activates a membrane
bound enzy me known as aden ylat e c y clase and
membrane b ound G-proteins. When the honn one
rec eptor complex is fo nned, the G-protein is trans-
formed in a way th at activates adenylate cyclas e
(See Figure 5-13 ). The active fonn of this enzyme
converts ATP to cyclic AMP (cAMP) within the cy-
toplasm of the cell. Cyclic AMP has been tenned the
“second messenger” in the pathway because cAMP
must be present before fur ther “downstream” events
can oc cur. T he primary messenger is the honnone
itself.
Step 3- Protein Kinase Activation. Cyclic
AMP activates a family of control enzymes located
in the cytoplasm called protein kinases. These pro-
tein kinases are responsible fo r activating enzymes in
the cytoplasm that convert substrates into products.
Protein kinase s consist of a regulatory and a catalytic
subunit. The regulatory subunit binds cAMP and this
binding causes activation of the catalytic subunit that
initiates the conversion of existing substrates to new
products.
Step 4 – Synthesis of New Products. The
products made by the cell are genera lly secreted and
these secretory products have sp ecific functions that
enhance reproductive processes. For example, the
gonadotropins (FSH and LH) bind to fo llicle cells in
the ovary that results in the synthesis of a new prod-
uct, estradiol. When steroids are synthesize d, they
are not actively secreted, but simp ly diffuse through
the plasma membrane into the interstitia l spaces and
into the blood.
Steroid hormones have two types
of receptors.
Until recently, it was thought that steroid hor-
mones acted exclusively thr ough nuclear receptors to
produce a response in target cells. Research has shown
that in addition to nuclear receptors, steroid honn ones
also bind to membrane receptors oftar·get cells. There
is a functional difference between membrane receptor
binding and nuclear receptor binding. N uclear recep-
tor binding caus es “slow” responses (hours to days)
that require transcriptional involvement, fo llowed by
product synthesis and secretion by the target cell. For
example, a target tissue for estradiol in the female is
the cervix . When estrad iol binds to nuclear receptors
in the cervical cells, it promotes the synthesis and
secretion of cervical mucus. This process requires
several days.
Nerves, Hormones and Target Tissues 115
Steroid hormone binding to membrane recep-
tors typica lly results in “fast” responses (seconds to
minutes). The myometrium has membrane estradiol
receptors. When estrogens bind to these receptors they
cause permeabilitity changes in the calcium channels
in myometrial smooth muscle, caus ing increased mo-
ti lity (contraction) of the myometrium. As illustrated
in Figure 5-14, it is thought that the steroid hormone
target cells contain both membrane-bound receptors
and nuclear receptors.
S t eps of Action for Steroid Hormones :
M embrane Recept ors ( ” Fast Response”)
Although several variations in the biochemical path-
ways followi ng binding to membrane receptors are
known, fo r this purpose we wi ll use the pathway as
described for protein hormones (See Figure 5-1 4).
Step 1- Steroid Binding to Membrane Receptor·s
Step 2- Adenylate C yclase Activation
Step 3- Protein Kinase Activation
Step 4- Changes in Ca++- channel permeability
Steps of Action for Steroid Hormones:
N uclear Receptors (“Slow Response”)
Step 1 – Steroid Transport. Steroid hor-
mones are transported in the blood by a complex
system. Steroids are not water soluble and therefore
cannot be transported as free molecules. Therefore,
they must attach to molecules that are water solub le.
Stero ids bind to a variety of plasma proteins in a
nonspecific manner althroug h some steroids have
spec ific carrier protein s. These transport proteins
carry steroids in the blood and interstitial flu id to the
cell membranes of all cells. The binding of stero ids to
plasma proteins tends to extend the ir ha lf-life .
Step 2 – Mo v ement Throu2h the Cell
Membrane and Cytoplasm. When the ster oid-
carrier protein complex travels into the interstitium
and comes in contact w ith target cells, the stero id
disassociates from the carrier pro tein and diffuses
thr ough the pl asma membrane because they are lipid
solubile (See Figure 5- 14 ). After the steroid m olecule
enters the cell, it diffuses through the cytop lasm and
into the nucleus.
Step 3 – Bindin2 of Steroid to Nuclear· Re-
ceptor. If the cell is a target cell, the steroid binds to
a spec ific nuclear receptor. The steroid-receptor bind-
ing is similar to protein-receptor binding in that the
steroid must “fit” the receptor. The steroid-receptor
complex is referred to as a transcription factor and
initiates DNA- direc ted messenger RNA synthesis
(transcr iption).
V
et
B
oo
ks
.ir

I
116 Nerves, Hormones and Target Tissues
Figure 5-14. Mechanisms of Steroid Hormone Action
(Circled numbers in the figure are steps of action described in the text )
Cell
membran e
New protein
products for
reprod u ction
Fast Response
Cyto plasm
0
N e w p rotein
synthesis
Km ases L[ c __ v_…_
Examples of Fast Respons es
I _ ion channel _ j Myometrial 0 –) al teration _;) contraction s
I I _ I on channel _ ! Myometrial ‘ • iffiil’JIImn –;) inhibition –) cont ractions
New prote in
products fo r
rep roduction
Steroid Hormone
(Bound to carrier)
Slow Response
Examples of Slow Res ponses
=> Muco us secretion
by femal e t r act
Steroid hormones can bind to membrane receptors and nuclear recept?rs causing
“downstream” effects. Numbers in each graphic represent th e steps m each mechanism
that are explained in the text.
Step 4 – mRNA Sv n t h es is a nd P r·o tei n
Syn thesis. T he newly synthesiz ed mRNA leaves the
nucl eus and a ttaches to ribosomes where it d irects
the synthesis of specific proteins that w ill enhance
the reproductive process. A few examples of s teroid-
directed synthesis are: I) mucus from the cervix during
estrus ; 2) uterine secretions from the uterine g lands;
and 3) semina l plasma components fro m the accessory
sex g lands in the male .
“Strength ” of hormone action depends on:
• pattern and duration of secretion
• half-life
• receptor density
• receptor-hormone affinity
The phys iologic activity of a horn1one de-
pends on several fac tors includi ng pattern an d dura-
tion of honnone secretion, ha lf- life of the hormone,
receptor density and receptor-hom1one affi nity. These
factors determine the magnitude and duration of action
of honnones. In general, honnones are secreted in
three types of patterns (See Fi gure 5- 15). One typ e
is episodic secretion that generally is associated with
Nerves, Hormones and Target Tissues 11 7
hormones under nervous control. When nerves in the
hypothalamus “fire,” neuropeptide s are released in a
s udden burst (episode) and thus hormones from the
anterior lobe of the pi tu itary tend to be released in an
episodic manner as well. A typ ical pattern of episodic
release is shown in Figure 5-15. Organ ization of epi-
sodes into a predictable pattern is referred to as pul-
satile secr etion . Pulsatile secretion is r equired for an
anima l to have a nonnal estrous cycl e. Prepubertal and
noncyc lic lactating animals are characterized by epi-
sodic secretion (unpredictable pattern) of h onnones.
A second type of secretion is a basal (tonic) pattern.
Here, the horn1one stays low, but fluctuates with low
amplitude pulses. A n examp le of a basa l pattern
would be GnRI-1 secretion from the tonic center in the
hyp othalamus. Susta ined is a third type of hormonal
pattern or profile. In this type, the hon n one remains
elevated, but in a relatively steady, stable fas hion for
a long period of time (days to weeks). Steroids tend
to be secreted in a more s tab le fashion because the
glands secreting the steroids are ge nera lly producing
them continuously rather than as a function of neural
activity (that causes a pulsatile release). High proges-
terone dur ing di estrus or pregnancy is an example of
a sustained pattern of honnone secretion.
Figure 5-15. Typ ical Patterns of Hormonal Secretion by
the Reproductive System
Ill
c:
0
:I.. …..
c:
CIJ u
c:
0 u
CIJ
c:
0
E
:I..
0
X
CIJ >
CIJ
D::
(Fast )
Episodic secretion is genera l-
ly associated with hormones
un der nervous control. When
nerves of the hypotha lamus
fi re, neuropeptid es are re-
lea sed in a sudden burst o r
pulse.
(Bac kg r ound)
Time
In a basal secretion patte rn,
the hormone stays low but
fl uctuates w ith low amplitude
pu lses .
(Cons istent)
In t he su sta ined h o rmo ne
release profile , t he hormone
re main s e levated, but in a
relatively steady fashion for a
long period (days to weeks).
Steroids tend to be secreted
in this manner.
V
et
B
oo
ks
.ir

I
116 Nerves, Hormones and Target Tissues
Figure 5-14. Mechanisms of Steroid Hormone Action
(Circled numbers in the figure are steps of action described in the text )
Cell
membran e
New protein
products for
reprod u ction
Fast Response
Cyto plasm
0
N e w p rotein
synthesis
Km ases L[ c __ v_…_
Examples of Fast Respons es
I _ ion channel _ j Myometrial 0 –) al teration _;) contraction s
I I _ I on channel _ ! Myometrial ‘ • iffiil’JIImn –;) inhibition –) cont ractions
New prote in
products fo r
rep roduction
Steroid Hormone
(Bound to carrier)
Slow Response
Examples of Slow Res ponses
=> Muco us secretion
by femal e t r act
Steroid hormones can bind to membrane receptors and nuclear recept?rs causing
“downstream” effects. Numbers in each graphic represent th e steps m each mechanism
that are explained in the text.
Step 4 – mRNA Sv n t h es is a nd P r·o tei n
Syn thesis. T he newly synthesized mRNA leaves the
nucl eus and a ttaches to ribosomes where it d irects
the synthesis of specific proteins that w ill enhance
the reproductive process. A few examples of s teroid-
directed synthesis are: I) mucus from the cervix during
estrus ; 2) uterine secretions from the uterine g lands;
and 3) semina l plasma components fro m the accessory
sex g lands in the male .
“Strength ” of hormone action depends on:
• pattern and duration of secretion
• half-life
• receptor density
• receptor-hormone affinity
The phys iologic activity of a horn1one de-
pends on several fac tors includi ng pattern an d dura-
tion of honnone secretion, ha lf- life of the hormone,
receptor density and receptor-hom1one affi nity. These
factors determine the magnitude and duration of action
of honnones. In general, honnones are secreted in
three types of patterns (See Fi gure 5- 15). One typ e
is episodic secretion that generally is associated with
Nerves, Hormones and Target Tissues 11 7
hormones under nervous control. When nerves in the
hypothalamus “fire,” neuropeptide s are released in a
s udden burst (episode) and thus hormones from the
anterior lobe of the pi tu itary tend to be released in an
episodic manner as well. A typ ical pattern of episodic
release is shown in Figure 5-15. Organ ization of epi-
sodes into a predictable pattern is referred to as pul-
satile secr etion . Pulsatile secretion is r equired for an
anima l to have a nonnal estrous cycl e. Prepubertal and
noncyc lic lactating animals are characterized by epi-
sodic secretion (unpredictable pattern) of h onnones.
A second type of secretion is a basal (tonic) pattern.
Here, the horn1one stays low, but fluctuates with low
amplitude pulses. A n examp le of a basa l pattern
would be GnRI-1 secretion from the tonic center in the
hyp othalamus. Susta ined is a third type of hormonal
pattern or profile. In this type, the hon n one remains
elevated, but in a relatively steady, stable fas hion for
a long period of time (days to weeks). Steroids tend
to be secreted in a more s tab le fashion because the
glands secreting the steroids are ge nera lly producing
them continuously rather than as a function of neural
activity (that causes a pulsatile release). High proges-
terone dur ing di estrus or pregnancy is an example of
a sustained pattern of honnone secretion.
Figure 5-15. Typ ical Patterns of Hormonal Secretion by
the Reproductive System
Ill
c:
0
:I.. …..
c:
CIJ u
c:
0 u
CIJ
c:
0
E
:I..
0
X
CIJ >
CIJ
D::
(Fast )
Episodic secretion is genera l-
ly associated with hormones
un der nervous control. When
nerves of the hypotha lamus
fi re, neuropeptid es are re-
lea sed in a sudden burst o r
pulse.
(Bac kg r ound)
Time
In a basal secretion patte rn,
the hormone stays low but
fl uctuates w ith low amplitude
pu lses .
(Cons istent)
In t he su sta ined h o rmo ne
release profile , t he hormone
re main s e levated, but in a
relatively steady fashion for a
long period (days to weeks).
Steroids tend to be secreted
in this manner.
V
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B
oo
ks
.ir

118 Nerves, Hormones and Target Tissues
Half-Life of a Hormone Determines
How Long It Will Act
Different honnones have different life expec-
tancies within the systemic circulation. The rate at
which the honnone is cleared from the circulation deter-
mines its half-life. The longer the half-life, the greater
the potential biological activity. Some hormones have
exceptionally short half-lives (seconds; e.g. PGF2a),
while other hormones have quite long half-lives (days;
e.g. eCG).
Hormonal potency is influenced by:
• receptor density
• hormone receptor affinity
The density of target tissue receptors varies
as a function of the cell type as well as the degree to
which hormones promote (up-regulate), or inhibit
(down-regulate) synthesis ofhormone receptors. Fac-
tors such as animal condition and nutrition may play
a role in influencing receptor numbers. As you will
see later on, different honnones promote synthesis of
receptors to either themselves or other hormones. For
example, FSH promotes the synthesis ofLH receptors
by the follicular cells. The higher the degree to which
a cell is populated with receptors, the higher potential
for target cell responses.
Receptor affinity for hom1ones vary. In gen-
eral, the greater the affinity of the hom1one for the
receptor, the greater the biologic response .
Honnone agonists are analogs (having a simi-
lar molecular structure) that bind to the specific receptor
and initially cause the same biologic effect as the native
hormone. Some agonists promote greater physiological
activity because they have greater affinity for the hor-
mone receptor. Other analogs, called antagonists, have
greater affinity for the hormone receptor, but promote
weaker biologic activity than the native honnone. An-
tagonists decrease the response oftm·get cells by having
a weaker biological activity than the native honnone or
by occupying hormone receptors and thus preventing
the native hotmone from binding. In either case, the
antagonist interferes with native hmmone action.
Hormones disappear from the body
because they are metabolized and then
eliminated in the urine and feces.
Figure 5-16. Metabolism of
Progesterone and Testosterone
– Blood
I Progesterone I
Sod ium pregmmadiol
Urine
Blood Blood 1
I Sodium c t iocholanolonc sulf01te: I
+ Urine
The half-life of a hormone is determined by the
rate at which it is metabolized within the body. Rela-
tively rapid htrnover of a hom1one is es sential so that
the biologic action will not last for an undesired p eriod
of time. Bloo d concentrations of hormones not only
reflect the secretion rate by the various organs but the
rate at which the hormone is metabolized.
Steroids are Metabolized (inactivated) by the
Liver and Excreted in the Urine and Feces
The liver inactivates steroid molecules in two
ways. First, any double bond wi thin the steroid
molecule becomes saturated. When double bonds
are reduced, the molecule is rendered inactive. The
second change to the steroid molecu le is that a sulfate
or glucuronide residue is attached (See Fi gure 5- 16).
The glucuronide fom1 of the steroid molecule is water-
soluble and thus it can be excreted into the urine. This is
important because there are no specific binding proteins
to cany steroids into the bladder. The fact that steroid
metabolites appear in the urine is the basi s for testing
athletes for “illegal” perfonnance enhancing steroids .
The equation in Figure 5-1 6 illustrates the transforma-
tion that occurs in the progesterone mo lecule in the
liver and its excretion metabolites. Notice that a ll three
uns aturation sites (double bonds) in progesterone have
been reduced . Each steroid is metabolized in slightly
different ways and produces different metabolites. For
example, testosterone forms both a glucuronide (like
progesterone) and a sulfate salt that is excreted in the
urine (See Figure 5- 16).
Steroids are also elimi nated in the feces. It is
assumed that they enter the gu t through the bi le duct
in a conjugated fom1 (glucuronide or sulfate). They
are not digested per se in the gut. But, bacterial action
undoubtedly modifie s the fonn of the steroid prior to
defecation. T he amount of time that steroids (or their
conjugates) remain intact (stable) in feces has yet to be
completely defined. It is known that fecal concentra-
tions change after defecation as a func tion of bacterial
metabolism, and exposure to ultraviolet r adiation.
The specific type of steroid molecu le also impacts its
longevity in the gut and the feces . Endocrinologists rec-
ommend that fecal samples be collected and analyzed
within one day after defecation. The general pathway
of excretion/elimination of steroids fro m the body after
they are metabolized is presented in Figure 5- 17.
The presence of steroids in the feces is fortuitous
because it enables steroid concentrations in wi ld ani-
mals to be described without collecting blood samp les.
Much of our knowledge about the reproductive endocri-
nology of elephants and wild fe lids has been generated
by evaluating fecal samples (See Key References).
The potential importance of progesterone me-
tabolism involves the high produci ng dai1y cow. H igh
producing dairy cows (20,000 lbs or more of mi lk
per year) have significan tly larger livers than do low
producing dairy cows . One theory suggests that high
producing dairy cows may me tabolize progesterone
and even estradiol at a faster rate than their lower pro-
ducing contemporaries. Such rapid metabolism may
cause temporary sub-fertility because the uterus, during
early pregnancy, may not be capable of providing an
optimum environment fo r embryo survival (because
progesterone is low). Further research is needed to
validate thi s theory. Nevertheless, the rate of hormone
metabolism may be an important ingredient that gov-
erns fertility of the female in many species.
Nerves, Hormones and Target Tissues 119
Figure 5-17. Fate of Steroids
After Secretion
Steroid secreted by gonad
Steroid enters blood and
goes to target tissue
Steroid causes change in target tissue
(see Figure 5-14)
Steroid in blood passes through liver
Liver renders steroid H20 soluble
(glucuronides and sulfates)
t
Reenters blood and enters kidney
or enters bile
Excreted in urine and/or feces as
glucuronide or sulfate
Protein Hormones are Degraded in
the Liver and Kidneys
The half-life of pituitary gonadotropins is very
short and is between 20 and 120 minutes depending
on the hormone and species. Chorionic gonadotro-
pins (human chorionic gonadotropin-hCG and equine
chorionic gonadot:ropin-eCG) have longer half- lives
(hours to days) . This longer half- life h as practical
application because hCG and eCG have been used as
superovulation drugs in domestic animals because their
physiologic activity generally lasts a longer period of
V
et
B
oo
ks
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118 Nerves, Hormones and Target Tissues
Half-Life of a Hormone Determines
How Long It Will Act
Different honnones have different life expec-
tancies within the systemic circulation. The rate at
which the honnone is cleared from the circulation deter-
mines its half-life. The longer the half-life, the greater
the potential biological activity. Some hormones have
exceptionally short half-lives (seconds; e.g. PGF2a),
while other hormones have quite long half-lives (days;
e.g. eCG).
Hormonal potency is influenced by:
• receptor density
• hormone receptor affinity
The density of target tissue receptors varies
as a function of the cell type as well as the degree to
which hormones promote (up-regulate), or inhibit
(down-regulate) synthesis ofhormone receptors. Fac-
tors such as animal condition and nutrition may play
a role in influencing receptor numbers. As you will
see later on, different honnones promote synthesis of
receptors to either themselves or other hormones. For
example, FSH promotes the synthesis ofLH receptors
by the follicular cells. The higher the degree to which
a cell is populated with receptors, the higher potential
for target cell responses.
Receptor affinity for hom1ones vary. In gen-
eral, the greater the affinity of the hom1one for the
receptor, the greater the biologic response .
Honnone agonists are analogs (having a simi-
lar molecular structure) that bind to the specific receptor
and initially cause the same biologic effect as the native
hormone. Some agonists promote greater physiological
activity because they have greater affinity for the hor-
mone receptor. Other analogs, called antagonists, have
greater affinity for the hormone receptor, but promote
weaker biologic activity than the native honnone. An-
tagonists decrease the response oftm·get cells by having
a weaker biological activity than the native honnone or
by occupying hormone receptors and thus preventing
the native hotmone from binding. In either case, the
antagonist interferes with native hmmone action.
Hormones disappear from the body
because they are metabolized and then
eliminated in the urine and feces.
Figure 5-16. Metabolism of
Progesterone and Testosterone
– Blood
I Progesterone I
Sod ium pregmmadiol
Urine
Blood Blood 1
I Sodium c t iocholanolonc sulf01te: I
+ Urine
The half-life of a hormone is determined by the
rate at which it is metabolized within the body. Rela-
tively rapid htrnover of a hom1one is es sential so that
the biologic action will not last for an undesired p eriod
of time. Bloo d concentrations of hormones not only
reflect the secretion rate by the various organs but the
rate at which the hormone is metabolized.
Steroids are Metabolized (inactivated) by the
Liver and Excreted in the Urine and Feces
The liver inactivates steroid molecules in two
ways. First, any double bond wi thin the steroid
molecule becomes saturated. When double bonds
are reduced, the molecule is rendered inactive. The
second change to the steroid molecu le is that a sulfate
or glucuronide residue is attached (See Fi gure 5- 16).
The glucuronide fom1 of the steroid molecule is water-
soluble and thus it can be excreted into the urine. This is
important because there are no specific binding proteins
to cany steroids into the bladder. The fact that steroid
metabolites appear in the urine is the basi s for testing
athletes for “illegal” perfonnance enhancing steroids .
The equation in Figure 5-1 6 illustrates the transforma-
tion that occurs in the progesterone mo lecule in the
liver and its excretion metabolites. Notice that a ll three
uns aturation sites (double bonds) in progesterone have
been reduced . Each steroid is metabolized in slightly
different ways and produces different metabolites. For
example, testosterone forms both a glucuronide (like
progesterone) and a sulfate salt that is excreted in the
urine (See Figure 5- 16).
Steroids are also elimi nated in the feces. It is
assumed that they enter the gu t through the bi le duct
in a conjugated fom1 (glucuronide or sulfate). They
are not digested per se in the gut. But, bacterial action
undoubtedly modifie s the fonn of the steroid prior to
defecation. T he amount of time that steroids (or their
conjugates) remain intact (stable) in feces has yet to be
completely defined. It is known that fecal concentra-
tions change after defecation as a func tion of bacterial
metabolism, and exposure to ultraviolet r adiation.
The specific type of steroid molecu le also impacts its
longevity in the gut and the feces . Endocrinologists rec-
ommend that fecal samples be collected and analyzed
within one day after defecation. The general pathway
of excretion/elimination of steroids fro m the body after
they are metabolized is presented in Figure 5- 17.
The presence of steroids in the feces is fortuitous
because it enables steroid concentrations in wi ld ani-
mals to be described without collecting blood samp les.
Much of our knowledge about the reproductive endocri-
nology of elephants and wild fe lids has been generated
by evaluating fecal samples (See Key References).
The potential importance of progesterone me-
tabolism involves the high produci ng dai1y cow. H igh
producing dairy cows (20,000 lbs or more of mi lk
per year) have significan tly larger livers than do low
producing dairy cows . One theory suggests that high
producing dairy cows may me tabolize progesterone
and even estradiol at a faster rate than their lower pro-
ducing contemporaries. Such rapid metabolism may
cause temporary sub-fertility because the uterus, during
early pregnancy, may not be capable of providing an
optimum environment fo r embryo survival (because
progesterone is low). Further research is needed to
validate thi s theory. Nevertheless, the rate of hormone
metabolism may be an important ingredient that gov-
erns fertility of the female in many species.
Nerves, Hormones and Target Tissues 119
Figure 5-17. Fate of Steroids
After Secretion
Steroid secreted by gonad
Steroid enters blood and
goes to target tissue
Steroid causes change in target tissue
(see Figure 5-14)
Steroid in blood passes through liver
Liver renders steroid H20 soluble
(glucuronides and sulfates)
t
Reenters blood and enters kidney
or enters bile
Excreted in urine and/or feces as
glucuronide or sulfate
Protein Hormones are Degraded in
the Liver and Kidneys
The half-life of pituitary gonadotropins is very
short and is between 20 and 120 minutes depending
on the hormone and species. Chorionic gonadotro-
pins (human chorionic gonadotropin-hCG and equine
chorionic gonadot:ropin-eCG) have longer half- lives
(hours to days) . This longer half- life h as practical
application because hCG and eCG have been used as
superovulation drugs in domestic animals because their
physiologic activity generally lasts a longer period of
V
et
B
oo
ks
.ir

120 Nerves, Hormones and Target Tissues
time in-vivo than GnRH. Removal of polysaccharide
side chains (glycosylation sites) from gonadotropins
significantly reduces their half-life. Gonadotropin
molecules that have lost their glycosylation, bind to
liver cells, are internalized and degraded within the
cytoplasm of the liver cell. In addition to denaturation
in the liver, the kidneys likely play an important role in
elimination of glycoprotein hormones. For example,
glycoprotein hormones are significantly smaller than
typical serum glycoproteins. The glomerular filtra-
tion limit for molecules within the kidney is around
55,000 Daltons. Any glycoprotein horn1one that has
a molecular weight of less than 55,000 potentially can
be eliminated in the urine. Such is the case for human
chorionic gonadotropin.
Human chorionic gonadotropin at least in part is
filtered through the kidney and eliminated in the urine
thus providing an avenue for a rapid patient-side preg-
nancy test in women. It should be emphasized that oral
administration of protein hormones is not effective be-
cause these proteins are denahtred in the gastrointestinal
tract and lose their biologic potency because here they
are broken-down into amino acid fragments.
Hormones can be detected in blood,
saliva, milk, urine, lymph, tears, and
feces using radioimmunoassay (RIA)
and enzyme-linked immunosorbent
assay (ELISA) technology.
The radioimmunoassay (RIA) has revolution-
ized our understanding of endocrine physiology in al-
most all species of animals during the past 50 years. The
radioimmunoassay requires the use of radioactive hor-
mones. In the test tube, radioactive honnone competes
with the same hormone from an animal’s blood that is
not radioactively labeled. The amount of radioactive
honnone that binds is inversely proportional to the con-
centration of unlabeled honnone in the animal’s blood.
A detailed description of the RIA is beyond the scope
ofthis text (See Key References). Radioimmunoassay
technology requires specialized radioisotope-approved
laboratories, expensive isotope detection equipment and
the need for expensive disposal methods.
The RIA is being replaced by a more user-
friendly assay called the enzyme-linked immunosor-
bent assay (ELISA). The ELISA has provided many
convenient ways to detect and measure hormones. The
principle of the ELISA involves a series of steps de-
signed to determine the presence or absence of specific
hom1ones under a variety of conditions. The ELISA
can also determine the quantity of the hormone present
in a sample under more sophisticated laboratory condi-
tions. The major steps of the ELISA are described in
Figure 5-1 8.
The advantage of the ELISA over the RIA is
that no radioi sotopes are required, the test can be con-
ducted on-site with minimal training, it has no health/
safety hazard issues and it is relatively inexpensive.
One of the most s ucce ssful and popular applications of
the ELISA is a one-step, over-the-counter pregnancy
test for women. ELISA tests are also being used for
pregnancy detection in cows and bison. A more com-
plete description of the hormones of pregnancy will
be presented in Chapter 14. In addition to pregnancy
detection, ELISA has very widespread on-site use ,
ranging from detection of pathologic microorganisms
to environmental contaminants. It should be empha-
sized that there are many variations and biochemical
strategies used to produce ELISA system s. However,
the basic principle involved in all applications is the
use of a color-generating enzyme linked to a specific
antibody (See Figure 5-18).
For a summary of hormone class ification,
source and target tissues, refer to Table 5. 2 at the end
of the chapter.
Nerves, Hormones and Target Tissues 121
Figure 5-18. Use of the ELISA as a Method to Measure Hormones
Step 1: Two types of antibodies are required.
One antibody react s specifica lly with a
hormone (“hormone antibody”). A second
antibody reacts with the hormone-a ntibody
complex and this antibody has an enzyme
attached to it (“enzyme antibody”).
Step 2: The “hormone antibody” (a protein) is
tightly attached to a solid support surface.
Step 3: When the specific hormone
(usually a protein) is present in a solution,
it binds (“immunosorbent”) to the “hormone
antibody” and forms a hormone-antibody
complex.
Step 4: The “enzyme antibody” then reacts
against the hormone-antibody complex,
generating a larger antibody complex with
the enzyme component exposed to the
solution.
Step 5: After the “enzyme antibody” binds
to the original complex, a substrate is added
to the solution and the enzyme attached to
the “enzyme antibody” causes a color to
be generated. Generation of a color is the
basis for the ELISA system.
Enzyme antibody Hormone antibody
Reactio n – gene rates color
V
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120 Nerves, Hormones and Target Tissues
time in-vivo than GnRH. Removal of polysaccharide
side chains (glycosylation sites) from gonadotropins
significantly reduces their half-life. Gonadotropin
molecules that have lost their glycosylation, bind to
liver cells, are internalized and degraded within the
cytoplasm of the liver cell. In addition to denaturation
in the liver, the kidneys likely play an important role in
elimination of glycoprotein hormones. For example,
glycoprotein hormones are significantly smaller than
typical serum glycoproteins. The glomerular filtra-
tion limit for molecules within the kidney is around
55,000 Daltons. Any glycoprotein horn1one that has
a molecular weight of less than 55,000 potentially can
be eliminated in the urine. Such is the case for human
chorionic gonadotropin.
Human chorionic gonadotropin at least in part is
filtered through the kidney and eliminated in the urine
thus providing an avenue for a rapid patient-side preg-
nancy test in women. It should be emphasized that oral
administration of protein hormones is not effective be-
cause these proteins are denahtred in the gastrointestinal
tract and lose their biologic potency because here they
are broken-down into amino acid fragments.
Hormones can be detected in blood,
saliva, milk, urine, lymph, tears, and
feces using radioimmunoassay (RIA)
and enzyme-linked immunosorbent
assay (ELISA) technology.
The radioimmunoassay (RIA) has revolution-
ized our understanding of endocrine physiology in al-
most all species of animals during the past 50 years. The
radioimmunoassay requires the use of radioactive hor-
mones. In the test tube, radioactive honnone competes
with the same hormone from an animal’s blood that is
not radioactively labeled. The amount of radioactive
honnone that binds is inversely proportional to the con-
centration of unlabeled honnone in the animal’s blood.
A detailed description of the RIA is beyond the scope
ofthis text (See Key References). Radioimmunoassay
technology requires specialized radioisotope-approved
laboratories, expensive isotope detection equipment and
the need for expensive disposal methods.
The RIA is being replaced by a more user-
friendly assay called the enzyme-linked immunosor-
bent assay (ELISA). The ELISA has provided many
convenient ways to detect and measure hormones. The
principle of the ELISA involves a series of steps de-
signed to determine the presence or absence of specific
hom1ones under a variety of conditions. The ELISA
can also determine the quantity of the hormone present
in a sample under more sophisticated laboratory condi-
tions. The major steps of the ELISA are described in
Figure 5-1 8.
The advantage of the ELISA over the RIA is
that no radioi sotopes are required, the test can be con-
ducted on-site with minimal training, it has no health/
safety hazard issues and it is relatively inexpensive.
One of the most s ucce ssful and popular applications of
the ELISA is a one-step, over-the-counter pregnancy
test for women. ELISA tests are also being used for
pregnancy detection in cows and bison. A more com-
plete description of the hormones of pregnancy will
be presented in Chapter 14. In addition to pregnancy
detection, ELISA has very widespread on-site use ,
ranging from detection of pathologic microorganisms
to environmental contaminants. It should be empha-
sized that there are many variations and biochemical
strategies used to produce ELISA system s. However,
the basic principle involved in all applications is the
use of a color-generating enzyme linked to a specific
antibody (See Figure 5-18).
For a summary of hormone class ification,
source and target tissues, refer to Table 5. 2 at the end
of the chapter.
Nerves, Hormones and Target Tissues 121
Figure 5-18. Use of the ELISA as a Method to Measure Hormones
Step 1: Two types of antibodies are required.
One antibody react s specifica lly with a
hormone (“hormone antibody”). A second
antibody reacts with the hormone-a ntibody
complex and this antibody has an enzyme
attached to it (“enzyme antibody”).
Step 2: The “hormone antibody” (a protein) is
tightly attached to a solid support surface.
Step 3: When the specific hormone
(usually a protein) is present in a solution,
it binds (“immunosorbent”) to the “hormone
antibody” and forms a hormone-antibody
complex.
Step 4: The “enzyme antibody” then reacts
against the hormone-antibody complex,
generating a larger antibody complex with
the enzyme component exposed to the
solution.
Step 5: After the “enzyme antibody” binds
to the original complex, a substrate is added
to the solution and the enzyme attached to
the “enzyme antibody” causes a color to
be generated. Generation of a color is the
basis for the ELISA system.
Enzyme antibody Hormone antibody
Reactio n – gene rates color
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122 Nerves, Hormones and Target Tissues
Table 5-2. Summary of Reproductive Hormones
(Colors shown below are used in graphics throughout the book)
Name of
Hormone (Abbrev.)
Gonadotropin Releasing
H ormone (GnRH)
(L .l-1)
Follicle Stimulating
Hormone (FSH )
Prolactin (PRL)
Oxytocin (OT)
Progesterone (P.1)
Testosterone (T )
lnhibin
Prostaglandin Fza (PGFzu)
Relaxin (RLN or RLX)
Human chorionic
gonadotropin (hCG)
Equine chorionic
gonadotropin (eCG)
Placental lactogen
Biochemical Source
Classification
Neuropeptide
(decapeptidc)
Protein
Neuropeptide
(octapeptide)
Steroid
Stero id
Steroid
Glycop rote in
Prostaglandin
(C-20 fatty acid)
Protein Polypeptide
Glycoprotein
Glycoprotein
Protein
Hypothalamic surge and
tonic centers
Juu<:: (pi tuitl ls (mal <: ) Uterine endometrium, vesicular glands Corpus lutem, placenta prostate Trophoblast of bl astocyst (chorion) Chorionic girdle cells Placenta Male Target Tissue Ante ri or lobe-pituitary (gonndotroph cells) T':::.:ti:; sr;!b L:;ydigJ Testis (Scrto li cells) Testis an d brain Smooth muscle of epididymal tail, ductus deferens and ampulla Brain Inh ibits long bone growth Accessory sex glands tunica da rtos of scrotum, seminiferous epitheli um, skeletal muscle Gonacl otrophs of' anterior lobe-pituitary Epididymi s Sperm and male tract Nerves, Hormones and Target Tissues 123 Table 5-2. Summary of Reproductive Hormones Female Target Tissue Anterior lobe-p ituitary (gonadotroph cell s) 0 vw:y ( o.f int:;rm! and lwt':::!.il v:::!l:.:J Ovary (gra nulosa! ce lls) Mammary cells, corpus luteum in some species (rat and mouse) My ometrium and endo- metrium of utems , myoepithelia l cells of mammary gland Hypothalamus, enti re re productive tract and mamma ry g land Uterine endometrium. mammary gla nd . myometrium. hypoth;J lai;lUS Bra in, skeleta l muscle, granulosa! cells Gonuclotrophs or anterior lobe-p ituitary Corpus luteum, uterine myometrium, ovu latory follicles Pelvic ligaments, cervix, mammary gland, nipples Ovary Ovary Mammary gland of dam Male Primary Action Re lease of FSI-l and Ll-l f-i·om anterior lobe-pitui tary .::; tiw ul!:.! te:; tu:; t<::rone prudusti'JIJ Sertoli cel l runction Can induce maternal behavior in fe ma les and males PG F 2" synthesis and pre-ejaculatory movement of spernmtozoa Sexual behavior Anabolic growth, promotes spermato- genesis, promotes secretion of accessory sex glands Inhibits FSI-l secretion Affects metabolic activity of spermatozoa, causes epididymal contractions Sperm motility, trac t growth Female Primary Action Re lease of FSI-1 and LH from anterior lobe-pituitary :::timu!ate:.: fommtiun uf wrpvn:1 Jutea ami 3er:;retiun fol licu lar cle\'clopmcnt and estrad iol sy nt hesis Lactation, maternal behavior and corpora lutea function (some species) Uterine motility, promotes uterine PGF2u synthesis, milk ejection Sexua l behavior, GnRH, eleva ted secretory activ ity of the entire tract. enhanced uterine moti lity - Enclometri;J \ secretion. inhib its GnR I-[ rckase, inhibits repro- ductive behavior. promotes ma intenance or pregnancy Substrate for E2 synthes is, abnorn1al mascu linization (hair patterns, voice, behavior, etc .) Inh ibits FSI-I secretion Luteolysis, promotes uterine tone and contraction, ovulation Softening of pelvic ligaments, cervix, connec tive tissue remodeling in tract Facilitate production of progesterone by ovary Causes formation of accessory corpora lutea Mammary stimulation of dam V et B oo ks .ir 122 Nerves, Hormones and Target Tissues Table 5-2. Summary of Reproductive Hormones (Colors shown below are used in graphics throughout the book) Name of Hormone (Abbrev.) Gonadotropin Releasing H ormone (GnRH) (L .l-1) Follicle Stimulating Hormone (FSH ) Prolactin (PRL) Oxytocin (OT) Progesterone (P.1) Testosterone (T ) lnhibin Prostaglandin Fza (PGFzu) Relaxin (RLN or RLX) Human chorionic gonadotropin (hCG) Equine chorionic gonadotropin (eCG) Placental lactogen Biochemical Source Classification Neuropeptide (decapeptidc) Protein Neuropeptide (octapeptide) Steroid Stero id Steroid Glycop rote in Prostaglandin (C-20 fatty acid) Protein Polypeptide Glycoprotein Glycoprotein Protein Hypothalamic surge and tonic centers Juu<:: (pi tuitl ls (mal <: ) Uterine endometrium, vesicular glands Corpus lutem, placenta prostate Trophoblast of bl astocyst (chorion) Chorionic girdle cells Placenta Male Target Tissue Ante ri or lobe-pituitary (gonndotroph cells) T':::.:ti:; sr;!b L:;ydigJ Testis (Scrto li cells) Testis an d brain Smooth muscle of epididymal tail, ductus deferens and ampulla Brain Inh ibits long bone growth Accessory sex glands tunica da rtos of scrotum, seminiferous epitheli um, skeletal muscle Gonacl otrophs of' anterior lobe-pituitary Epididymi s Sperm and male tract Nerves, Hormones and Target Tissues 123 Table 5-2. Summary of Reproductive Hormones Female Target Tissue Anterior lobe-p ituitary (gonadotroph cell s) 0 vw:y ( o.f int:;rm! and lwt':::!.il v:::!l:.:J Ovary (gra nulosa! ce lls) Mammary cells, corpus luteum in some species (rat and mouse) My ometrium and endo- metrium of utems , myoepithelia l cells of mammary gland Hypothalamus, enti re re productive tract and mamma ry g land Uterine endometrium. mammary gla nd . myometrium. hypoth;J lai;lUS Bra in, skeleta l muscle, granulosa! cells Gonuclotrophs or anterior lobe-p ituitary Corpus luteum, uterine myometrium, ovu latory follicles Pelvic ligaments, cervix, mammary gland, nipples Ovary Ovary Mammary gland of dam Male Primary Action Re lease of FSI-l and Ll-l f-i·om anterior lobe-pitui tary .::; tiw ul!:.! te:; tu:; t<::rone prudusti'JIJ Sertoli cel l runction Can induce maternal behavior in fe ma les and males PG F 2" synthesis and pre-ejaculatory movement of spernmtozoa Sexual behavior Anabolic growth, promotes spermato- genesis, promotes secretion of accessory sex glands Inhibits FSI-l secretion Affects metabolic activity of spermatozoa, causes epididymal contractions Sperm motility, trac t growth Female Primary Action Re lease of FSI-1 and LH from anterior lobe-pituitary :::timu!ate:.: fommtiun uf wrpvn:1 Jutea ami 3er:;retiun fol licu lar cle\'clopmcnt and estrad iol sy nt hesis Lactation, maternal behavior and corpora lutea function (some species) Uterine motility, promotes uterine PGF2u synthesis, milk ejection Sexua l behavior, GnRH, eleva ted secretory activ ity of the entire tract. enhanced uterine moti lity - Enclometri;J \ secretion. inhib its GnR I-[ rckase, inhibits repro- ductive behavior. promotes ma intenance or pregnancy Substrate for E2 synthes is, abnorn1al mascu linization (hair patterns, voice, behavior, etc .) Inh ibits FSI-I secretion Luteolysis, promotes uterine tone and contraction, ovulation Softening of pelvic ligaments, cervix, connec tive tissue remodeling in tract Facilitate production of progesterone by ovary Causes formation of accessory corpora lutea Mammary stimulation of dam V et B oo ks .ir 124 Nerves, Hormones and Target Tissues Further PHENOMENA for Fertility In the 19th century, French doctors reported that the eating of frog legs by French soltliers in Nm·th Africa caused hvo outbreaks of priapism (painful and prolonged penile erection). The attending physicians noted that the symptoms amongst the soldiers resembled those seen in men who had overimlulged in a drug called cantharidin (popularly known as ''Spanish Fly''). This material is extracted from a beetle fol' its purported value as an aphrodisiac. One of the attending French physicians dissected a local frog and discove1·ed that its gut was full of beetles that produced cantharidin. Recently, researchers have shown that frogs eating this beetle have levels of cantharidin in their thigh muscles that are high enough to cause human priapism. The word pituitary is derived from the Latin word "pituita" that means mucus. The existence of the pituitary gland was recognized as early as 200 AD. It was thought to be a mucus-secreting organ for lubrication of the throat. Mucus from the pituitary was thought to be transported into the nose and then into the nasophmynx where it could lubricate the throat. The dramatic effects of male castration have been recognized for over 2,000 years. The testis was known to control virility and sterility. Castration was always (and still is) regarded as a catastrophic e11ent. However, it was deemed useful under certain sets of conditions such as generating guardians for harems and male singers with high pitched voices. The scientific discipline of endocrinology originated from a belief in "organ magic." Consumption of human or animal organs was thought to increase powers or cure ailments. For example, warriors thought that eating the hearts of their enemy increased their courage. Eating the thyroids of sheep was thought to improve the intelligence of the mentally chal- lenged; liver from wolves cured liver ailments; brain from rabbits cured nervousness and fox lungs cured respiratmy disorders. Throughout recorded history sex gland consumption was believed to increase sexual prowess. As early as 1400 BC, Hindus prescribed testicular tissue for male impotence. The "birthday" of modem en- docrinology was stimulated by the famous report of Brown-Sequard who injected himself with testicular e.:'Ctracts. The aging Brown-Sequard reported in1889 that these extracts reversed the effects of age, made him feel significantly more vigorous and corrected his failing memmy. His report, even though erroneous, prompted a rush of "gland treatments" by the medical profession of the day. Brown-Sequard's error stimulated careful scrutiny by scientists and physicians. This scientific scrutiny led to the development of modem endocrinology. The leading cause of death in the early 1900's in young women was childbirth ... they bled to death. The discovery that an extmct from the brain caused uterine contractions and reduced uterine blood flow was a major breakthrough. It was soon discovered that the brain extmct was o>.:ytocin. It was and still is administered
to women to prevent bleeding during childbirth
as well as to enhance uterine contractions for
e..’.:ytocin. It was and still is administered
to women to prevent bleeding during childbirth
as well as to enhance uterine contractions for
e..’ ·.;:;
111
CJ a:
Male
\ i\’N/1\W,\
0 1 .. 6 0 10 111 ,·.. 16 ,o 20 22 2-t 26 20 30 32 3-t 36 38 <4 Time (days) Males have small LH episodes that occur every 2 to 6 hours. Testosterone is se- creted soon after each LH episode. avai lable to be ejaculated. To determine preci sely w hen the first spermatozoa are availab le, one must col- lect ejaculates at least once per week. This is relative ly t.o do, ejaculates can be collected by an artificial vagma from the boar, bull, dog, ram or stal- lion. After behavioral characteristics have developed and the male is willing to mount a receptive female (or surrogate female), frequent seminal collections can be made. This enables determi nation of the age at which spermatozoa appear in the ejaculate. Age when the ejaculate contains a thresh- old of spet·matozoa . Even t h ough an eJaculate may con tain spe rm atozoa, th ere may be in s ufficien t n u mbers for fe rtil iz at io n . Therefore, the presence of a thresho ld (mi nimu m number) of spermatozoa is required. These thresho lds vary among species. In general, they reflect minimum seminal characteristics required to achieve pregnancy copulation. From a practical viewpoint, th is the most valid criterion for puberty in the m ale since It defines the ability of the male to provide enough spermatozoa for successful ferti lization. .. c 0 E ... "' o-.... >-‘ .. ..
-.;
a:
..
c
0
E … “‘ o-
.. ..
>-‘ ·z ..
-.;
a:
LH LH
LH
LH LH
LH
I l
·······:··················································El
o 2 4 6 a to 12 14 t6 to 20 n 2 ..
Time (hours)
Male
LH LH
Ail\
0 2 6 B 10 12 H 16 1B 20 22 2-4
T ime (hours)
The female must reach a threshold
body size before puberty can
be achieved.
The age at puberty varies amono and within
• 1:>
species. This var iat ion is sum marized in Tab les 6 – 1
and 6 -2. The factors con h·ibuting to the variatio n in
p ubertal o nset consti tute the d iscussion in the remain-
der of this chapter.
At least two general fac tors impact the de-
velopment o f the hypothalamic GnRH neurons in the
They are: 1) development of a threshol d body
size and/or composition and 2 ) exposure to certain
environmental or social cues.
Certain extemal or social factors influ-
ence the onset ofpuberty in the female.
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6
128 Puberty
Figure 6-1. Alpha Fetoprotein
(a-FP) and the Blood Brain Barrier
In the female, a-FP prevents E2 from entering
the brain. The hypothalamus is thus “femi-
nized” and the surge center develops .
In the male, Testosterone freely enters the
brain because a-FP does not bind it. Testoster-
one is aromatized into estradiol and the male
brain is “defeminized”. Therefore, a GnRH
surge center does not develop.
Male
GnRI-I neurons. In other words, the limiting factor for
pubertal onset appears to be the ability of presynaptic
neurons to transmit information to GnRH neurons so
that GnRH secretion will increase. Function of these
presynaptic neurons may be influenced by: 1) plane
of nutrition, 2) exposure to certain environmental or
social cues and 3) the genetics ofthe individual.
The Onset of Puberty has Many
Definitions in Females
Several criteria can be used to define puberty
in the female. Some examples are presented below.
Age at first estrus (heat). This is the age that
the female becomes sexually receptive and displays
her first estrus. The age at first estrus is relatively
easy to detennine because females show outward be-
havioral signs of sexual receptivity, especially in the
presence of the male. The firs t ovulation generally is
not accompanied by behavioral estrus in heifers and
ewes. This has been termed “silent ovulation.” Thus,
the age at first estrus may not reflect true acquisition
of puberty.
Age at first ovulation. This is the age when
the first ovulation occurs. To determine this critically,
manual or visual validation is required. This can be
accomplished using palpation or ultrasonography of
the ovary per rectum in animals. Also, laparoscopy
and endoscopy can be used to determine when ovula-
tion has occured. All ofthe above techniques require
frequent observations of the ovary to determine
precisely when ovulation occurred. Thus, although
age at ovulation is a good criterion for puberty, it is
difficult to detem1ine.
Age at which a female can support preg-
nancy without deleterious effects. This definition
is most applicable from a practical standpoint in all
domestic animals and humans.
The Onset of Puberty has Many
Definitions in Males
As in the female , the onset of puberty in the
male can be defined in several ways.
Age when behavioral traits are expressed.
Generally, males of most species acquire reproductive
behavioral h·aits (mounting and erection) well before
they acquire the ability to ejaculate and p roduce sper-
matozoa. These behavioral traits are relatively easy
to detennine since mounting behavior and erection of
the penis can be observed readily.
Age at first ejaculation. The process of
ejaculation is quite complex and requires closely
coordinated development of nerves , specific muscles
and secretion of seminal fluids from the accessory
sex glands . When development of all these compo-
nents occurs, ejaculation can take place. Generally,
the ability to ejaculate substantially precedes the
ability to produce sufficient spennatozoa to achieve
fertilization.
Age when spermatozoa first appear in the
ejaculate. The male acquires the ability to produce
seminal fl uid and to ejaculate before spermatozoa are
Puberty 129
Figure 6-2. Females and Males are Quite Different in Their LH
Secretory Pattern
Females have high amplitude preovula-
tory episodes of LH once every several
weeks and basal pulsatile episodes be-
tween the large preovulatory surges. I Female J
I Female j LH
“‘ E, LH E,
” E.:l :.LH
.··’/\ .• I g i \ I
… · \ … . …… ../ \ …. ……. . .
0 20 ..
> ·.;:;
111
CJ a:
Male
\ i\’N/1\W,\
0 1 .. 6 0 10 111 ,·.. 16 ,o 20 22 2-t 26 20 30 32 3-t 36 38 <4 Time (days) Males have small LH episodes that occur every 2 to 6 hours. Testosterone is se- creted soon after each LH episode. avai lable to be ejaculated. To determine preci sely w hen the first spermatozoa are availab le, one must col- lect ejaculates at least once per week. This is relative ly t.o do, ejac ulates can be collected by an artificial vagma from the boar, bull, dog, ram or stal- lion. After behavioral characteristics have developed and the male is willing to mount a receptive female (or surrogate female), frequent seminal collections can be made. This enables determi nation of the age at which spermatozoa appear in the ejaculate. Age when the ejaculate contains a thresh- old of spet·matozoa . Even t h ough an eJaculate may con tain spe rm atozoa, th ere may be in s ufficien t n u mbers for fe rtil iz at io n . Therefore, the presence of a thresho ld (mi nimu m number) of spermatozoa is required. These thresho lds vary among species. In general, they reflect minimum seminal characteristics required to achieve pregnancy copulation. From a practical viewpoint, th is the most valid criterion for puberty in the m ale since It defines the ability of the male to provide enough spermatozoa for successful ferti lization. .. c 0 E ... "' o-.... >-‘ .. ..
-.;
a:
..
c
0
E … “‘ o-
.. ..
>-‘ ·z ..
-.;
a:
LH LH
LH
LH LH
LH
I l
·······:··················································El
o 2 4 6 a to 12 14 t6 to 20 n 2 ..
Time (hours)
Male
LH LH
Ail\
0 2 6 B 10 12 H 16 1B 20 22 2-4
T ime (hours)
The female must reach a threshold
body size before puberty can
be achieved.
The age at puberty varies amono and within
• 1:>
species. This var iat ion is sum marized in Tab les 6 – 1
and 6 -2. The factors con h·ibuting to the variatio n in
p ubertal o nset consti tute the d iscussion in the remain-
der of this chapter.
At least two general fac tors impact the de-
velopment o f the hypothalamic GnRH neurons in the
They are: 1) development of a threshol d body
size and/or composition and 2 ) exposure to certain
environmental or social cues.
Certain extemal or social factors influ-
ence the onset ofpuberty in the female.
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130 Puberty
Table 6·1. Mean Age (Range) of Puberty in Males
and Females of Various Species
Sgecies Male Female
Alpaca2 2-3 yrs 1 yr
Bovine 11 mo (7-18) 11 mo (9-24)
CameF 3-5 yrs 3 yrs
Canine1 9 mo (5-12) 12 mo (6-24)
Equine 14 mo (10-24) 18 mo (12-19)
Feline 9 mo (8-10) 8 mo (4-12)
Llama2 2-3 yrs 6-12 mo
Ovine 7 mo (6-9) 7 mo (4-14)
Porcine 7 mo (5-8) 6 mo (5-7)
1 Very breed dependent – See Johnston et a/. in
Key References.
2 See Tibary and Anouassi in Key References.
As far as we know, all female mammals must
acquire a certain body size before the onset of puberty
can be initiated. A current hypothesis contends that
the female must develop a certain degree of”fatness”
before reproductive cycles can be initiated. The re-
lationship between metabolic status and function of
GnRI-I neurons has not been completely described,
but there is good evidence that metabolic signals affect
GnRH secretion.
Several external factors modulate the timing
of puberty and these vary significantly among species.
These factors include: I) season during which the ani-
mal is born (sheep); 2) the photoperiod that the animal
is experiencing during the onset of puberty (sheep); 3)
the presence or absence of the opposite sex during the
petipubertal period (swine and cattle) and 4) the density
ofthe groups (within the same sex) in which the animals
are housed (swine). Almost certainly, similar external
factors impact puberty in humans but these have not
been shtdied intensively. Whatever the species-specific
factor( s) may be, they affect the secretion of GnRI-I.
Genetics (breed) influence age at puberty.
The breed of the animal has an important in-
fluence on the age at which puberty is attained in both
the male and the female. For example, dairy heifers
reach puberty at around 7 to 9 months of age while
British beef breeds reach puberty between 12 and 13
months. Bas indicus breeds may not reach puberty
until 24 months of age. Table 6-2 summarizes the
influence of breed on age of puberty in cattle, swine,
sheep and dogs.
Table 6-2. Influence of Breed on Age at Puberty
in Domestic Animals
Sgecies Averaj,!e Al,!e at (Months}
Female Male
Cattle
Holstein 8 9
Brown Swiss 12 9
Angus 12 10
Hereford 13 11
Brahman 19 17
Dogs
Border Collie 9
Bloodhound 12
Whippet 18
Sheeg
Rambou illet 9
Finnish Land race 8
Swine
Meishan 3 3
Large White 6 6
Yorkshire 7 7
How Do the Hypothalamic GnRH Neurons
Acquire the Ability to Release GnRH
in High Frequency Pulses?
It has been well established that the onset of
puberty is not limited by the potential performance
of the gonads or the anterior lobe of the pih1itary. For
example, the anterior lobe of the pituitary of the pre-
pubettal animal w ill secrete FSH and LH if stimulated
by exogenous GnRH. Also, the ovaries of prepubertal
females will respond by producing follicles and estra-
diol when stimulated with FSH and LI-I. The major
factor limiting onset of puberty is the failure of the
hypothalamus to secrete sufficient quantities of GnRH
to cause gonadotropin release.
The developing hypothalamus can be compared
to a rheostatically controlled switch for a lighting sys-
tem. As the rheostatically controlled switch is gradu-
ally hirned up, the lights in the room gradually become
brighter and brighter until they reach full intensity.
Likewise, the development of the hypothalamus oc-
curs in a gradual fashion during growth of the animal,
rather than suddenly, like an on-off switch. The fa ctors
that cause the rheostatically controlled switch (hypo-
thalamus) to tum on completely will be described in
subsequent sections of this chapter.
As you have read previously in Chapter 5, the
hypothalamus contains a tonic GnRH center and a
preovulatory GnRH center (surge center). Before
ovulation can occur, full neural activity of the surge
center must be achieved (See Figure 6-3). Such an
activity results in sudden bursts of GnRH known as
the preovulatory GnRH surge. In other words, the
GnRH neurons must fi re frequently and release large
quantities of GnRH in order to cause the preovulatory
LH surge (See Figure 6-3). As you will soon discover
in Chapter 8 the preovu latory GnRI-I surge is a series
of rapid, high amplih1de pulses. Inability of the surge
center to fun ction results in ovulation fai lure. In ad-
dition to the need to have a fu nctional surge center in
the fema le, the tonic center must also reach a certain
functional state. The tonic GnRH center regulates the
pulse frequency of GnlU-1.
Even though the neurons in the surge
center in prepubertal females are sensi-
tive to estradiol, they cannot secrete much
GnRH because estradiol is too low.
Puberty 131
The prepubertal fe male is characterized by hav-
ing a lack of gonadal estradiol to stimulate the surge cen-
ter. T he surge center is capable of functioning at a very
early age when experimentally stimulated. However,
under normal conditions it remains relative ly inactive
unti l puberty. For example, in the prepubertal female ,
the tonic GnRI-1 center stimulates LH pu lses from the
anterior lobe of the pih1itary. The amplitude of these
LH pulses can be as great as those of the postpubertal
fe male . However, the frequency of the GnRH pulses
in the prepubertal fe male is much lower than the fre-
quency ofGnRH pulses in the postpubertal female ( See
Figures 6-3 and 6-4). Prior to puberty, low-frequency
GnRH pulses provide insufficient stimuli to cause the
anterior lobe of the pituitary to release FSH and LI-I at
high levels. Therefore, fo ll icular deve lopment (even
though it does occur before puberty), cannot result in
high circulating esh·adiol concentrations. Estradio l
therefore remains below the minimum tlu-eshold that
is necessary to trigger fi ring of GnRH neurons in the
surge center.
Figure 6-3. Changes in Hypothalamic Secretion of GnRH
Before and After Puberty
I Before Puberty I
,_ )
Cftrt” J
“‘
CJ
>
CJ …..
J:
a:
c
!.’
CJ
> …
10 l:lfiiml Qj
a: 0 10 20
Days
Before puberty in both the fema le and
male, GnRH neurons in the ton ic center
and the surge center of the hypotha la-
mus release low amplitude and low
frequency pulses of G n RH.
!!
CJ
>
CJ …..
J:
a:
c
!.’
C)
.:: …
10
C)
a: 0
I After Puberty I
I
10
Days
20
‘GnRH
30
After puberty in the female, the ton ic center co n-
trols basa l levels of GnRH, but they are hig her
than in the prepubertal fema le because the pu lse
freque ncy increases. The surge center controls
t he p reovulatory surge of GnRH. T he male does
not develop a su rge center.
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130 Puberty
Table 6·1. Mean Age (Range) of Puberty in Males
and Females of Various Species
Sgecies Male Female
Alpaca2 2-3 yrs 1 yr
Bovine 11 mo (7-18) 11 mo (9-24)
CameF 3-5 yrs 3 yrs
Canine1 9 mo (5-12) 12 mo (6-24)
Equine 14 mo (10-24) 18 mo (12-19)
Feline 9 mo (8-10) 8 mo (4-12)
Llama2 2-3 yrs 6-12 mo
Ovine 7 mo (6-9) 7 mo (4-14)
Porcine 7 mo (5-8) 6 mo (5-7)
1 Very breed dependent – See Johnston et a/. in
Key References.
2 See Tibary and Anouassi in Key References.
As far as we know, all female mammals must
acquire a certain body size before the onset of puberty
can be initiated. A current hypothesis contends that
the female must develop a certain degree of”fatness”
before reproductive cycles can be initiated. The re-
lationship between metabolic status and function of
GnRI-I neurons has not been completely described,
but there is good evidence that metabolic signals affect
GnRH secretion.
Several external factors modulate the timing
of puberty and these vary significantly among species.
These factors include: I) season during which the ani-
mal is born (sheep); 2) the photoperiod that the animal
is experiencing during the onset of puberty (sheep); 3)
the presence or absence of the opposite sex during the
petipubertal period (swine and cattle) and 4) the density
ofthe groups (within the same sex) in which the animals
are housed (swine). Almost certainly, similar external
factors impact puberty in humans but these have not
been shtdied intensively. Whatever the species-specific
factor( s) may be, they affect the secretion of GnRI-I.
Genetics (breed) influence age at puberty.
The breed of the animal has an important in-
fluence on the age at which puberty is attained in both
the male and the female. For example, dairy heifers
reach puberty at around 7 to 9 months of age while
British beef breeds reach puberty between 12 and 13
months. Bas indicus breeds may not reach puberty
until 24 months of age. Table 6-2 summarizes the
influence of breed on age of puberty in cattle, swine,
sheep and dogs.
Table 6-2. Influence of Breed on Age at Puberty
in Domestic Animals
Sgecies Averaj,!e Al,!e at (Months}
Female Male
Cattle
Holstein 8 9
Brown Swiss 12 9
Angus 12 10
Hereford 13 11
Brahman 19 17
Dogs
Border Collie 9
Bloodhound 12
Whippet 18
Sheeg
Rambou illet 9
Finnish Land race 8
Swine
Meishan 3 3
Large White 6 6
Yorkshire 7 7
How Do the Hypothalamic GnRH Neurons
Acquire the Ability to Release GnRH
in High Frequency Pulses?
It has been well established that the onset of
puberty is not limited by the potential performance
of the gonads or the anterior lobe of the pih1itary. For
example, the anterior lobe of the pituitary of the pre-
pubettal animal w ill secrete FSH and LH if stimulated
by exogenous GnRH. Also, the ovaries of prepubertal
females will respond by producing follicles and estra-
diol when stimulated with FSH and LI-I. The major
factor limiting onset of puberty is the failure of the
hypothalamus to secrete sufficient quantities of GnRH
to cause gonadotropin release.
The developing hypothalamus can be compared
to a rheostatically controlled switch for a lighting sys-
tem. As the rheostatically controlled switch is gradu-
ally hirned up, the lights in the room gradually become
brighter and brighter until they reach full intensity.
Likewise, the development of the hypothalamus oc-
curs in a gradual fashion during growth of the animal,
rather than suddenly, like an on-off switch. The fa ctors
that cause the rheostatically controlled switch (hypo-
thalamus) to tum on completely will be described in
subsequent sections of this chapter.
As you have read previously in Chapter 5, the
hypothalamus contains a tonic GnRH center and a
preovulatory GnRH center (surge center). Before
ovulation can occur, full neural activity of the surge
center must be achieved (See Figure 6-3). Such an
activity results in sudden bursts of GnRH known as
the preovulatory GnRH surge. In other words, the
GnRH neurons must fi re frequently and release large
quantities of GnRH in order to cause the preovulatory
LH surge (See Figure 6-3). As you will soon discover
in Chapter 8 the preovu latory GnRI-I surge is a series
of rapid, high amplih1de pulses. Inability of the surge
center to fun ction results in ovulation fai lure. In ad-
dition to the need to have a fu nctional surge center in
the fema le, the tonic center must also reach a certain
functional state. The tonic GnRH center regulates the
pulse frequency of GnlU-1.
Even though the neurons in the surge
center in prepubertal females are sensi-
tive to estradiol, they cannot secrete much
GnRH because estradiol is too low.
Puberty 131
The prepubertal fe male is characterized by hav-
ing a lack of gonadal estradiol to stimulate the surge cen-
ter. T he surge center is capable of functioning at a very
early age when experimentally stimulated. However,
under normal conditions it remains relative ly inactive
unti l puberty. For example, in the prepubertal female ,
the tonic GnRI-1 center stimulates LH pu lses from the
anterior lobe of the pih1itary. The amplitude of these
LH pulses can be as great as those of the postpubertal
fe male . However, the frequency of the GnRH pulses
in the prepubertal fe male is much lower than the fre-
quency ofGnRH pulses in the postpubertal female ( See
Figures 6-3 and 6-4). Prior to puberty, low-frequency
GnRH pulses provide insufficient stimuli to cause the
anterior lobe of the pituitary to release FSH and LI-I at
high levels. Therefore, fo ll icular deve lopment (even
though it does occur before puberty), cannot result in
high circulating esh·adiol concentrations. Estradio l
therefore remains below the minimum tlu-eshold that
is necessary to trigger fi ring of GnRH neurons in the
surge center.
Figure 6-3. Changes in Hypothalamic Secretion of GnRH
Before and After Puberty
I Before Puberty I
,_ )
Cftrt” J
“‘
CJ
>
CJ …..
J:
a:
c
!.’
CJ
> …
10 l:lfiiml Qj
a: 0 10 20
Days
Before puberty in both the fema le and
male, GnRH neurons in the ton ic center
and the surge center of the hypotha la-
mus release low amplitude and low
frequency pulses of G n RH.
!!
CJ
>
CJ …..
J:
a:
c
!.’
C)
.:: …
10
C)
a: 0
I After Puberty I
I
10
Days
20
‘GnRH
30
After puberty in the female, the ton ic center co n-
trols basa l levels of GnRH, but they are hig her
than in the prepubertal fema le because the pu lse
freque ncy increases. The surge center controls
t he p reovulatory surge of GnRH. T he male does
not develop a su rge center.
V
et
B
oo
ks
.ir

132 Puberty
18
16 –
14
‘Ui’
Q)
..!!! 12
:I
Q. -C’i 10
c
Q)
:I 8
C'”
Q)
I..
LL
Q)
6
Ul
“3 4 D..
::r:
…I 2
Figure 6-4. LH Frequency
Before and After Puberty
Before After
Puberty Puberty
JUl
LH —
-5 -4 -3 -2 0 2 3
Months Before and After Puberty
Frequency of LH pulses (as a reflection of
GnRH pulses) in heifers prior to the onset of
puberty. Note the substantial time required
(approximately 2 months-shaded area) for
the pulse frequency to become high enough
for puberty to be achieved. The variation in
LH pulse frequency after puberty reflects the
changes occurring during the estrous cycle.
(Modified from Kinder eta/. 1994)
In the male, the onset of puberty is
brought about because of decreased hy-
pothalamic sensitivity to negative
feedback by testosterone/estradiol.
As you recall from Chapter 5, the secretion of
GnRH from neurons in the surge center and the tonic
center is controlled by positive and negative feedback
to gonadal steroids. Puberty will be initiated when
GnRI-1 neurons can respond completely to positive
and negative feedback. Understanding the acquisi-
tion of this ability is the key to understanding how
the onset of puberty occurs. We know that GnRH
neurons are similar in number, funct ion and distribu-
tion within the hypothalamus in both the male and the
female. We also know that the endocrine profiles of
males and females are quite different after puberty
(See Figure 6-2).
As described earlier in this chapter, the male
does not develop a surge center because the hypothala-
mus is completely defeminized shortly before or after
birth. Thus, the male has a very simple feedback system
after puberty. It involves a negative feedback loop only.
You should recognize that the negative feedback in the
male is due to some testosterone and most ly to estradiol
because testosterone is converted to estTadiol within
the brain by aromatization (See Figure 6-1 ). In the
male the GnRH neurons become less and less sensitive
to the negative feedback of testosterone and estradiol
as puberty approaches. This means larger and larger
quantities of testosterone and estradiol are needed to
inhibit the GnRI-1 neurons. With this decreased sensitiv-
ity to the negative feedbac k of testosterone/ estradiol,
the hypothalamus can secrete more and more GnRH
and thus more and more LI-1/ FSH to stim ulate the testis
and stimulate puberty.
In the prepubertal female, the
surge center is quite sensitive to the
positive feedback of estradiol. But,
the surge center cannot release
“ovulatory quantities” ofGnRH
because the ovmy cannot secrete
high levels of estradiol.
From a functional perspective, the surge center
responds primarily t o a posi t ive feedback stimulus.
For example, the prepubertal female does not ovulate
although the sensitivity of the surge center to positive
feedback by estradiol is quite high. Failure to ovulate
occurs because the ovaries do not secrete enough es-
tradiol to activate the highly sensitive surge center. In
a sense, the surge center lies ” dormant” in the prepu-
bertal female even though it is capable of responding
to estradiol. The reason that it lies “dormant” is that
the prepubertal ovruy does not secrete sufiicient quanti-
ties of estradiol to stimulate the surge center to secrete
high amplitude pulses ofGnRH. At low concentrations
of estradiol, the tonic center has a high sensitivi ty to
negative feedback and therefore does not secrete high
levels ofGnRH and gonadotropins remain low. During
the pubertal transition, however, the negative feedback
sensitivity by the tonic center to estradiol decreases and
consequently higher and higher amounts ofGnRH are
secreted causing an increase in pulse frequenc y of LH.
This elevated pulse frequency stimulates the ovary to
secrete more and more estradiol. When estradiol con-
centrations reach a certain threshold, it now causes a
massive discharge ofGnRH from the surge center (posi-
tive feedba ck) . Ovulation can take place and puberty
follows. It should be emphasized that the sensitivity of
the surge center to positive fe edback changes ve1y little
and remains high even be fore birth. It is the sensitiv-
ity to negative feedb ack that is decreased and triggers
the onset of puberty in the fem ale. T he decreased
sensitivity to negative feedback by the tonic center
means that smaller and smaller q uan tities o f estrad io l
can stimulate the release o f GnRH and thus LI-1 and
FSH are secreted. These gonado tro pins then st imulate
more follicles and more and more estradio l is secreted
until finally the surge center releases the preovulato ry
surge of GnRH.
A Certain Degree of “Fatness”
is Required for the Onset of Puberty
in the Female
The priority fo r the neonate is to use its energy
towards maintenance o f vital p hys iolog ic func tions.
Therefore, nonessent ial processes suc h as reprod uc-
tion are of low prior ity. A s the neo na te beg ins to
grow, energy consumption increases, its body m ass
becomes larger and the relative surface area of the body
decreases . This al lows a shift in the metaboli c exp en-
diture so that nonvital p hysio lo g ical functions begin to
develop. As this shift occurs, the overa ll metabo lic rate
Puberty 133
decreases and more in temal energy becomes avai la ble
for nonvital fu nctions . T his excess intem al energy
can be converted into fat stores and the yo ung animal
begins to place pr iority on reproduc tion and the o nset
of p uberty begins. However, the threshold leve l of fa t
accu m ulatio n required for the o nset o f p uberty has not
been detenn ined.
Hypothalamic neurons that regulate
GnRH secretion detect
“moment-to-moment” changes in blood
glucose and fatty acids.
The central q uestion regarding how meta bolic
status triggers puberty is, ” W hat m eta bolic factors affect
G n RH neurons and how are the se factors recognized?”
There is evidence to indicate t hat initiation o f h igh fre-
q uency GnRH p ulses is under the influence of glucose
an d free fatty acid concentrations in the blood. For
example, w hen female ham sters were treated concur-
rently with inhibitors o ffatty acid (m ethy lpalmoxorate)
and glucose ox idation (2-deox yg luc ose , 2DG) their
estrous cycles w ere d isrupted due to th eir effect on
GnRH secretion (See Figure 6-5) . These results suggest
Figure 6-5. Glucose Can Affect Hypothalamic
Control of GnRH Secretion
3
E –DO c 2 -::r:
…I
(Modified from Foster, 1994)
In ova riectom ized ewe
lambs, low amplitude LH
pulses occurred ho urly
before 2-d eoxyg lucose
(Before 2DG) was injected
into to each animal.
Before 2DG
0 2 3 4
When the ewe lambs
we r e i nject ed w ith
2DG, t he f requency
and am plitude of the
LH pul ses were re-
d uced signi fi ca nt ly
(During 2DG ).
GnRH
During 2DG
1
1\ A
5 6 7 8
Time (hours)
9
When the same animals
receiv ing 2DG were in-
jected w ith exoge nous
GnRH , a su rge of LH
resulted. These data sug-
gest that moment-to-mo-
ment regulation of GnRH
occurs only when signifi-
cant glucose is available
for metabolism.
10 II 12
6
V
et
B
oo
ks
.ir

132 Puberty
18
16 –
14
‘Ui’
Q)
..!!! 12
:I
Q. -C’i 10
c
Q)
:I 8
C'”
Q)
I..
LL
Q)
6
Ul
“3 4 D..
::r:
…I 2
Figure 6-4. LH Frequency
Before and After Puberty
Before After
Puberty Puberty
JUl
LH —
-5 -4 -3 -2 0 2 3
Months Before and After Puberty
Frequency of LH pulses (as a reflection of
GnRH pulses) in heifers prior to the onset of
puberty. Note the substantial time required
(approximately 2 months-shaded area) for
the pulse frequency to become high enough
for puberty to be achieved. The variation in
LH pulse frequency after puberty reflects the
changes occurring during the estrous cycle.
(Modified from Kinder eta/. 1994)
In the male, the onset of puberty is
brought about because of decreased hy-
pothalamic sensitivity to negative
feedback by testosterone/estradiol.
As you recall from Chapter 5, the secretion of
GnRH from neurons in the surge center and the tonic
center is controlled by positive and negative feedback
to gonadal steroids. Puberty will be initiated when
GnRI-1 neurons can respond completely to positive
and negative feedback. Understanding the acquisi-
tion of this ability is the key to understanding how
the onset of puberty occurs. We know that GnRH
neurons are similar in number, funct ion and distribu-
tion within the hypothalamus in both the male and the
female. We also know that the endocrine profiles of
males and females are quite different after puberty
(See Figure 6-2).
As described earlier in this chapter, the male
does not develop a surge center because the hypothala-
mus is completely defeminized shortly before or after
birth. Thus, the male has a very simple feedback system
after puberty. It involves a negative feedback loop only.
You should recognize that the negative feedback in the
male is due to some testosterone and most ly to estradiol
because testosterone is converted to estTadiol within
the brain by aromatization (See Figure 6-1 ). In the
male the GnRH neurons become less and less sensitive
to the negative feedback of testosterone and estradiol
as puberty approaches. This means larger and larger
quantities of testosterone and estradiol are needed to
inhibit the GnRI-1 neurons. With this decreased sensitiv-
ity to the negative feedbac k of testosterone/ estradiol,
the hypothalamus can secrete more and more GnRH
and thus more and more LI-1/ FSH to stim ulate the testis
and stimulate puberty.
In the prepubertal female, the
surge center is quite sensitive to the
positive feedback of estradiol. But,
the surge center cannot release
“ovulatory quantities” ofGnRH
because the ovmy cannot secrete
high levels of estradiol.
From a functional perspective, the surge center
responds primarily t o a posi t ive feedback stimulus.
For example, the prepubertal female does not ovulate
although the sensitivity of the surge center to positive
feedback by estradiol is quite high. Failure to ovulate
occurs because the ovaries do not secrete enough es-
tradiol to activate the highly sensitive surge center. In
a sense, the surge center lies ” dormant” in the prepu-
bertal female even though it is capable of responding
to estradiol. The reason that it lies “dormant” is that
the prepubertal ovruy does not secrete sufiicient quanti-
ties of estradiol to stimulate the surge center to secrete
high amplitude pulses ofGnRH. At low concentrations
of estradiol, the tonic center has a high sensitivi ty to
negative feedback and therefore does not secrete high
levels ofGnRH and gonadotropins remain low. During
the pubertal transition, however, the negative feedback
sensitivity by the tonic center to estradiol decreases and
consequently higher and higher amounts ofGnRH are
secreted causing an increase in pulse frequenc y of LH.
This elevated pulse frequency stimulates the ovary to
secrete more and more estradiol. When estradiol con-
centrations reach a certain threshold, it now causes a
massive discharge ofGnRH from the surge center (posi-
tive feedba ck) . Ovulation can take place and puberty
follows. It should be emphasized that the sensitivity of
the surge center to positive fe edback changes ve1y little
and remains high even be fore birth. It is the sensitiv-
ity to negative feedb ack that is decreased and triggers
the onset of puberty in the fem ale. T he decreased
sensitivity to negative feedback by the tonic center
means that smaller and smaller q uan tities o f estrad io l
can stimulate the release o f GnRH and thus LI-1 and
FSH are secreted. These gonado tro pins then st imulate
more follicles and more and more estradio l is secreted
until finally the surge center releases the preovulato ry
surge of GnRH.
A Certain Degree of “Fatness”
is Required for the Onset of Puberty
in the Female
The priority fo r the neonate is to use its energy
towards maintenance o f vital p hys iolog ic func tions.
Therefore, nonessent ial processes suc h as reprod uc-
tion are of low prior ity. A s the neo na te beg ins to
grow, energy consumption increases, its body m ass
becomes larger and the relative surface area of the body
decreases . This al lows a shift in the metaboli c exp en-
diture so that nonvital p hysio lo g ical functions begin to
develop. As this shift occurs, the overa ll metabo lic rate
Puberty 133
decreases and more in temal energy becomes avai la ble
for nonvital fu nctions . T his excess intem al energy
can be converted into fat stores and the yo ung animal
begins to place pr iority on reproduc tion and the o nset
of p uberty begins. However, the threshold leve l of fa t
accu m ulatio n required for the o nset o f p uberty has not
been detenn ined.
Hypothalamic neurons that regulate
GnRH secretion detect
“moment-to-moment” changes in blood
glucose and fatty acids.
The central q uestion regarding how meta bolic
status triggers puberty is, ” W hat m eta bolic factors affect
G n RH neurons and how are the se factors recognized?”
There is evidence to indicate t hat initiation o f h igh fre-
q uency GnRH p ulses is under the influence of glucose
an d free fatty acid concentrations in the blood. For
example, w hen female ham sters were treated concur-
rently with inhibitors o ffatty acid (m ethy lpalmoxorate)
and glucose ox idation (2-deox yg luc ose , 2DG) their
estrous cycles w ere d isrupted due to th eir effect on
GnRH secretion (See Figure 6-5) . These results suggest
Figure 6-5. Glucose Can Affect Hypothalamic
Control of GnRH Secretion
3
E –DO c 2 -::r:
…I
(Modified from Foster, 1994)
In ova riectom ized ewe
lambs, low amplitude LH
pulses occurred ho urly
before 2-d eoxyg lucose
(Before 2DG) was injected
into to each animal.
Before 2DG
0 2 3 4
When the ewe lambs
we r e i nject ed w ith
2DG, t he f requency
and am plitude of the
LH pul ses were re-
d uced signi fi ca nt ly
(During 2DG ).
GnRH
During 2DG
1
1\ A
5 6 7 8
Time (hours)
9
When the same animals
receiv ing 2DG were in-
jected w ith exoge nous
GnRH , a su rge of LH
resulted. These data sug-
gest that moment-to-mo-
ment regulation of GnRH
occurs only when signifi-
cant glucose is available
for metabolism.
10 II 12
6
V
et
B
oo
ks
.ir

134 Puberty
that the hypothalamic GnRH secretion is sensitive to
concentrations of a variety of energy-related materials
such as glucose in the circulating blood.
A practical illustration of the impact of nutri-
tion on the age of pubertal onset in dairy heifers is
shown in Figure 6-6. A major goal in the management
of the dairy heifer is to achieve a successf11l, uncom-
plicated birth by 24 months of age. In order for this
to occur, appropriate nutrition and adequate body size
must be achieved. Figure 6-6 describes the relation-
ship between age and weight of heifers as it relates to
the onset of puberty and nutritional level. Curve A
illustrates the growth rate and age at onset of puberty
(first estnts) when heifers were fed to gain 2.0 pounds
per day for the first 12 months. Heifers fed this diet
reached puberty between 6 and 8 months. If continued
into the second year, this feeding regimen can result
in over-conditioned heifers. The second nutritional
level (curve B) allows the heifer to reach the same
target weight (1200 pounds at 24 months), but heifers
grow at a unifonn weight of 1.5 pounds per day for the
entire 24 month period. All heifers in this group will
be in estrus for the first time between 9 and 11 months
of age. Growth illustrated in curve C is slower ( 1.2
pounds per day), resulting from restricted feeding or
lower quality feeds. Most of these heifers will reach
puberty by 12 months, but they will be too small for
successful pregnancy and parturition even though they ·
are capable of becoming pregnant.
Any discussion of the metabolic signals that
may influence the onset of puberty would not be com-
plete without mentioning leptin. Leptin is a hormonal
peptide, discovered in 1994, that is secreted by adipo-
cytes (fat cells). The amount of leptin in the blood is
directly related to the amount of fat in the body. Re-
ceptors to leptin are found in the liver, kidney, heart,
skeletal muscles and pancreas.
The discovery that leptin receptors are also
present in the anterior lobe of the pituitaty and hypothal-
amus has sparked significant interest in the possibility
that leptin might play an important role in mediating the
onset of puberty in ma1m11als. Leptin may be an im-
portant signal that “notifies” key hypothalamic neurons
that influence GnRH secretion that nutritional stahts is
adequate because a threshold degree of “fatness” has
been achieved (See Figure 6-7).
Kisspeptin neurons may act
directly on GnRH neurons.
-;;;-
:f!
0
0
.:s. …
.c
I>G
>..
‘tl
0
Ill
Figure 6-6. The Relationship
Between Plane of Nutrition,
Growth and Average Daily
Gains with Onset of Puberty in
Dairy Heifers
4
Age (months)
I
28
A= High plane of nutrition (2.0 lb/day average
daily gain)
B = Moderate plane of nutrition (1.51b/day
average daily gain)
C = Low plane of nutrition (1.2 lb/day average
daily gain)
Age at first parturition should be 24 months and
the prim iparous heifer should weigh 1 ,200 lb.
(Modified from Head in Lame Herd Dairv Management, Van Horn
and Wilcox, ed s. America n Dai ry Science Association. 1992)
The exact mechanisms whereby metabolic sig-
nals are detected and converted to hypothalamic neural
activity have not been described. K isspeptin neurons
in the hypothalamus send dendritic arborizations into
hypothalamic areas containing high populations of
GnRH cell bodies. This suggests that there may be
direct synaptic connections between kisspeptin neu-
rons and GnRH neurons. Signals from hypothalamic
neurons that respond to leptin, fatty acids and glucose
may promote neural activity in kisspeptin neurons and
thus stimulate the firi ng of GnRI-I neurons (See Figure
6-7). It is important to recognize that these possibilities
have yet to be proven. Therefore, Figure 6-7 should
be interpreted as a hypothetical model based on current
evidence and not as a final documented mechanism.
Puberty 135
Figure 6-7. Possible Influence of Metabolic Signals Upon GnRH Neurons
Adipocytes (fat ce lls) se-
crete leptin that enters the
blood . Leptin may stimu-
late neuropeptide Y neu-
rons or directly stimulate
GnRH neurons. B lood
leptin reflects the nutri-
tional status of the animal
because the greater the
amount of fat the greater
Blood g lucose concentra-
tions, another indicator of
metaboli c status , might
stimulate glucose sensing
neurons that in turn stimu-
late GnRH neurons.
the amount of leptin.
d.’\ ..,’1- ‘
“·
O”” ‘l
Environmental and Social Conditions I mpact
the Onset of Puberty in the Female
External facto rs have a significant influence
upon the onset of puberty. These factors include season
ofbirth and social cues such as the presence of the male
or size of the social group in which females are housed.
In general, environmental infonnation that influences
pubertal onset is perceived by sensory neurons of the
optic and olfactory systems. Stimuli ar e processed
by the central nervous system and delivered as neural
inputs to the GnRH neurons of the hypothalamus. T he
net effect is that the hypotha lamus gains the ability to
produce high frequency and low amp li h1de pulses of
GnRH at an earlier age (provided that optimum size
and energy balance requirements are met) .
sensing
neurons
Kisspeptin
neurons
… ••••• • • K lsspeptin ° 0 Gn RH • neur ons
Fatty Ac id
sensi ng
neurons
Blood fatty acids may stimulate
neurons that in turn stimulate
the GnRH neurons. Blood fatty
acids would be an indicator of
nutritional status of the animal.
Season of Birth and Photope.-iod are
Important Modulators of Pubertal Onset
The month of birth wi ll influence the age of
puberty, par ticular ly in seasonal breeders, provided no
artificial illumination alters natural photoperiod cues.
Sheep are a good example because they are seasonal
breeders that begin their estrous cycles in response to
short day lengths. In natural photoperiods, spring-bam
(February-M arch) lambs receivi ng adequate nutrition
attain puberty during the subsequent fall (September-
October). The age at puberty is about 5 to 6 months
after birth. In contrast, fall-born Iambs do not reach
puberty until about I 0 to 12 months.
In heifers there is good evidence that age at
puberty is infl uenced by the season of birth. For ex-
ample , heifers born in autum n tend to reach puberty
V
et
B
oo
ks
.ir

134 Puberty
that the hypothalamic GnRH secretion is sensitive to
concentrations of a variety of energy-related materials
such as glucose in the circulating blood.
A practical illustration of the impact of nutri-
tion on the age of pubertal onset in dairy heifers is
shown in Figure 6-6. A major goal in the management
of the dairy heifer is to achieve a successf11l, uncom-
plicated birth by 24 months of age. In order for this
to occur, appropriate nutrition and adequate body size
must be achieved. Figure 6-6 describes the relation-
ship between age and weight of heifers as it relates to
the onset of puberty and nutritional level. Curve A
illustrates the growth rate and age at onset of puberty
(first estnts) when heifers were fed to gain 2.0 pounds
per day for the first 12 months. Heifers fed this diet
reached puberty between 6 and 8 months. If continued
into the second year, this feeding regimen can result
in over-conditioned heifers. The second nutritional
level (curve B) allows the heifer to reach the same
target weight (1200 pounds at 24 months), but heifers
grow at a unifonn weight of 1.5 pounds per day for the
entire 24 month period. All heifers in this group will
be in estrus for the first time between 9 and 11 months
of age. Growth illustrated in curve C is slower ( 1.2
pounds per day), resulting from restricted feeding or
lower quality feeds. Most of these heifers will reach
puberty by 12 months, but they will be too small for
successful pregnancy and parturition even though they ·
are capable of becoming pregnant.
Any discussion of the metabolic signals that
may influence the onset of puberty would not be com-
plete without mentioning leptin. Leptin is a hormonal
peptide, discovered in 1994, that is secreted by adipo-
cytes (fat cells). The amount of leptin in the blood is
directly related to the amount of fat in the body. Re-
ceptors to leptin are found in the liver, kidney, heart,
skeletal muscles and pancreas.
The discovery that leptin receptors are also
present in the anterior lobe of the pituitaty and hypothal-
amus has sparked significant interest in the possibility
that leptin might play an important role in mediating the
onset of puberty in ma1m11als. Leptin may be an im-
portant signal that “notifies” key hypothalamic neurons
that influence GnRH secretion that nutritional stahts is
adequate because a threshold degree of “fatness” has
been achieved (See Figure 6-7).
Kisspeptin neurons may act
directly on GnRH neurons.
-;;;-
:f!
0
0
.:s. …
.c
I>G
>..
‘tl
0
Ill
Figure 6-6. The Relationship
Between Plane of Nutrition,
Growth and Average Daily
Gains with Onset of Puberty in
Dairy Heifers
4
Age (months)
I
28
A= High plane of nutrition (2.0 lb/day average
daily gain)
B = Moderate plane of nutrition (1.51b/day
average daily gain)
C = Low plane of nutrition (1.2 lb/day average
daily gain)
Age at first parturition should be 24 months and
the prim iparous heifer should weigh 1 ,200 lb.
(Modified from Head in Lame Herd Dairv Management, Van Horn
and Wilcox, ed s. America n Dai ry Science Association. 1992)
The exact mechanisms whereby metabolic sig-
nals are detected and converted to hypothalamic neural
activity have not been described. K isspeptin neurons
in the hypothalamus send dendritic arborizations into
hypothalamic areas containing high populations of
GnRH cell bodies. This suggests that there may be
direct synaptic connections between kisspeptin neu-
rons and GnRH neurons. Signals from hypothalamic
neurons that respond to leptin, fatty acids and glucose
may promote neural activity in kisspeptin neurons and
thus stimulate the firi ng of GnRI-I neurons (See Figure
6-7). It is important to recognize that these possibilities
have yet to be proven. Therefore, Figure 6-7 should
be interpreted as a hypothetical model based on current
evidence and not as a final documented mechanism.
Puberty 135
Figure 6-7. Possible Influence of Metabolic Signals Upon GnRH Neurons
Adipocytes (fat ce lls) se-
crete leptin that enters the
blood . Leptin may stimu-
late neuropeptide Y neu-
rons or directly stimulate
GnRH neurons. B lood
leptin reflects the nutri-
tional status of the animal
because the greater the
amount of fat the greater
Blood g lucose concentra-
tions, another indicator of
metaboli c status , might
stimulate glucose sensing
neurons that in turn stimu-
late GnRH neurons.
the amount of leptin.
d.’\ ..,’1- ‘
“·
O”” ‘l
Environmental and Social Conditions I mpact
the Onset of Puberty in the Female
External facto rs have a significant influence
upon the onset of puberty. These factors include season
ofbirth and social cues such as the presence of the male
or size of the social group in which females are housed.
In general, environmental infonnation that influences
pubertal onset is perceived by sensory neurons of the
optic and olfactory systems. Stimuli ar e processed
by the central nervous system and delivered as neural
inputs to the GnRH neurons of the hypothalamus. T he
net effect is that the hypotha lamus gains the ability to
produce high frequency and low amp li h1de pulses of
GnRH at an earlier age (provided that optimum size
and energy balance requirements are met) .
sensing
neurons
Kisspeptin
neurons
… ••••• • • K lsspeptin ° 0 Gn RH • neur ons
Fatty Ac id
sensi ng
neurons
Blood fatty acids may stimulate
neurons that in turn stimulate
the GnRH neurons. Blood fatty
acids would be an indicator of
nutritional status of the animal.
Season of Birth and Photope.-iod are
Important Modulators of Pubertal Onset
The month of birth wi ll influence the age of
puberty, par ticular ly in seasonal breeders, provided no
artificial illumination alters natural photoperiod cues.
Sheep are a good example because they are seasonal
breeders that begin their estrous cycles in response to
short day lengths. In natural photoperiods, spring-bam
(February-M arch) lambs receivi ng adequate nutrition
attain puberty during the subsequent fall (September-
October). The age at puberty is about 5 to 6 months
after birth. In contrast, fall-born Iambs do not reach
puberty until about I 0 to 12 months.
In heifers there is good evidence that age at
puberty is infl uenced by the season of birth. For ex-
ample , heifers born in autum n tend to reach puberty
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136 Puberty
earlier than those born in spring. Exposure during the
second six months of their life to long photoperiods
and spring/summer-like temperatures hastens the onset
of puberty.
In the bitch there is little seasonality associ-
ated with the onset of puberty. However, in the queen
increased photoperiod prompts the onset of puberty.
For example, the onset of puberty occurs in January and
February in the Northern Hemisphere where length of
daylight begins to increase. Queens born in February
and March may not reach puberty until the following
spring. Those queens bom in the summer or fall are
likely to display their first estrus the following January.
These pubertal time lines in the dog and cat assume
adequate nutrition and growth.
Social Cues Alter the Onset of Puberty
Social cues s ignificantly impact the on set of
puberty in many mammalian species. Such m ediation
is caused by olfactory recognition of pheromonal
substances present in the urine. While the original
work demonstrating this phenomenon was conducted
in rodents , enhancement of the onset of puberty by the
presence of the male has been demonstrated in the ewe,
sow and cow. The evolutionary advantage of such a
stimulus is obvious. Females reaching puberty in the
presence of the male have a greater opportunity to be-
come pregnant. One should be reminded that pubertal
onset cannot be accelerated in animals that have not
achieved the appropriate metabolic body size to trigger
hypothalamic responsiveness to estradiol.
Figure 6-8. The Effects of Small Groups vs. Male Exposure
on the Onset of Puberty
(Large Groups (>1 0) =Normal Puberty) Small Groups (2-3 gilts)= Delayed Puberty
28 weeks 32 weeks
(Exposure to a Boar= Accelerated Pubert0
24 weeks
(no physical contact)
24 weeks
(physica l contact)
Small groups of gilts housed together
have delayed onset of puberty.
Certain social cues inhibit the onset of puberty.
Gilts housed in small groups have delayed puberty
when compared to gilts housed in larger groups. I f
prepubertal gilts are housed in groups of I 0 or more,
these females will enter pub erty at the expected time
(28 weeks). However, if the group size is decreased to
only two or three gilts, they will enter puberty at a later
time than their counterparts housed in larger groups
(See Figure 6-8).
Presence of the male hastens the
onset of puberty.
Gilts housed in small groups and exposed to a
boar will enter puberty at an earlier age than their large
or small grouped counterparts that are not exposed to
a boar. An important p oint to recognize is that the
presence of the male, either in visual contact w ith the
females or in direct physical contact with them, will
hasten the onset of puberty in gilts (See F igure 6-8).
Such observations are valuable for swine management
because the age of puberty can be reduced by properly
managing the social environment.
Nebraska researchers have shown conclusively
that bulls accelerate the onset of puberty in beefheifers.
However, there was an interaction between growth rate
and exposure to the bull (See Figure 6-9). For example,
heifers with a high growth rate ( 1.75 lb/day) and ex-
posure to a bull for about 6 months reached puberty at
about 375 days. Those with a moderate growth rate (1.4
lb/day) coupled with bull exposure (6 months) reached
puberty at about 422 days. Figure 6-9 sununarizes the
influence of growth rate and exp osure to a bull upon
the age at puberty in beef he ifers.
Metabolic status for puberty in the
male is not well understood.
Little research has been conducted on the
influence of metabolic status on the onset of puber ty
in the male. The energy expenditure associated with
spermatogenes is and copulation is “microscopic” in
comparison to the energy expenditure associated with
gestation, parhirition and lactation. In addition, little
research has been conducted describing the effect of
female -on-male or male-on-male social influences and
their impact on the onset of puberty. Virtually all of the
research has been conducted describing the influence
of the male on the onset of puberty in the female rather
than the opposite.
Puberty 137
Figure 6-9. Influence of Growth Rate
and Bull Exposure Upon the Age of
Puberty in Beef Heifers
sao
4SO
400
-;;;-
3SO
300 t’
C1l
2SO .0
:::1
D.
….
nl
200
C1l
bO
1 0) =Normal Puberty) Small Groups (2-3 gilts)= Delayed Puberty
28 weeks 32 weeks
(Exposure to a Boar= Accelerated Pubert0
24 weeks
(no physical contact)
24 weeks
(physica l contact)
Small groups of gilts housed together
have delayed onset of puberty.
Certain social cues inhibit the onset of puberty.
Gilts housed in small groups have delayed puberty
when compared to gilts housed in larger groups. I f
prepubertal gilts are housed in groups of I 0 or more,
these females will enter pub erty at the expected time
(28 weeks). However, if the group size is decreased to
only two or three gilts, they will enter puberty at a later
time than their counterparts housed in larger groups
(See Figure 6-8).
Presence of the male hastens the
onset of puberty.
Gilts housed in small groups and exposed to a
boar will enter puberty at an earlier age than their large
or small grouped counterparts that are not exposed to
a boar. An important p oint to recognize is that the
presence of the male, either in vis ual contact w ith the
females or in direct physical contact with them, will
hasten the onset of puberty in gilts (See F igure 6-8).
Such observations are valuable for swine management
because the age of puberty can be reduced by properly
managing the social environment.
Nebraska researchers have shown conclusively
that bulls accelerate the onset of puberty in beefheifers.
However, there was an interaction between growth rate
and exposure to the bull (See Figure 6-9). For example,
heifers with a high growth rate ( 1.75 lb/day) and ex-
posure to a bull for about 6 months reached puberty at
about 375 days. Those with a moderate growth rate (1.4
lb/day) coupled with bull exposure (6 months) reached
puberty at about 422 days. Figure 6-9 sununarizes the
influence of growth rate and exp osure to a bull upon
the age at puberty in beef he ifers.
Metabolic status for puberty in the
male is not well understood.
Little research has been conducted on the
influence of metabolic status on the onset of puber ty
in the male. The energy expenditure associated with
spermatogenes is and copulation is “microscopic” in
comparison to the energy expenditure associated with
gestation, parhirition and lactation. In addition, little
research has been conducted describing the effect of
female -on-male or male-on-male social influences and
their impact on the onset of puberty. Virtually all of the
research has been conducted describing the influence
of the male on the onset of puberty in the female rather
than the opposite.
Puberty 137
Figure 6-9. Influence of Growth Rate
and Bull Exposure Upon the Age of
Puberty in Beef Heifers
sao
4SO
400
-;;;-
3SO
300 t’
C1l
2SO .0
:::1
D.
….
nl
200
C1l
bO

tJ
0 z
u
C1J
0
Examples of other words that can lead to
confusion in spelling and usage are: anestrous vs.
anestrus and polyestrous vs . polyestrus. If the word
is used as an adjective, it is spelled -ous. For example,
“polyestrous fema les have repeated estrous cycles.”
If the word is used as a noun, it is spe lled -us. For
example, “the female is experiencing anestrus.”
The three types of estrous cyclicity are:
• polyestrus
• seasonally polyestrus
• monoestrus
Estrous cycles are categorized accord ing
to the frequency of occurrence throughout the year.
These classifications are polyestrus, seasonally
polyestrus and monoestrus (See Figure 7- 1 ). Poly-
estrous females, such as cattle, swine and rodents,
are characterized as having a uniform distribution of
estrous cycles throughout the entire year. Polyestrous
females can become pregnant throughout the year
without regard to season. Seasonally po lyestrous
females (sheep, goats , mares, deer a nd elk) display
“clusters” of estrous cycles that occur only during a
certain season of the year. For example, sheep and
goats are short-day breeders because they begin to
cycle as day length decreases in autumn. In contrast,
the mare is a long-day breeder because she initiates
cyclicity as day length increases in the spring.
Monoestrous females are defined as having
only one cycle per year. Dogs, wo lves, foxes and
bears are animals that are characterized as having a
single estrous cycle per year. Domestic canids typi-
cally have three estrous cycles every two years but
they are generally classified as monoestrus. In general,
monoestrous females have periods of estrus that last
for several days. Such a pro longed period of estrus
increases the probability that mating and pregnancy
can occur. Each type of cycle pattern is represented
in Figure 7-1.
The Estrous Cycle Consists of
Two Major Phases
The e strous cycle can be d iv ided into two
distinct phases that are named after the dominant
struchrre present on the ovaty during each phase of
the cycle. These divisions ofthe estrous cycle are the
follicular phase and the luteal phase. The follicu lar
phase is the period from the regression of corpora
Reproductive Cyclicity 143
lutea to ovulation. In general, the foll icular phase
is relatively short, encompassing about 20% of the
estrous cycle (See Figure 7-2). During the foll icular
phase, the primary ovarian stmctures are large grow-
ing follicles that secrete the primary reproductive
hormone, estradiol.
During the follicular phase:
• large antral follicles = the
primary ovarian structure
• estradiol (secreted by follicles)
= the primmy hormone
The luteal phase is the period from ovula-
tion until corpora lutea regression. The luteal phase
is much longer than the follicular phase and, in most
mammals, occupies about 80% of the estrous cycle
(See Figure 7 -2). During this phase, the dominant
ovarian struchtres are the corpora lutea (CL) and the
primary reproductive hormone is progesterone. Even
though the luteal phase is dominated by progesterone
from the CL, fo llicles continue to grow and regress
during this phase but they do not produce high con-
centrations of estradiol. Details of follicular growth
are presented in Chapter 8.
During the luteal phase:
• cmpora lutea = the primary
ovarian structures
• progesterone (secreted by
corpora lutea) = the primary
hormone
The Estrous Cycle can Also be Divided
into Four Stages
The four stages of an estrous cycle are
proestrus, estrus, metestrus and diestrus. Each
of these stages is a subdivision of the foll icular and
luteal phases of the cycle. For example, the follic ular
phase includes proestrus and estrus. The luteal phase
includes metestrus and diestrus.
Follicular phase= Proestrus+ Estrus
Luteal phase =Metestrus +Diestrus
7
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7
142 Reproductive Cyclicity
Terminology Describing Reproductive
Cyclicity can be Confusing
The words used to describe the estrous cycle
are spelled similarly, but have subtly different mean-
ings. The proper use of the words estrus and estrous
must be understood to prevent confusion. The word
estrus is a noun, while estrous is an adjective. Oestrus
and oestrous are the preferred spellings in British and
European literature. Estrual is also an adjective and
is used to identify a condition related to estrus. For
example, an estrual female is a female in estrus. An
estrous cycle is the period between one estrus and
the next. Estrus is the period of sexual receptivity.
Estrus is commonly referred to as heat. The term
estrus (oestrus) originated from a Greek word mean-
ing “gadfly, sting or frenzy”. This word (oestrus) was
used to describe a family of parasitic biting insects
(Oestridae). These insects caused cattle to stampede
with their tails flailing in the air as the insect buzzed
around them. The behavior occurring in females in
estrus was deemed similar to that observed during
these insect attacks. T hus , the term oestrus or estrus
was applied to the period of sexual receptivity in
mammalian females . Another common term used
to describe a reproductive pattern is season. T his
refers to several estrous cycles that may occur during
a certain season of the year. For example, a mare
“coming into season” begins to show cyclicity and
visible signs of estrus. She will cycle several times
during her “season” (See Figure 7-1 ).
ESTRUS is a noun.
“The cow is displaying estrus.”
ESTROUS is an adjective.
“The length of the estrous cycle in
the pig is 21 days.”
Figure 7-1. Types of Estrous Cycles as Described by Annual
Estradiol (E2 ) Profiles
N w
‘0
Ill c
0
1.. ..,
c cu u c
0 u
“‘C
0
0
::0
POLYESTRUS
(Cow, queen, pig, rodents)
SEASONAL POL YESTRUS (Long Day)
(Mare)
Spring breeding season
I I
SEASONAL POL YESTRUS (Short Day)
(Ewe, doe, elk, nanny) Autumn
breeding season
I I
MONOESTRUS
(Dog ®, wolf, fox, bear) 0 See Figure 7-4
:::J …….. a. C1J
V>
tJ
0 z
u
C1J
0
Examples of other words that can lead to
confusion in spelling and usage are: anestrous vs.
anestrus and polyestrous vs . polyestrus. If the word
is used as an adjective, it is spelled -ous. For example,
“polyestrous fema les have repeated estrous cycles.”
If the word is used as a noun, it is spe lled -us. For
example, “the female is experiencing anestrus.”
The three types of estrous cyclicity are:
• polyestrus
• seasonally polyestrus
• monoestrus
Estrous cycles are categorized accord ing
to the frequency of occurrence throughout the year.
These classifications are polyestrus, seasonally
polyestrus and monoestrus (See Figure 7- 1 ). Poly-
estrous females, such as cattle, swine and rodents,
are characterized as having a uniform distribution of
estrous cycles throughout the entire year. Polyestrous
females can become pregnant throughout the year
without regard to season. Seasonally po lyestrous
females (sheep, goats , mares, deer a nd elk) display
“clusters” of estrous cycles that occur only during a
certain season of the year. For example, sheep and
goats are short-day breeders because they begin to
cycle as day length decreases in autumn. In contrast,
the mare is a long-day breeder because she initiates
cyclicity as day length increases in the spring.
Monoestrous females are defined as having
only one cycle per year. Dogs, wo lves, foxes and
bears are animals that are characterized as having a
single estrous cycle per year. Domestic canids typi-
cally have three estrous cycles every two years but
they are generally classified as monoestrus. In general,
monoestrous females have periods of estrus that last
for several days. Such a pro longed period of estrus
increases the probability that mating and pregnancy
can occur. Each type of cycle pattern is represented
in Figure 7-1.
The Estrous Cycle Consists of
Two Major Phases
The e strous cycle can be d iv ided into two
distinct phases that are named after the dominant
struchrre present on the ovaty during each phase of
the cycle. These divisions ofthe estrous cycle are the
follicular phase and the luteal phase. The follicu lar
phase is the period from the regression of corpora
Reproductive Cyclicity 143
lutea to ovulation. In general, the foll icular phase
is relatively short, encompassing about 20% of the
estrous cycle (See Figure 7-2). During the foll icular
phase, the primary ovarian stmctures are large grow-
ing follicles that secrete the primary reproductive
hormone, estradiol.
During the follicular phase:
• large antral follicles = the
primary ovarian structure
• estradiol (secreted by follicles)
= the primmy hormone
The luteal phase is the period from ovula-
tion until corpora lutea regression. The luteal phase
is much longer than the follicular phase and, in most
mammals, occupies about 80% of the estrous cycle
(See Figure 7 -2). During this phase, the dominant
ovarian struchtres are the corpora lutea (CL) and the
primary reproductive hormone is progesterone. Even
though the luteal phase is dominated by progesterone
from the CL, fo llicles continue to grow and regress
during this phase but they do not produce high con-
centrations of estradiol. Details of follicular growth
are presented in Chapter 8.
During the luteal phase:
• cmpora lutea = the primary
ovarian structures
• progesterone (secreted by
corpora lutea) = the primary
hormone
The Estrous Cycle can Also be Divided
into Four Stages
The four stages of an estrous cycle are
proestrus, estrus, metestrus and diestrus. Each
of these stages is a subdivision of the foll icular and
luteal phases of the cycle. For example, the follic ular
phase includes proestrus and estrus. The luteal phase
includes metestrus and diestrus.
Follicular phase= Proestrus+ Estrus
Luteal phase =Metestrus +Diestrus
7
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144 Reproductive Cyclicity
Figure 7-2. Phases of the Estrous Cycle
-“0
Cl) 0
c.S! o.o e-
s.. Ill
0 c
J: .2
Cl)tJ
Luteal Phase
> s.. ·-
Cl) u o:::c
0 u
——————— ——
-6 -S -4 -3 -2 ·I 0 I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20 0 I 2 3 4 5 6
Day of Cycle
The follicular phase begins after luteolysis
that causes the decline in progesterone.
Gonadotropins (FSH and LH) are therefore
secreted that cause follicles to secrete
estradiol (E2 ). The follicular phase is dominated
by estradiol secreted by ovarian follicles.
The follicular phase ends at ovulation. Estrus
is designated as day 0.
Proestrus is the Period Immediately
Preceding Estrus
Proestrus begins when progesterone declines
as a result ofluteolysis (destruction of the corpus lu-
teum) and terminates at the onset of estrus. Proestrus
lasts from 2 to 5 days depending on species and is
characterized by a major endocrine transition, from
a period of progesterone dominance to a period of
estradiol dominance (See Figure 7-3). The pituitary
gonadotropins, FSH and LH, are the primary hor-
mones responsible for this transition. It is during
proestrus that antral follicles mature for ovulation and
the female reproductive system prepares for the onset
of estrus and mating.
The luteal phase begins after ovulation and
includes the development of corpo ra lutea that
secrete progesterone (P4). The luteal phase
also includes luteolysis that is accompanied
by a rapid drop in progesterone. Luteo lysis is
brought about by prostaglandin F2u .
Estrus is the Period During Which
the Female Allows Copulation
Estrus is the most recognizable stage of the
estrous cycle becaus e it is characterized by v isible
behavioral symptoms such as sexual receptivity and
mating. Estradiol is the dominant honnone during this
stage of the estrous cycle. Estradiol not only induces
profound behav ioral alterations, but causes maj or
physiologic changes in the reproductive tract.
When a fem ale enters estrus, she does so
gradually and is not sexually receptive at firs t. She
may di splay behav io ra l characteristics that are
indicati ve of her approaching sexual receptiv ity.
Proestrus =Formation of ovulatory follicles + E 2 secretion
Estrus= Sexual receptivity+ peak E2 secretion
Metestrus= CLformation +beginning of P4 secretion
Diestrus =Sustained luteal secretion of P4
Reproductive Cyclicity 145
Figure 7-3. Stages of the Estrous Cycle
-“C
Cl.l 0
0.!:1 e-s.. Ill oc
J: .2
>S.. ·- .. .. c
Cl.l u cr:c
0 u
I
I
I
I
I
I
I
E2 ,’
Diestrus
‘ I
I
I
I
I
I
I
_, —– E2 ,/ ————————–
·6 -5 -4 ·3 · 2 ·I 0 I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20 0 I 2 3 ·1 5 6
Day of Cycle
Proestrus is character- When estrad iol reach-
ized by a significant rise e s a certa in level , the
in estradiol (E2) secreted fe male shows be ha v-
by maturing follic les. ioral estrus and then
ovulates.
These include increased locomotion, phonation (vo-
cal expression), nervousness and attempts to mount
other animals. However, during this early period she
will not accept the male for mating. As the period of
estrus progresses, so does the fema le ‘s will ingne ss
to accept the male for mating. This willingness is
referred to as standing estrus. It is during the time
of estrus that the fem ale displays a characteristic
mating posture known as lordosis, so named because
of a characteristic arching of the back in preparation
for mating. Standing behavior (lordosis) is easily
observed and is used as a diagnostic tool to identify
the appropriate time to inseminate the fe male arti-
ficially or to expose her to the breeding ma le. The
average duration of estrus is characteristic for each
species. However, the range in the duration of estrus
can be quite large even within species (See Table
7-1). Understanding and appreciating the magnitude
of these ranges is important because it allows one to
predict cyclic events with a degree of accuracy.
Fo llowi ng ovul ation , Diestrus is characterized
cells of the fo ll icle are by a fully functiona l CL
tra nsforme d into luteal a nd high progesterone
cell s th at form the cor- (P4) .
pus luteum (CL) during
metestrus.
Metestrus is the Transition from Estradiol
Dominance to Progesterone Dominance
Metestrus is the peri od between ovulation
and the formation of functional corpora lute a. During
early metestrus both estradiol and progesterone are
relatively low (See Figure 7-3 ). The newly ovulated
follicle undergoes cellular and structural remodeling
resulting in the fo nnation of an intraovarian endocrine
gland called the corpus luteum. This cellular trans-
formatio n is called luteinization (See Chapter 9).
Progesterone secretion begins in metestrus and is
detectable soon after ovulation. However, two to five
days are usually required after ovulation before the
newly fann ed corpora lutea produce significant quanti-
ties of progesterone (See Figure 7-3).
Diestrus is the Period of Maximum
Luteal Function
Diestrus is the longest stage of the estrous
cycle and is the period of time when the corpus luteum
is fully funct ional and progesterone secretion is high.
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144 Reproductive Cyclicity
Figure 7-2. Phases of the Estrous Cycle
-“0
Cl) 0
c.S! o.o e-
s.. Ill
0 c
J: .2
Cl)tJ
Luteal Phase
> s.. ·-
Cl) u o:::c
0 u
——————— ——
-6 -S -4 -3 -2 ·I 0 I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20 0 I 2 3 4 5 6
Day of Cycle
The follicular phase begins after luteolysis
that causes the decline in progesterone.
Gonadotropins (FSH and LH) are therefore
secreted that cause follicles to secrete
estradiol (E2 ). The follicular phase is dominated
by estradiol secreted by ovarian follicles.
The follicular phase ends at ovulation. Estrus
is designated as day 0.
Proestrus is the Period Immediately
Preceding Estrus
Proestrus begins when progesterone declines
as a result ofluteolysis (destruction of the corpus lu-
teum) and terminates at the onset of estrus. Proestrus
lasts from 2 to 5 days depending on species and is
characterized by a major endocrine transition, from
a period of progesterone dominance to a period of
estradiol dominance (See Figure 7-3). The pituitary
gonadotropins, FSH and LH, are the primary hor-
mones responsible for this transition. It is during
proestrus that antral follicles mature for ovulation and
the female reproductive system prepares for the onset
of estrus and mating.
The luteal phase begins after ovulation and
includes the development of corpo ra lutea that
secrete progesterone (P4). The luteal phase
also includes luteolysis that is accompanied
by a rapid drop in progesterone. Luteo lysis is
brought about by prostaglandin F2u .
Estrus is the Period During Which
the Female Allows Copulation
Estrus is the most recognizable stage of the
estrous cycle becaus e it is characterized by v isible
behavioral symptoms such as sexual receptivity and
mating. Estradiol is the dominant honnone during this
stage of the estrous cycle. Estradiol not only induces
profound behav ioral alterations, but causes maj or
physiologic changes in the reproductive tract.
When a fem ale enters estrus, she does so
gradually and is not sexually receptive at firs t. She
may di splay behav io ra l characteristics that are
indicati ve of her approaching sexual receptiv ity.
Proestrus =Formation of ovulatory follicles + E 2 secretion
Estrus= Sexual receptivity+ peak E2 secretion
Metestrus= CLformation +beginning of P4 secretion
Diestrus =Sustained luteal secretion of P4
Reproductive Cyclicity 145
Figure 7-3. Stages of the Estrous Cycle
-“C
Cl.l 0
0.!:1 e-s.. Ill oc
J: .2
>S.. ·- .. .. c
Cl.l u cr:c
0 u
I
I
I
I
I
I
I
E2 ,’
Diestrus
‘ I
I
I
I
I
I
I
_, —– E2 ,/ ————————–
·6 -5 -4 ·3 · 2 ·I 0 I 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19 20 0 I 2 3 ·1 5 6
Day of Cycle
Proestrus is character- When estrad iol reach-
ized by a significant rise e s a certa in level , the
in estradiol (E2) secreted fe male shows be ha v-
by maturing follic les. ioral estrus and then
ovulates.
These include increased locomotion, phonation (vo-
cal expression), nervousness and attempts to mount
other animals. However, during this early period she
will not accept the male for mating. As the period of
estrus progresses, so does the fema le ‘s will ingne ss
to accept the male for mating. This willingness is
referred to as standing estrus. It is during the time
of estrus that the fem ale displays a characteristic
mating posture known as lordosis, so named because
of a characteristic arching of the back in preparation
for mating. Standing behavior (lordosis) is easily
observed and is used as a diagnostic tool to identify
the appropriate time to inseminate the fe male arti-
ficially or to expose her to the breeding ma le. The
average duration of estrus is characteristic for each
species. However, the range in the duration of estrus
can be quite large even within species (See Table
7-1). Understanding and appreciating the magnitude
of these ranges is important because it allows one to
predict cyclic events with a degree of accuracy.
Fo llowi ng ovul ation , Diestrus is characterized
cells of the fo ll icle are by a fully functiona l CL
tra nsforme d into luteal a nd high progesterone
cell s th at form the cor- (P4) .
pus luteum (CL) during
metestrus.
Metestrus is the Transition from Estradiol
Dominance to Progesterone Dominance
Metestrus is the peri od between ovulation
and the formation of functional corpora lute a. During
early metestrus both estradiol and progesterone are
relatively low (See Figure 7-3 ). The newly ovulated
follicle undergoes cellular and structural remodeling
resulting in the fo nnation of an intraovarian endocrine
gland called the corpus luteum. This cellular trans-
formatio n is called luteinization (See Chapter 9).
Progesterone secretion begins in metestrus and is
detectable soon after ovulation. However, two to five
days are usually required after ovulation before the
newly fann ed corpora lutea produce significant quanti-
ties of progesterone (See Figure 7-3).
Diestrus is the Period of Maximum
Luteal Function
Diestrus is the longest stage of the estrous
cycle and is the period of time when the corpus luteum
is fully funct ional and progesterone secretion is high.
V
et
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oo
ks
.ir

7
146 Reproductive Cyclicity
lt ends when the corpus luteum is destroyed (luteoly-
sis). High progesterone prompts the uterus to prepare
a suitable environment for early embryo development
and eventual attachment of the concephis to the endo-
metrium. Diestrus usually lasts about I 0 to 14 days
in most large mammals. The duration of diestrus is
directly related to the length of time that the corpus
luteum remains functional (i.e. secretes progesterone).
Females in diestrus do not display estrous behavior.
The Estrous Cycle of the Bitch and Queen
Varies from Patterns Previously Described
The estrous cycle of the domestic bitch has
a different stage sequence than other mammals. The
cycle consists of anestrus, proestrus, estrus and di-
estrus. Anestrus usually lasts for about 20 weeks in
the nonpregnant bitch. The long anestrus (5 months)
causes the the bitch to display two estrous periods
in three years. However, wild canids (wolf, coyote,
Australian dingo) display only one estrous period per
year and these periods are usually seasonal. Figure 7-4
illustrates the stages, sequence, relative time line and the
endocrine profiles of the cycle in the bitch. The onset
of proestrus is usually considered to be the beginning
of the estrous cycle. The drop in blood FSH that occurs
during proestrus is presumably due to negative feedback
on FSH by inhibin secreted from developing follicles.
The bitch becomes receptive to the male during decreas-
ing estradiol and rising progesterone concentrations.
Ovulation occurs 2-3 days after the LH surge. Fertiliza-
tion generally takes place 48-72 hours after ovulation.
This delay between ovulation and fertilization allows
for superfecundation to occur fre quently in canids.
Superfecundation occurs when multiple ovulations
produce multiple oocytes during a single estrus period
that are fertilized by spermatozoa from different males.
Therefore, bitches that are allowed to “roam free” dur-
ing estrus have a high probability of delivering litters
with multiple breeds of puppies.
Figure 7-4. The Annual Reproductive Cycle of the Bitch
(Modified from Johnston, Root Kustritz and Olson. 2001. Canine and Feline Therioqenology)
ANESTRUS
5 Mo
……. .,
QJ 0
c 0
o::C
E’-”
I.. Ill
0 c
J: ….
QJ ns > I.. ·- …. -4-‘c
QJ u a::c
0 u
Anestrus
A period of reproduc-
tive quiescence. This
long anestrus period is
responsible for a cyclic
profile of three cycles
in two years.
7 6 5 4 3
Weeks
Proestrus
Proestrus is considered the
beginning of the cycle and is
characterized by the appear-
ance of a blood-tinged vaginal
discharge. It ends when the
bitch copulates with the male.
Estradiol gradually increases
and peaks slightly before the
onset of estrus.
Days
Estrus
” OJ
ii.
E
8
Days
Shortly after peak estradiol,
behavioral estrus begins.
Both LH and FSH peak
in early estrus. Ovulation
is completed at about the
third day of estrus and
fertilization is completed at
about the sixth day. Pro-
gesterone increases dur-
ing the latter part of estrus
signifying luteinization.
e
” ti.
E
0
u
c
0
-g
2 3 4 5 6 7 8
Weeks
Diestrus
Both pregnant and open
bitches are cons idered to
be in diestrus . Pregnancy
status does not alter the
length of diestrus. Pro-
gesterone peaks at about
15 days then decreases
gradually. Bitches that
do not become pregnant
are often considered to
be pseudopregnant.
As you can see from F igure 7-4, the bitch
does not have a defined metestrus as in other species.
The initial development ofluteal tissue occurs duri ng
estrus shortly after ovulation as in other mammals .
In the queen, stages of th e es trous cycle
include proestrus, estrus, postestrus, diestrus and
anestrus. There is little evidence for seasonality in
queens and they tend to be polyestrus. However, as
photoperiod increases, the length of estrus increases.
Felids are induced ovulators and copulation is required
for induction of the LH surge.
Postestrus is a term used to descr ibe an inter-
estrus period that fo llows estrus in a queen that has
not been induced to ovulate by copulation (See Figure
7-5). In queens that have not copulated, no ovulation
occurs and no corpora lutea fonn . T herefore, neither
metestrus (CL fo nnation) nor diestru s occurs. As in
most induced ovulators, it would be appropriate to
consider that the female would remain in a constant
Reproductive Cyclicity 14 7
follicular phase until copulation occurs. After copula-
tion the female ovulates and only then do corpora lutea
fom1 . In this context induced ovulators constirute a
special fonn of estrous cycle that does not have a true
luteal phase.
Anestrus Means “Without Estrus (Heat)”
Anestrus is a condition when the female does
not exhibit estrous cycles. During anestrus the ovaries
are relative ly inactive and neither ovulatory follicles
nor func tional corpora lutea are present. Anestrus is
the result of insufficient GnlU-I release from the hy-
pothalamus to stimulate and maintain gonadotrop in
secretion by the piruitary.
It is important to distingu ish between true
anestrus caused by insufficient hormonal stimul i and
apparent anestrus caused by fa ilure to detect estrus
Figure 7-5. Reproductive Cyclicity Profile of Queens With and Without Copulation
-“C
Cll 0
c:.B
o.c E-
1. Ill
0 c:
:I: .!2
.4J
CU!II > I.
·- .4J .4Jc:
.!!!CII
CIIU o::c:
0 u
Q ueen in estrus – no mating
4 8 12 16
A queen enters estrus (about 9 days)
every 17 days. If copulation does not
occur, the queen enters a postestrus
phase and comes into estrus a few days
later. Since the queen is an induced
ovulator, when mating does not occur,
ovulation does not occur and a CL is
not formed .
(
Mating
. .. Uji..,Qn[,•],•i
4 8 12 16 20
Weeks
W he n mating occu rs during estrus ,
ovulation is induced , fertilization occurs
a nd pregnancy t a kes place. After
ovulation corpora lutea are formed causing
a marked e levation in progesterone .
After a 60 day gestati on peri od ,
parturition occurs and lactation ensues .
Lactational anestrus does not occur in
the cat because she will come into estrus
while lactating.
V
et
B
oo
ks
.ir

7
146 Reproductive Cyclicity
lt ends when the corpus luteum is destroyed (luteoly-
sis). High progesterone prompts the uterus to prepare
a suitable environment for early embryo development
and eventual attachment of the concephis to the endo-
metrium. Diestrus usually lasts about I 0 to 14 days
in most large mammals. The duration of diestrus is
directly related to the length of time that the corpus
luteum remains functional (i.e. secretes progesterone).
Females in diestrus do not display estrous behavior.
The Estrous Cycle of the Bitch and Queen
Varies from Patterns Previously Described
The estrous cycle of the domestic bitch has
a different stage sequence than other mammals. The
cycle consists of anestrus, proestrus, estrus and di-
estrus. Anestrus usually lasts for about 20 weeks in
the nonpregnant bitch. The long anestrus (5 months)
causes the the bitch to display two estrous periods
in three years. However, wild canids (wolf, coyote,
Australian dingo) display only one estrous period per
year and these periods are usually seasonal. Figure 7-4
illustrates the stages, sequence, relative time line and the
endocrine profiles of the cycle in the bitch. The onset
of proestrus is usually considered to be the beginning
of the estrous cycle. The drop in blood FSH that occurs
during proestrus is presumably due to negative feedback
on FSH by inhibin secreted from developing follicles.
The bitch becomes receptive to the male during decreas-
ing estradiol and rising progesterone concentrations.
Ovulation occurs 2-3 days after the LH surge. Fertiliza-
tion generally takes place 48-72 hours after ovulation.
This delay between ovulation and fertilization allows
for superfecundation to occur fre quently in canids.
Superfecundation occurs when multiple ovulations
produce multiple oocytes during a single estrus period
that are fertilized by spermatozoa from different males.
Therefore, bitches that are allowed to “roam free” dur-
ing estrus have a high probability of delivering litters
with multiple breeds of puppies.
Figure 7-4. The Annual Reproductive Cycle of the Bitch
(Modified from Johnston, Root Kustritz and Olson. 2001. Canine and Feline Therioqenology)
ANESTRUS
5 Mo
……. .,
QJ 0
c 0
o::C
E’-”
I.. Ill
0 c
J: ….
QJ ns > I.. ·- …. -4-‘c
QJ u a::c
0 u
Anestrus
A period of reproduc-
tive quiescence. This
long anestrus period is
responsible for a cyclic
profile of three cycles
in two years.
7 6 5 4 3
Weeks
Proestrus
Proestrus is considered the
beginning of the cycle and is
characterized by the appear-
ance of a blood-tinged vaginal
discharge. It ends when the
bitch copulates with the male.
Estradiol gradually increases
and peaks slightly before the
onset of estrus.
Days
Estrus
” OJ
ii.
E
8
Days
Shortly after peak estradiol,
behavioral estrus begins.
Both LH and FSH peak
in early estrus. Ovulation
is completed at about the
third day of estrus and
fertilization is completed at
about the sixth day. Pro-
gesterone increases dur-
ing the latter part of estrus
signifying luteinization.
e
” ti.
E
0
u
c
0
-g
2 3 4 5 6 7 8
Weeks
Diestrus
Both pregnant and open
bitches are cons idered to
be in diestrus . Pregnancy
status does not alter the
length of diestrus. Pro-
gesterone peaks at about
15 days then decreases
gradually. Bitches that
do not become pregnant
are often considered to
be pseudopregnant.
As you can see from F igure 7-4, the bitch
does not have a defined metestrus as in other species.
The initial development ofluteal tissue occurs duri ng
estrus shortly after ovulation as in other mammals .
In the queen, stages of th e es trous cycle
include proestrus, estrus, postestrus, diestrus and
anestrus. There is little evidence for seasonality in
queens and they tend to be polyestrus. However, as
photoperiod increases, the length of estrus increases.
Felids are induced ovulators and copulation is required
for induction of the LH surge.
Postestrus is a term used to descr ibe an inter-
estrus period that fo llows estrus in a queen that has
not been induced to ovulate by copulation (See Figure
7-5). In queens that have not copulated, no ovulation
occurs and no corpora lutea fonn . T herefore, neither
metestrus (CL fo nnation) nor diestru s occurs. As in
most induced ovulators, it would be appropriate to
consider that the female would remain in a constant
Reproductive Cyclicity 14 7
follicular phase until copulation occurs. After copula-
tion the female ovulates and only then do corpora lutea
fom1 . In this context induced ovulators constirute a
special fonn of estrous cycle that does not have a true
luteal phase.
Anestrus Means “Without Estrus (Heat)”
Anestrus is a condition when the female does
not exhibit estrous cycles. During anestrus the ovaries
are relative ly inactive and neither ovulatory follicles
nor func tional corpora lutea are present. Anestrus is
the result of insufficient GnlU-I release from the hy-
pothalamus to stimulate and maintain gonadotrop in
secretion by the piruitary.
It is important to distingu ish between true
anestrus caused by insufficient hormonal stimul i and
apparent anestrus caused by fa ilure to detect estrus
Figure 7-5. Reproductive Cyclicity Profile of Queens With and Without Copulation
-“C
Cll 0
c:.B
o.c E-
1. Ill
0 c:
:I: .!2
.4J
CU!II > I.
·- .4J .4Jc:
.!!!CII
CIIU o::c:
0 u
Q ueen in estrus – no mating
4 8 12 16
A queen enters estrus (about 9 days)
every 17 days. If copulation does not
occur, the queen enters a postestrus
phase and comes into estrus a few days
later. Since the queen is an induced
ovulator, when mating does not occur,
ovulation does not occur and a CL is
not formed .
(
Mating
. .. Uji..,Qn[,•],•i
4 8 12 16 20
Weeks
W he n mating occu rs during estrus ,
ovulation is induced , fertilization occurs
a nd pregnancy t a kes place. After
ovulation corpora lutea are formed causing
a marked e levation in progesterone .
After a 60 day gestati on peri od ,
parturition occurs and lactation ensues .
Lactational anestrus does not occur in
the cat because she will come into estrus
while lactating.
V
et
B
oo
ks
.ir

150 Reproductive Cyclicity
Onset of Seasonal Cyclicity is Similar
to the Onset of Puberty
Seasonal anestrus is characterized by a reduc-
tion in the frequency of hypothalamic GnRH secretion
(as in the prepubertal female). Before the breeding
season can begin, the hypothalamus must be able
to secrete sufficient quantities of GnRH to elicit a
response by the anterior lobe of the piruitary. The
release of FSH and LH at levels capable of maintain-
ing follicular development and causing ovulation is
required.
Seasonal breeders can be categorized as either
long-day breeders or short-day breeders (See Figure
7-1 ). The mare is characterized as a long-day breeder
because as the day length increases in the spring the
mare begins to cycle. During the short days of the
winter months, the mare is anestms. Short-day breed-
ers are animals that begin to cycle during the shorter
days of fall. Animals such as sheep, deer, elk and goats
are categorized as short-day breeders. The duration of
the breeding season varies among and within spec ies.
For example, in sheep, the Merino breed has a period
of cyclicity that ranges from 200 to 260 days, while
blackface breeds have shorter periods of cyclicity
ranging from 100 to 140 days.
The two primary factors that influenc e the
onset of the breeding season are photoperiod and
temperahtre. Photoperiod is by far the most impor-
tant. It is well known that artificial manipulation of
the photoperiod can alter the cyclicity of the seasonal
breeder.
Figure 7-7. Possible Role of Kisspeptin Neurons in the Regulation of
Cyclicity in Long-Day and Short-Day Breeders
Suprachiasmatic
nucleus
Long photoperiods
(shorter dark periods)
I
Hypothalamus
– J_–
\
—Posterior
lobe
Anterior
lobe
Pineal gland e
Ex ‘
0
Superior
cervical
ganglion
r-
Low norep inephrine
secretion
0
Low mela tonin release
t
RFRP neu ron
t RFRP-3
Ot
Short-day
kiss neurons
in hibited
t
Low kiss -10 0
t RFRP-3
tO
Long-day
kiss neurons
stimulated
High kiss -10
0
Hypothalamus- t t
O t Daylength –+ t excitation of retinal neurons
f) Retinal neurons synapse in suprachiasmatic nucleus
8 Inhibitory neurons {black neuron) convert excitatory
response to an inhibitory response
8 Postsynaptic adrenergic fiber–>! norepinephrine secretion
0 ! norepinephrine –+ ! melatonin by pinealocyte
0 ! melatonin –+ t RFRP-3 from RFRP neuron
8 t RFRP-3–+ t Kiss-10–> t GnRH –+ t FSH & LH
–+ ! Kiss-1 0 –> ! GNRH –+ ! FSH & LH
• i-GnRH f) tGnR H
t
f) t FSH + LH
t
FSH} LH
No cycles 0 Cyclicity
A major question that must be answered in
order to understand the influence of day length on the
onset of reproductive activity is, “How is photoperiod
translated into a physiologic signal?”
A proposed pathway for both the long-day and
shori-day breeder is presented in Figure 7-7. During
long photoperiods, the retina of the eye is stimulated by
light. This results in elevated tonic excitation of retinal
neurons. This excitation is transmitted by a nerve tract
to a spec ific area of the hypothalamus known as the
suprachiasmatic nucleus. From the suprachiasmatic
nucleus a second nerve tract travels to the superior
cervical ganglion. The presynaptic neurons synapse
with inhibitory neurons that convert an excitatory sig-
nal into into an inhibitory response . As a result, the
postsynaptic adrenergic fibers are inhibited and they
reduce their secretion of norepinephrine. Reduced
norepinephrine results in low melatonin secretion from
the pineal gland. Low melatonin results in excitation
of RFRP neurons and they increase secretion of their
neurotransmitter, RFRP-3. T he RFRP neLu·on ‘s name is
derived from the following: a) the “RF” designation re-
fers to “amide related proteins” that are small peptides
secreted by the neurons ; b) the second ” R” refers to the
amino acid arginine and c) the second “P” refers to the
amino acid phenylalanine. The RF amide molecule has
Reproductive Cyclicity 151
an at the C terminus and is probab ly I 0
ammo actds mlength. Elevated RFRP-3 has different
in the short and long-day breeder. For example,
111 the long-day breeder, RFRP-3 stimulates groupings
of kisspeptin neurons in the hypothalamus and they
secrete high levels of kisspe ptin-1 0. It is thought
that k isspeptin-10 acts directly on GnR.I-I neurons to
stimulate the secretion of FSH and LH. As as conse-
quence, the long-day fe male begins to cycle. In the
short-day breeder, kisspeptin neurons are thought to
be inhibited by RFRP-3 and thus k isspeptin-10 secre-
tion is reduced and GnRH neurons do not stimulate
the release ofFSH and LI-1.
In summary, it is thought that the fund amental
reason that differences between seasonal breeders ex-
ists (short-day versus long-day) is related to genetic
differences in the responsiveness of certain groups
of kisspeptin neurons to RFRP-3 . When days are
short, melatonin increases, which in tum decreases
the RFRP-3 inhibition on kis speptin neurons . In
short-day breeding females, this signal elevates levels
of GnRH and thus FSH and LH to initiate cyclicity.
On the other hand, these conditions (h igh melatonin
during short days) signal the long-day breeding female [1]
to reduce levels of GnRH and thus low FSH and LH
terminates cyclicity.
Figure 7-8. Influence of Suckling Frequency Upon Blood LH (a Direct
Indication of GnRH Release) in Postpartum Beef Cows
(Derived from the data of Dr. G.L. Will iams, Texas A& M University, Beeville)
When the number of suckling sessions is between
3 and 20 per day, amplitude and pulse frequency
of blood LH are quite low and the cow rema ins
in anestrus.
Ill
c …..
res
E b.O c Cll
::1·- Q.
Z:i
u
:I
(/]
s
4
3
2
i
Parturi t ion
ANESTRUS
2 3
Blood
LH
4
)
5 6
When the number of suckling sessions is limited
to two or less per day, the amplitude and pulse
frequency of LH increases dramatically and the
cow will begin to cycle.
Blood LH
7 8 9 10 II 12 13
Weeks Postpartum
V
et
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oo
ks
.ir

150 Reproductive Cyclicity
Onset of Seasonal Cyclicity is Similar
to the Onset of Puberty
Seasonal anestrus is characterized by a reduc-
tion in the frequency of hypothalamic GnRH secretion
(as in the prepubertal female). Before the breeding
season can begin, the hypothalamus must be able
to secrete sufficient quantities of GnRH to elicit a
response by the anterior lobe of the piruitary. The
release of FSH and LH at levels capable of maintain-
ing follicular development and causing ovulation is
required.
Seasonal breeders can be categorized as either
long-day breeders or short-day breeders (See Figure
7-1 ). The mare is characterized as a long-day breeder
because as the day length increases in the spring the
mare begins to cycle. During the short days of the
winter months, the mare is anestms. Short-day breed-
ers are animals that begin to cycle during the shorter
days of fall. Animals such as sheep, deer, elk and goats
are categorized as short-day breeders. The duration of
the breeding season varies among and within spec ies.
For example, in sheep, the Merino breed has a period
of cyclicity that ranges from 200 to 260 days, while
blackface breeds have shorter periods of cyclicity
ranging from 100 to 140 days.
The two primary factors that influenc e the
onset of the breeding season are photoperiod and
temperahtre. Photoperiod is by far the most impor-
tant. It is well known that artificial manipulation of
the photoperiod can alter the cyclicity of the seasonal
breeder.
Figure 7-7. Possible Role of Kisspeptin Neurons in the Regulation of
Cyclicity in Long-Day and Short-Day Breeders
Suprachiasmatic
nucleus
Long photoperiods
(shorter dark periods)
I
Hypothalamus
– J_–
\
—Posterior
lobe
Anterior
lobe
Pineal gland e
Ex ‘
0
Superior
cervical
ganglion
r-
Low norep inephrine
secretion
0
Low mela tonin release
t
RFRP neu ron
t RFRP-3
Ot
Short-day
kiss neurons
in hibited
t
Low kiss -10 0
t RFRP-3
tO
Long-day
kiss neurons
stimulated
High kiss -10
0
Hypothalamus- t t
O t Daylength –+ t excitation of retinal neurons
f) Retinal neurons synapse in suprachiasmatic nucleus
8 Inhibitory neurons {black neuron) convert excitatory
response to an inhibitory response
8 Postsynaptic adrenergic fiber–>! norepinephrine secretion
0 ! norepinephrine –+ ! melatonin by pinealocyte
0 ! melatonin –+ t RFRP-3 from RFRP neuron
8 t RFRP-3–+ t Kiss-10–> t GnRH –+ t FSH & LH
–+ ! Kiss-1 0 –> ! GNRH –+ ! FSH & LH
• i-GnRH f) tGnR H
t
f) t FSH + LH
t
FSH} LH
No cycles 0 Cyclicity
A major question that must be answered in
order to understand the influence of day length on the
onset of reproductive activity is, “How is photoperiod
translated into a physiologic signal?”
A proposed pathway for both the long-day and
shori-day breeder is presented in Figure 7-7. During
long photoperiods, the retina of the eye is stimulated by
light. This results in elevated tonic excitation of retinal
neurons. This excitation is transmitted by a nerve tract
to a spec ific area of the hypothalamus known as the
suprachiasmatic nucleus. From the suprachiasmatic
nucleus a second nerve tract travels to the superior
cervical ganglion. The presynaptic neurons synapse
with inhibitory neurons that convert an excitatory sig-
nal into into an inhibitory response . As a result, the
postsynaptic adrenergic fibers are inhibited and they
reduce their secretion of norepinephrine. Reduced
norepinephrine results in low melatonin secretion from
the pineal gland. Low melatonin results in excitation
of RFRP neurons and they increase secretion of their
neurotransmitter, RFRP-3. T he RFRP neLu·on ‘s name is
derived from the following: a) the “RF” designation re-
fers to “amide related proteins” that are small peptides
secreted by the neurons ; b) the second ” R” refers to the
amino acid arginine and c) the second “P” refers to the
amino acid phenylalanine. The RF amide molecule has
Reproductive Cyclicity 151
an at the C terminus and is probab ly I 0
ammo actds mlength. Elevated RFRP-3 has different
in the short and long-day breeder. For example,
111 the long-day breeder, RFRP-3 stimulates groupings
of kisspeptin neurons in the hypothalamus and they
secrete high levels of kisspe ptin-1 0. It is thought
that k isspeptin-10 acts directly on GnR.I-I neurons to
stimulate the secretion of FSH and LH. As as conse-
quence, the long-day fe male begins to cycle. In the
short-day breeder, kisspeptin neurons are thought to
be inhibited by RFRP-3 and thus k isspeptin-10 secre-
tion is reduced and GnRH neurons do not stimulate
the release ofFSH and LI-1.
In summary, it is thought that the fund amental
reason that differences between seasonal breeders ex-
ists (short-day versus long-day) is related to genetic
differences in the responsiveness of certain groups
of kisspeptin neurons to RFRP-3 . When days are
short, melatonin increases, which in tum decreases
the RFRP-3 inhibition on kis speptin neurons . In
short-day breeding females, this signal elevates levels
of GnRH and thus FSH and LH to initiate cyclicity.
On the other hand, these conditions (h igh melatonin
during short days) signal the long-day breeding female [1]
to reduce levels of GnRH and thus low FSH and LH
terminates cyclicity.
Figure 7-8. Influence of Suckling Frequency Upon Blood LH (a Direct
Indication of GnRH Release) in Postpartum Beef Cows
(Derived from the data of Dr. G.L. Will iams, Texas A& M University, Beeville)
When the number of suckling sessions is between
3 and 20 per day, amplitude and pulse frequency
of blood LH are quite low and the cow rema ins
in anestrus.
Ill
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4
3
2
i
Parturi t ion
ANESTRUS
2 3
Blood
LH
4
)
5 6
When the number of suckling sessions is limited
to two or less per day, the amplitude and pulse
frequency of LH increases dramatically and the
cow will begin to cycle.
Blood LH
7 8 9 10 II 12 13
Weeks Postpartum
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152 Reproductive Cyclicity
Lactational Anestrus Prevents a New
Pregnancy Before Young are Weaned
Almost all mammalian females nursing their
young experience lactational anestrus that lasts for
variable periods of time. The mare and the alpaca
are exceptio ns and do no t experience lactational
anestrus . Both begin cycling soon after they give
birth. Cyclicity is completely suppressed during lacta-
tion in the sow. When weaning takes place, the sow
will display estrus and ovulate w ithin 4 to 8 days. In
the suckled cow, cyclicity is delayed by as much as
60 days after parturition. The duration of lactational
anestrus is influenced by the degree of suckling in the
cow. However, suckling by itse lf does not appear to
be important w hen the frequency is greater than two
suckling sessions per day. Suc kling sessions of two or
less per day prom ote return to cycli city, while greater
than two sessions per day tend to cause postpartum
anestrus ( See Figure 7-8). There is a threshold of
about two sessions per day. Greater than two suck ling
session causes anestrus. If fewer than two per day, the
cow will re turn to cyclicity. It does not seem to matter
whether the re are 3 or 20 suckling sessions per day. In
other words, the effect of suckling does not operate in
a continuum but rather in a thr eshold manner.
Mammmy stimulation is not totally
responsible for lactational anestrus.
Figure 7-9. Ad Libitum Suckling Results in Suppression of LH Amplitude
and Pulse Frequency
Intact cow
When calves are weaned suddenly from cows with
intact mammary nerves, the LH pulse frequency
and amplitude increases dramatically.
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iii
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Acute we a ning
Ad libitum
sucklin g
2 3
P os tpartum cycl icity
4 5 6
Parturition Weeks
Time after parturition
Mammary denervated cow
In cows with the afferent neural pathway severed ,
acute weaning causes the same effect as in cows
with intact afferent pathways. Conclusion-suck-
ling cannot be totally respo nsible for suppressing
LH in the postpartum cow.
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0
iii
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Acute w ea ning
Ad li bitum
suc klin g
2 3
Pos t p a rtu m c ycli ci ty
4 5 6
Parturitio n Weel
Qj
a::
Acute we a ning
Ad libitum
sucklin g
2 3
P os tpartum cycl icity
4 5 6
Parturition Weeks
Time after parturition
Mammary denervated cow
In cows with the afferent neural pathway severed ,
acute weaning causes the same effect as in cows
with intact afferent pathways. Conclusion-suck-
ling cannot be totally respo nsible for suppressing
LH in the postpartum cow.
:I:
…J
‘tl
0
0
iii
Cll
> …
Ill
Qj
a::
Acute w ea ning
Ad li bitum
suc klin g
2 3
Pos t p a rtu m c ycli ci ty
4 5 6
Parturitio n Weel 0
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The Estrous Cycle
Luteal
Day of Cycle Es trus
The Menstrual Cycle
Luteal
LH
21
I Proliferative I
I Secretory I
14 2 1
Day of Cycle
the initial 3-5 of proliferative phase the endometrium decreases rapidly in th ickness because it
;s to the extenor dunng menses. With rising E2, the endometrium begins to prol iferate and increase
n t_hl_ckness. After ovu!ation , the CL produces P 4 that causes further proliferation and initiates secretory
act1v1ty of the endometnum. Luteolysis initiates an other menstrual period.
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