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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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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

Neural control requires: • simple neural reflexes or • neuroendocrine reflexes

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

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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 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.

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

Sphenoid Bone

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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

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.

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

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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

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.

Endocrine Control is Generally Slower, but Longer Lasting than Neural Control

Name gram

milligram

microgram

nanogram

picogram

Positive and Negative Feedback are the Major "Controllers" of Reproductive Hormones

Negative feedback= suppression of GnRll neurons

Positive feedback= stimulation of GnRllneurons

Nerves, Hormones and Target Tissues 1 07

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

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108 Nerves, Hormones and Target Tissues

LH surge= Ovulation

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

Hormones can be classified by: • source • mode of action • biochemical classification

Tissue Origin Constitutes One Method of Hormonal Classification

Figure 5-6. Amino Acid Sequence of GnRH

NH 2

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

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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

'-------< 25 24

A , B, C and D designate specific rings. Numbers designate specific carbons.

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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.

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.

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.

Biochemical classifications include: • peptides • glycoproteins • steroids • prostaglandins

Figure 5-B. Standardized Labeling of the Steroid

Molecule

21 22

'-------< 25 24

A , B, C and D designate specific rings. Numbers designate specific carbons.

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112 Nerves, Hormones and Target Tissues

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

( 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 I I I

COOH

Prostaglandin E2 (PGE2)

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

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112 Nerves, Hormones and Target Tissues

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

( 21 carbons)

Enzymatic conversion

Testosterone

( 19 carbons)

Enzymatic conversion

(I 8 carbons)

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 I I I

COOH

Prostaglandin E2 (PGE2)

I I I

OH OH

COOH

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)

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

known to influence the onset of puberty, the tdentrfication offemales in estrus by the males and other behavioral traits.

No Bin ding

Hormone action requires the presence of specific receptors on target cells.

Figure 5-12. Hypothetical Model of the LH Receptor

Extrace ll ular domain

Intrace llu lar domain

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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).

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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.

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

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

New protein products for reproduction

Cytoplasm

0 New protein

synthesis

Kinases

Steroid hormones have two types of receptors.

Nerves, Hormones and Target Tissues 115

S t eps of Action for Steroid Hormones : M embrane Recept ors ( " Fast Response")

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")

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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.

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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

Nerves, Hormones and Target Tissues 11 7

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.

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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

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118 Nerves, Hormones and Target Tissues

Half-Life of a Hormone Determines How Long It Will Act

Hormonal potency is influenced by: • receptor density • hormone receptor affinity

Receptor affinity for hom1ones vary. In gen- eral, the greater the affinity of the hom1one for the receptor, the greater the biologic response .

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

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

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

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 et B oo ks .ir

120 Nerves, Hormones and Target Tissues

Hormones can be detected in blood, saliva, milk, urine, lymph, tears, and

feces using radioimmunoassay (RIA) and enzyme-linked immunosorbent

assay (ELISA) technology.

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 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.

Enzyme antibody Hormone antibody

Reactio n - gene rates color

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

Protein

Hypothalamic surge and tonic centers

Juu<:: (pi tuit<try) (gunudotrupJJ s'::lb)

Anterior lobe-pit uit ary (gonadotroph ce lls)

Anterior lobe-pituitary (lactotroph cells)

Synthesized in the hypo- thalamus, stored in the posterior lobe-pituitary; synthesized by corpus luteum.

Granulosa! cells of follicle, pl acenta, Serto li cell s of testis

L'oqms lut eum and placenta

Interstitial cells o f Leydig, cells of theca inte rna in female

Granul os;J\ cells ( !Cmak) Sertol i ct.>l 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

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

Protein

Hypothalamic surge and tonic centers

Juu<:: (pi tuit<try) (gunudotrupJJ s'::lb)

Anterior lobe-pit uit ary (gonadotroph ce lls)

Anterior lobe-pituitary (lactotroph cells)

Synthesized in the hypo- thalamus, stored in the posterior lobe-pituitary; synthesized by corpus luteum.

Granulosa! cells of follicle, pl acenta, Serto li cell s of testis

L'oqms lut eum and placenta

Interstitial cells o f Leydig, cells of theca inte rna in female

Granul os;J\ cells ( !Cmak) Sertol i ct.>l 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

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..'<pulsion of the fetus.

The first interest in reproductive physiology was strongly linked to human se..t:. The first account of "reproductive physiology" was 1·ecorded in about 3200 B.C. in Mesopotamia. People of that age had no idea how the reproductive system fimctioned or even what its parts were (except for the extemal genitalia). However, they were apparently quite anxious to apply "technology" to evaluate reproduction. For example, women in Mesopotamia devised "home pregnancy tests" that involved urinat- ing on different materials such as grain and sprouts. Whether or not the sprouts germinated determined the pregnancy status of the female. Also, women wishing to know their pregnancy status would insert an onion into the vagina. If the onion smell was detected on her breath she was deemed pregnant.

Key References

Bartol, _F.F. and C.A. Bagnell (20 I I ). Lactocrine pro- grammmg of female reproductive tract development: E nvironmental connections to the reproductive con- tinuum. Molecular and Celu/ar Biology, I 0 : 10 I 6.

Bear, M.F., B. W. Connors and M.A. Paradiso. 1996. Neuroscience: Exploring th e Brain. Williams & Wilkins, Baltimore . ISBN 0-683 -00488 -3.

Brow n, J.L., L.H. Graham, N . Wielebnowski, W.F. Swanson, D.E. Wi ldt and J.G . Howard. 2001. "Un- derstand ing the bas ic reproductive biology of wild fel ids by monitoring faecal steroids " in Advances in Reproduction in Dor:s. Cats and Exotic Carnivores. P.W. Concan non, G.C.W. Eng land, W. Farstad , C. Linde-Forsberg, J.P. Verstegen and C . Doberska, eds. J. Reprod. Ferti/. Suppl. 57, p71 -82. Portland Press, Colchester, UK.

Combarnous, Y. 1993. "Gonado tropins: S truc ture- Synthesis-Functions" in Reproduction in Mammals and Man. p61-78. Thibault, C. , M.C . Levasseur and R.I-I.F. Hunter, eds. Ellipses, Paris ISBN 2-7298 -9354-7.

Cupps, P.T., ed. 1991. Reproduction in Domestic Ani- mals, 4th Edition. Academic Press, San Diego. fSBN 0- 12-1 96575-9.

Dubois, P. 1993 . "The hypotha lamic-p ituitary axis: em- bryological, morphological and functional aspects" in Reproduction in Mammals and Man. p 17- 50. Thibault, C., M.C. Levasseur and R.I-I .F. Hunter, eds. Ellipses, Paris. fSBN 2-7298-9354-7.

Nalbandov, A. 1976. Reproductive PhvsiolofJY o[Mam ma/s and Birds. W.I-1. Freeman Co., San Francisco. ISBN 0-7167-0843-4.

Nett, T.M. and J.M. Ma1vey. 1998. " Radioimmunoas- say" in Encvc/opedia o[Reproduction. Vol. 4 . pI 8 1- I 94. E. and J .D. Neill ( eds.) Academic Press, San Dtego. ISBN 0- I 2-227024-X .

Roa, J. , V.M. Nararro and M. Tena-Sempere. 20 11. "Kisspepti ns in reproductive biology: Concensus lmowledge and recent developments." Bioi. Reprod . 85:650-660.

Nerves, Hormones and Target Tissues 125 V et B oo ks .ir

124 Nerves, Hormones and Target Tissues

Key References

Bear, M.F., B. W. Connors and M.A. Paradiso. 1996. Neuroscience: Exploring th e Brain. Williams & Wilkins, Baltimore . ISBN 0-683 -00488 -3.

Cupps, P.T., ed. 1991. Reproduction in Domestic Ani- mals, 4th Edition. Academic Press, San Diego. fSBN 0- 12-1 96575-9.

Nalbandov, A. 1976. Reproductive PhvsiolofJY o[Mam ma/s and Birds. W.I-1. Freeman Co., San Francisco. ISBN 0-7167-0843-4.

Nett, T.M. and J.M. Ma1vey. 1998. " Radioimmunoas- say" in Encvc/opedia o[Reproduction. Vol. 4 . pI 8 1- I 94. E. and J .D. Neill ( eds.) Academic Press, San Dtego. ISBN 0- I 2-227024-X .

Roa, J. , V.M. Nararro and M. Tena-Sempere. 20 11. "Kisspepti ns in reproductive biology: Concensus lmowledge and recent developments." Bioi. Reprod . 85:650-660.

Nerves, Hormones and Target Tissues 125 V et B oo ks .ir

The Puerperium & Lactation

Parturition

Fetal Attachment & Gestation

Early Embryogenesis & Maternal Recognition of Pregnancy

Ovulation & Fertilization

Cyclicity

Regulation of Reproduction

Tract Function

Prenatal Development

" ,. ( ',

Spermatogenesis

Regulation of Reproduction

Tract Function

Prenatal Development

Take Home Message Puberty is the acquisition of reproductive competence. It is a process that occurs over

time, not an event. The onset of puberty depends on the ability of specific hypothalamic neurons to produce GnRH in sufficient quantities to promote and support gametogenesis. In the female, hypothalamic GnRH neurons must de velop the ability to respond to estradiol positive feedback before they can cause sufficient quantities ofGnRH to induce ovulation. Development of hypothalamic GnRH neurons is influenced by genetic and environmental factors and their itzteractions.

Before engaging the subject of puberty it is necessary fo r you to understand that there are fun da- mental differences in the hypothalamus of the male and fema le. These differences are established prena- tally and remain throughout the reproductive life of both sexes.

The hypothalamus is inherently female. Testosterone defeminizes the hypothalamus during embryogenesis

and "eliminates" the GnRH surge center in the male.

During prenatal development in the male, testosterone from the feta l testis " defeminizes" the brain. In contrast, the fem ale fetus has no testis to secrete testosterone and she therefore develops a GnRH surge center in the hypotha lamus. In order for testosterone to "defeminize" the hypoth alamus, it must first be converted to estradiol. Since the feta l ovaries produce estradio l, a logical question is, "Why doesn't the female hypothalamus become de- feminized?" The answer to this question lies in the inability of fetal estradio l in the female to cross the blood-brain barrier of the hypothalamus. A protein called alpha-fetoprotein binds estradiol and prevents it from crossing the blood-brain barrier (See Figure 6-1 ) . Therefore, estradiol cannot affect the hyp othala- mus. Alpha-fetoprotein is a glycoprotein synthesized by the embryonic yolk sac and later the fe tal liver. It serves as a feta l blood osmotic regulator and a CatTier offatty acids.

In the male, testosterone crosses the blood- brain banier, is converted to estradiol in the brain and the estradio l "defe minizes" the hypothalamus, thus minimizing surge center func tion. T here is good evidence that complete "defeminization" of the male hypoth alamus requires postnatal exp osure to

androgens. For examp le, if bulls are castrated at or near birth, they have som e ability to secrete a GnRH surge. Continued exposure to androgens is apparently required to render the surge center inoperative .

The female hypothalamus contains a surge center and a tonic cente1: The male hypothalamus does not

appear to have a surge center.

The fundamental difference in the endocrine profi les of the postpuber tal male and fe male is that LH does not surge in the ma le, but maintains a relatively consistent day-in and day- out p ulsati le pattern of secreti on. These pulses occur eve1y 2 to 6 hours in the postpubertal male. This steady GnRH pulsati le rhythm results in steady pulses of LH and, in turn, steady pulsatile secretion of testosterone. In contrast, you can readily see in Figure 6-2 that estradiol and LH surge about every 20 days in the fema le depending on the length of the cycle. D uring the time between the surges, low amplitude, repeated LH pulses are present.

Genera lly, pub er ty can be defined in both the male and femal e as the ability to accomplish reproduc- tion successfully. Puberty should be considered as a process that occurs over time , not a single event. The fun damental requirement for puberty is the secretion of GnRH at the appropriate frequency and quantities to stimulate gonadotropin release by the pituitmy. Go- nadotrop ins promote gametogenesis, stero idogenesis and the development of reproductive tiss ues. The number of neurons that secrete GnRH, their morphol- ogy and their distribution within the hypothalamus are established well before puberty. However, the degree to which they function increases as puberty begins. Neuroendocrino logists believe that the most important " drivers" of pubertal onset are the ability of presynaptic neurons to provide information to the

V et B oo ks .ir

The Puerperium & Lactation

Parturition

Fetal Attachment & Gestation

Early Embryogenesis & Maternal Recognition of Pregnancy

Ovulation & Fertilization

Cyclicity

Regulation of Reproduction

Tract Function

Prenatal Development

" ,. ( ',

Spermatogenesis

Regulation of Reproduction

Tract Function

Prenatal Development

Take Home Message Puberty is the acquisition of reproductive competence. It is a process that occurs over

The hypothalamus is inherently female. Testosterone defeminizes the hypothalamus during embryogenesis

and "eliminates" the GnRH surge center in the male.

The female hypothalamus contains a surge center and a tonic cente1: The male hypothalamus does not

appear to have a surge center.

V et B oo ks .ir

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, 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

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.

V et B oo ks .ir

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 .

Male

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 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 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.

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

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.

V et B oo ks .ir

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

10 Days

'GnRH

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

130 Puberty

Table 6·1. Mean Age (Range) of Puberty in Males and Females of Various Species

1 Very breed dependent - See Johnston et a/. in Key References.

2 See Tibary and Anouassi in Key References.

Genetics (breed) influence age at puberty.

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?

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

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

10 Days

'GnRH

V et B oo ks .ir

132 Puberty

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

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\ A 5 6 7 8

Time (hours)

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

V et B oo ks .ir

132 Puberty

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

In the male, the onset of puberty is brought about because of decreased hy-

pothalamic sensitivity to negative feedback by testosterone/estradiol.

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.

A Certain Degree of "Fatness" is Required for the Onset of Puberty

in the Female

Puberty 133

Hypothalamic neurons that regulate GnRH secretion detect

"moment-to-moment" changes in blood glucose and fatty acids.

Figure 6-5. Glucose Can Affect Hypothalamic Control of GnRH Secretion

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\ A 5 6 7 8

Time (hours)

10 II 12

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

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.

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

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)

Puberty 135

Figure 6-7. Possible Influence of Metabolic Signals Upon GnRH Neurons

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

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

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

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 <t ISO

100

so 0

Treat ment

The Story of Puberty is Not Complete

As you now know, the onset of puberty involves the capability of the hypotha lamic neurons to produce high frequency and low amplih1de GnRH pulses. This capability is influenced by achieving the appropriate energy metabolism/body size and appropriate exposure to external modulators such as photoperiod, size of soc ial groups and the presence of the male. Genetics of the animal likely plays a role in how these cues are generated within the animal (metabo lic signals) and/or perceived (external cues, metabolic signals).

T he exact mechani sms that enable estradiol to control G nRH secretion by the hypothalamus during the peripubertal period are unknown . A major cha llenge is to understand the impact of metabolism on the develop- ment of the hypothalamus. Currently, there is shallow understanding of how the brain recognizes growth so that the proper signals are sent to the hypothalamus and reproduction can commence.

With regard to soc ial cues, the presence of certain pheromones secreted by the same or opposite sex alters puberty. The pathway whereby these phero- mones send their message to the hypothalamus is, as yet, not well defined. The pathway is mediated through the olfactory and the vomeronasal organs (See Chapter 1 I), but neither specific agents nor a clear pathway have been described. Further, the visual pathway may be quite important in mediating pubertal onset, but this sensory avenue has received little research attention.

V et B oo ks .ir

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.

Social Cues Alter the Onset of Puberty

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.

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.

Metabolic status for puberty in the male is not well understood.

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 <t ISO

100

so 0

Treat ment

The Story of Puberty is Not Complete

V et B oo ks .ir

138 Puberty

Further PHENOMENA for Fertility An anomaly ofthe captive environment for the endangered clouded leopard is that males and females must be paired before they reach puberty. If they are housed together after pu- berty the male becomes very aggressive and frequently injures or even kills the female. This happens even after long introduction efforts with animals kept in adjacent pens and making sure that animals are placed together only when the female is in estrus. This behavior does not happen in the wild.

It is said that puberty begins during the night in children. Concentrations of gonadotro- pins are low during the day and night in prepubertal children but as the transition into adulthood occurs, the nighttime concen- trations also increase as puberty progresses. The notion that night is a special time for maturation is really not true because when the sleep cycle is reversed, the pubertal rises in gonadotropin secretion are also reversed. It seems as if these increases in GnRH se- cretion are associated with REM (rapid eye movement) stages of sleep, although the physiological and adaptive reasons for this phenomenon are not known.

The famous boys' choirs in Europe consisted entirely of prepubertal boys. It was recog- nized that their high pitched clear voices were "ruined" during and after puberty. Many of these boys were orchidectomized so that their boyhood voices could be retained. Castrato choirs were composed of adult male singers castrated in boyhood so as to retain soprano or alto voices.

The age of puberty in girls is decreasing. From records kept (in Norway) about the time of menarche (first menses) we know that puberty occurred at about 17 years of age in the mid-1800s. Today, this same reproductive endpoint occurs at 12 years of

age in Europe and the US. Interestingly, the body weight at menarche is the same now as it was 150 years ago. Young women today are growing faster than they did 150 years ago. The likely explanation for this is that nutrition today is much better ami that more energy is available in wealthy coun- tries. In poorer countries where nutrition is not adequate, puberty continues to occur at older ages.

In naked mole rats, the dominant female (called the queen) suppresses puberty in the subordinates (i.e. there is no vaginal opening that occurs at puberty). Once thought to be due to the suppressive effects of pheromones, a more recent tltemy is that the queen actually uses tactile stimulation to suppress puberty by regularly having physi- cal contact with each female.

Some young women do not jim/ out until puberty that they are genetically males but their sex cannot be reassigned. The condi- tion is most commonly diagnosed when girls are brought to the clinic because of delayed pubertal progression (no breast develop- ment, no menarche). Upon genetic evalua- tion, such rare individuals are diagnosed as males having a deficiency in receptors for androgens. Clearly, they will never be able to bear children, but they also cannot be treated to become norma/males physiologi- cally as exogenous testosterone will have no effect because of the receptor deficiency. The only course of action is to administer estrogens and to produce the secondary sex characteristics typical of a woman. The testes should be removed surgically to pre- vent the development of carcinomas that are often associated with intra-abdominal testicular tissue.

Victorian women (1837-1901 AD) inserted wooden blocks inside their vaginas to ob- struct the passage of sperm.

Kev References

Clarke, I.J. and B.A. H eruy, 1999. "Leptin and Reproduc- tion." R eviews of Reproduction. 4:48-55.

Foster, D.L. 1994. "Puberty in the Sheep" in The Phvsi- ology o{Reproduction 2nd Edit ion, Vol. 2 p 4 11-452 . E. Knobil and J.D. Neill, eds. Raven Press, Ltd., New York. ISBN 0-7817-0086-8.

Foster, D.L. and S. Nagatani. 1999. "Physiological per- spectives ofleptin as a regulator of reproduction: role in t iming puberty." Bioi. Reprod. 60:205-215 .

Head, H.H. 1992. " H eifer performan ce standards: rearing systems, growth rates a nd lactation" in Large Herd Dairv Managem ent. Van Horn and Wi lcox, eds. A meric an Dairy Science Association . Champ ai gn, Illinois. ISBN 0-963449 1-0-9.

Johnston, S.D., M. V. Root Kustritz and P.N.S . Olson. 2001. Canine and Feline Theriogenolo't)J. W.B. Saunder s Company, Philadelphia. IS BN 0-72 16-5607-2.

Kinder, J.E., M. S . Rob erson, M.W. Wo lfe and T. T. Stamp f. 1994. "Management factors affecting puberty in the heifer" in Factors Affocting Cal( Crop M.J. F ields and R. Sands, eds.CRC Press, Inc.ISBN 0- 8493 -8754-X.

Plant, T.M. 1994. " Puberty in primates" in The Phvsiol- ogy o(Reproduction, 2nd Edition, Vol 2 p 45 3-486. E. Knobil and J.D. Neill, eds. Raven Press, Ltd., New York. ISBN 0-781 7-00 86-8.

Roa, J., V.M. Nararro and M . Tena-Sempere. 20 11. "Kiss- pep tins in reproductive biology: Concensus knowl edge and recent developments." Bioi. Reprod. 85:650-660.

Tibary, A. and A. Anouassi. 1997. Theriogenolo'S)' in Camelidae . United Arab E mirates, M inistry of Cul- ture and Information. Pub lication authorization No . 3849/ 1116. ISBN 998 1- 80 1-32-1.

Williams, G.L. 1999. "Nutritional Factors and Reproduc- tion" in Encvclopedia ofReproduction, Vol3 p 4 12-42 I. Knobil E . and J.D. Neil, eds.Academic Press, San Diego. ISBN 0-12-227023- 1.

Puberty 139 V et B oo ks .ir