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Chapter 8: Puberty.

CHAPTER OBJECTIVES

* Define and characterize puberty in mammals.

* Describe the biological significance of puberty.

* Provide a theoretical framework for understanding puberty.

* Describe the physiologic events leading to onset of puberty.

* Describe the physiologic mechanisms regulating timing of puberty onset.

CHARACTERISTICS AND SIGNIFICANCE OF PUBERTY

This chapter marks the beginning of detailed discussions concerning physiologic mechanisms controlling reproduction in mammals. These discussions rely heavily on the background information provided in earlier chapters. Therefore, you should make sure you have a firm understanding of terminology, anatomy, sexual differentiation, and basic endocrinology. We begin with an analysis of sexual maturation, which can be viewed as a continuation of the previous discussion of sexual differentiation.

What is Puberty?

It is likely that humans became cognizant of the biological changes associated with sexual maturity long before recorded history. The transition between childhood and adulthood is recognized as a significant event in virtually all human societies, and in many cases is celebrated by rites of passage. The physical and emotional changes that children express as they become adults are attributed to development of various secondary sex characteristics. One of the more noticeable changes is the development and distribution of body hair. In fact, the term puberty is derived from the Latin word pubescere, which means "becoming covered with hair." This literal translation is quite anthropocentric because it refers to a change that occurs only in humans. In other mammals a change in pelage does not accompany sexual maturation.

In the modern sense of the word, puberty refers to all of the physiologic, morphologic, and behavioral changes that occur in association with developing the ability to reproduce. This involves both the ability to produce viable gametes (gonadal maturation) and the behavioral capacity to engage in sexual activity (behavioral maturation). Specifically, these abilities require maturation of the genital organs and development of secondary sex traits. It is important to understand that puberty is a process involving temporal changes in the reproductive system. Thus, there is no simple definition of puberty. For most female mammals (those that express estrous cycles as adults), puberty is typically assumed to be completed when an individual first expresses sexual receptivity (estrus). In the so-called higher primates, puberty is usually thought of as the time at which first menstruation occurs. However, neither of these definitions is adequate because the first estrus and first menstruation aren't necessarily correlated with fertility. A more useful definition of puberty in females is the time at which an individual ovulates and experiences a fertile estrous or menstrual cycle. In males, puberty occurs when the individual expresses copulatory behavior and produces sufficient viable spermatozoa to impregnate a female.

Although development of the gonads and reproductive behavior are intimately related, they are distinct processes involving different neurobiological mechanisms. This is illustrated by the fact that in some species such as cattle, the first expression of estrus is not normally accompanied by ovulation. In this chapter we will view puberty in terms of maturation of the gonads and focus our attention on mechanisms controlling development of the gonads.

Biological Significance of Puberty

The reproductive success of an individual depends on the number of offspring it produces in a lifetime. According to this Darwinian perspective, one might conclude that an animal that begins reproducing at an early age will have a high reproductive rate in its lifetime. However, there are significant biological risks associated with early sexual maturity. Recall from our earlier discussions that reproduction, like all other biological activities, depends on availability of metabolic energy. Although animals that express reproductive activity at early ages have the opportunity to produce more offspring in a lifetime than later maturing animals, they might also have their reproductive abilities compromised by not having sufficient energy to find and defend territories and mates as well as care for their young. Moreover, they may experience higher mortality rates because they divert less energy to life-sustaining processes. In light of these trade-offs it would seem that the timing of sexual maturation is a critical determinant of lifetime reproductive success and therefore is subject to natural selection. Indeed, selection pressure seems to have promoted considerable plasticity in age at puberty among mammals. Age at puberty varies considerably within a particular species, and depends largely on environmental conditions. As a rule, mammals become pubertal only when the opportunity for successful reproduction arises; for example, when the individual has access to adequate dietary energy to support vital processes and lives in social and physical conditions that promote high reproductive success. This means that mechanisms governing sexual maturation are responsive to cues that provide information about the individual's internal and external environments.

Management of domestic livestock relies heavily on the principles discussed in the previous paragraph. For example, the greatest source of variation in lifetime production of beef cows is the age at which the cow first produces a calf. The same thing can be said for sheep, swine, or any animal used for food production. This realization is responsible for the fact that most modern production systems emphasize management of the developing female in ways that minimize age at puberty. However, as noted previously, there are significant costs associated with this type of management. In order to reach puberty at an early age, an animal must be fed a high plane of nutrition to ensure that it maintains adequate growth as well as other vital processes. Feed costs represent one of the major expenses of livestock producers. Unless there is abundant energy available at low costs, it may not be profitable to manage animals to reach puberty at an early age. In some climates (e.g., parts of North America and Europe) it may be economically feasible to feed livestock high planes of nutrition to minimize age at puberty. Such practices may not be possible under different circumstances.

THEORETICAL FRAMEWORK FOR PUBERTY

The previous discussion on the biological importance of puberty illuminates an extremely important concept; that is, the timing of puberty is a major determinant of the lifetime reproductive success of an individual. From a theoretical perspective, this means that a comprehensive understanding of the mechanism of puberty onset requires insight into how sexual development proceeds, as well as how the time of puberty onset is determined.

Permissive Signals and a Developmental Clock

Decades of research involving laboratory animals, domestic animals, and humans has lead to development of a general theory for puberty onset (Figure 8-1). The theory consists of two parts. First, it is generally accepted that multiple "permissive signals" determine when onset of puberty begins. These signals provide information about an individual's metabolic status, its social relationship with other individuals, as well as the physical environment in which it lives. These signals work in consort with each other and collectively determine when the individual becomes pubertal. The second part of the theory involves a "developmental clock." According to this idea, the development and coordinated activities of the reproductive organs unfold in an ordered fashion and results from expression of particular "puberty genes" (Figure 8-2). Some of the more important puberty genes govern:

* Hypothalamic release of gonadotropin-releasing hormone (GnRH).

* Release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland.

* Release of gonadal hormones.

* Positive and negative feedback systems.

[FIGURE 8-1 OMITTED]

Of these regulatory genes, those mediating responses to permissive signals may be most important. For example, the extent to which an increase in dietary energy intake enhances puberty depends on the extent to which feedback mechanisms controlling LH secretion are developed. Using the clock metaphor, timing of puberty is regulated by permissive signals that influence when the puberty alarm sounds, rather than the rate at which the clock ticks.

[FIGURE 8-2 OMITTED]

[FIGURE 8-3 OMITTED]

Theories are considered true only if they have high explanatory power. How well can the aforementioned theory of puberty explain well-documented claims concerning the effects of various environmental factors on sexual development? For example, how is it that animals fed high-energy diets reach puberty at earlier ages than those fed low-energy diets? Consider beef heifers for instance (Figure 8-3). These animals typically attain puberty at an average of 12 months of age. However, if they are raised on a low plane of nutrition (e.g., grazing poor-quality pastures or rangeland), or if they are depleting energy reserves to cope with internal parasites or stress, they may not become sexually mature until much later. In contrast, feeding an extremely high plane of nutrition induces puberty as early as 6 months of age. These observations support the previously mentioned idea that age at puberty is plastic; that is, it can occur at any time after a certain minimum age. According to the aforementioned theory, the developmental clock appears to be fully developed (i.e., puberty genes are expressed) by 6 months of age, but the puberty alarm doesn't sound until nutritional (permissive) signals allow it to (i.e., until certain nutritional signals appear). Other signals also influence timing of puberty. For example, demographics (e.g., sex ratio and presence of mature individuals) and seasonal changes in environment (e.g., temperature and day-length) play roles in determining when the puberty alarm sounds.

Importance of GnRH in Puberty

The precise nature of the developmental clock controlling puberty onset remains elusive. This notion is complicated by the fact that each reproductive organ undergoes a series of developmental changes leading up to puberty. In addition, successful reproduction depends on the coordinated activity of all components of the reproductive system. Thus, activity of one reproductive tissue affects and is affected by other reproductive tissues. There is variation among mammalian species regarding the nature of the developmental clock. In later sections, we will examine three major developmental patterns: rodents, domestic ungulates, and primates. Although the sequence of puberty gene activation appears to differ among these groups, mechanisms regulating secretion of GnRH and LH are of critical importance in all cases.

In spite of differences in developmental steps leading to puberty among mammals, there are some important similarities. A voluminous amount of puberty research supports the hypothesis that development of the hypothalamic-pituitary system is of pivotal importance in sexual maturation. In particular, a high-frequency pattern of LH release appears to be a necessary condition for puberty onset in all species of mammals. This depends on the ability of the hypothalamus to release GnRH in an episodic manner. Thus research that seeks to illuminate the mechanisms controlling sexual maturation focuses heavily on regulation of GnRH release.

Regulation of GnRH Release

GnRH is a neurohormone produced by neurosecretory cells that are sparsely distributed in the anterior hypothalamus. These cells release GnRH into the hypothalamic-hypophysial portal vessels in pulses. The hormone then travels to the anterior pituitary gland and induces the release of LH. The pattern of LH release from the pituitary gland is also pulsatile and corresponds closely to the pattern of GnRH release. This relationship can be seen when concentrations of GnRH and LH are measured in sequential blood samples collected simultaneously from hypophysial portal and peripheral blood vessels (Figure 8-4). The close association between patterns of GnRH and LH means that changes in LH concentrations in peripheral blood provide an accurate characterization of GnRH release from the hypothalamus. Because of the difficulty in measuring GnRH concentrations in portal blood, most studies rely on LH patterns to assess GnRH release.

[FIGURE 8-4 OMITTED]

GnRH Pulse Generator

The neural mechanisms regulating the pulsatile pattern of GnRH release are thought to involve a "GnRH pulse generator." Although this is an extremely useful concept, the anatomic nature of such a system has not been adequately described. Precise characterization of the GnRH pulse generator is difficult because 1) the number of GnRH neurons (1,000-3,000 cells) is very small compared to other types of nerve cells, 2) GnRH neurons are scattered and not clustered in particular hypothalamic nuclei, and 3) the innervation of GnRH neurons is extremely sparse compared to neighboring nerve cells. Although we know very little about the physical nature of the GnRH pulse generator, we do know that the system is subject to regulation by various neuronal and humoral mechanisms. As you will soon learn, maturation of the GnRH pulse generator appears to be an important rate-limiting step leading to onset of puberty. In other words, animals do not attain puberty until they can exhibit adult patterns of GnRH release. Using language consistent with the prevailing theory of puberty onset, one can say that expression of genes that comprise the pulse generator is a prerequisite for puberty onset, but the precise timing of the onset of adult patterns of GnRH depends on the presence of appropriate permissive signals.

[FIGURE 8-5 OMITTED]

Steroid-Independent and Steroid-Dependent Control

Two major types of neural mechanisms regulate the pulsatile secretion of GnRH: steroid-independent and steroid-dependent (Figure 8-5). The former type regulates GnRH release in the absence of gonadal steroids, whereas the latter type requires the presence of gonadal steroids. Steroid-independent changes in patterns of LH secretion typically involve changes in patterns of GnRH release. In contrast, changes in sensitivity of the hypothalamic-pituitary axis to the feedback actions of gonadal steroids mediate steroid-dependent control of LH release. A change in sensitivity of a target cell to a particular hormone means that the response to a particular amount of hormone changes. This concept can be expressed mathematically as [T.sub.s] = [DELTA]R/[DELTA][H], where [T.sub.s] is the sensitivity of the target cell, [DELTA]R is the change in response of the target cell, and [DELTA][H] is the change in concentration of the hormone. For example, the amount of estradiol required to suppress LH concentrations in ovariectomized females increases during the late prepubertal period. In terms of the sensitivity formula, [DELTA]R[DELTA][H] becomes smaller as females approach sexual maturity. Changes in sensitivity to hormones are undoubtedly attributed to changes in hormone receptors. In some cases, this involves changes in receptor number. However, changes in receptor type and postreceptor events might also be involved.

The sites at which gonadal steroids act to influence GnRH release have not been precisely identified in most species. However, it is clear that these hormones do not act directly on GnRH neurons: few if any receptors for steroid hormones have been found on GnRH neurons. Therefore, steroid-dependent effects appear to be mediated by other neurons that innervate GnRH-producing cells.

Two steroid-dependent mechanisms control GnRH release; that is, positive and negative. Gonadal steroids feed back on the hypothalamus to influence GnRH release in both positive and negative ways. You should understand that positive and negative feedback mechanisms are separate and most likely involve different populations of GnRH neurons. With respect to puberty, we will be concerned with the negative and positive feedback actions of estradiol in females and the negative feedback actions of testosterone in males. The negative feedback effects of estradiol and testosterone result in a low-frequency pattern of GnRH release. The positive feedback action of estradiol produces an LH surge.

MECHANISMS CONTROLLING PUBERTY

The vast majority of research on puberty has focused on the female. Although much of this information is applicable to the male, there are important differences. In the next several sections, we will examine mechanisms controlling puberty in several types of females, and then consider some general characteristics that are unique to males.

Regulation of Puberty in Females

As noted earlier, sexual maturity involves both behavioral and physiologic development. Our current discussion will emphasize the physiologic changes that result in the ability to reproduce. With respect to females, the ability to ovulate is the physiologic endpoint of greatest concern. Therefore, our anal ysis of puberty in mammalian females will be restricted to events leading to first ovulation. We know virtually nothing about the physiology of sexual maturation in most mammalian species. Almost all of the research in this area has been confined to laboratory rodents, the so-called higher primates (Old World monkeys, apes, and humans), and domesticated ungulates. Because there are important differences among these groups, we will consider each group separately.

Rodents

Virtually all of our knowledge of rodent reproduction is based on research done with rats. Rats were first used for research in the mid-nineteenth century, and were domesticated during the early twentieth century. Since that time, laboratory rats have been used extensively for all types of biological and medical research, including reproductive physiology. Much of our understanding of mammalian reproduction stems from experiments involving this species.

As with all species, the sexual development of rats encompasses both the pre-and postnatal periods. The gestation period of rats is 22 to 23 days in length. Studies of postnatal development are facilitated by dividing the period between birth and puberty into neonatal (0 to 7 days), infantile (8 to 21 days), juvenile (21 to 35 days) and peripubertal (35 to 60 days) periods. Rat pups are born at a highly immature stage of development (comparable to a 150-day-old human fetus) and reach puberty at an early age (35 to 45 days).

In spite of the fact that the neonatal rat is underdeveloped compared to other mammals, components of its reproductive system are intact and functional at the time of birth or shortly thereafter. Neurosecretory cells in the hypothalamus are producing GnRH by day 17 and 18 of gestation, and LH and FSH can be detected in the anterior pituitary gland by 21 days of gestation. However, circulating concentrations of these gonadotropins remain low until birth. Production of steroid hormones and the appearance of primordial follicles occur within the first 2 days after birth.

The sequence of major physiologic events leading to first ovulation in the female rat is summarized in Figure 8-6. As mentioned previously, these events can be understood as time points on a developmental clock, and represent expression of critical puberty genes. Among the most important of these events are three "activational periods of the hypothalamic-pituitary unit." These events set into motion responses that coordinate activity of various reproductive tissues culminating in first ovulation.

[FIGURE 8-6 OMITTED]

The first activational period occurs during the infantile stage of development. This period is characterized by elevated concentrations of FSH and variable concentrations of LH in blood. These patterns of gonadotropins have been attributed to disorganized activity of GnRH-secreting cells. The resulting pattern of GnRH release induces a sustained release of FSH, but only low-frequency pulses of LH. The elevated concentrations of FSH stimulate development of some primordial follicles, moving them into a pool of follicles that will develop further (i.e., a proliferative pool).

Much of the juvenile period of development is characterized by low circulating concentrations of LH and FSH. This is due to the fact that GnRH release by the hypothalamus is restrained during this period of development. This restraint is likely attributed to a dominance of inhibitory neuronal inputs regulating GnRH-secreting neurons; that is, a central restraint. A second activational period occurs at the end of the juvenile period. At this time, the influence of inhibitory inputs diminishes and the effects of excitatory inputs increase. This results in activation and synchronization of GnRH neurons, which causes a high-frequency mode of pulsatile LH secretion. Interestingly, this pattern of LH secretion is confined to the afternoon. The occurrence of high-frequency LH pulses has tremendous physiologic significance. The elevation in LH resulting from this pattern of secretion coincides with appearance of LH receptors in the ovary. An increase in LH release, coupled with the ability of follicles to respond to LH, results in enhanced development of the ovarian follicles that entered the proliferative pool during the infantile period. Follicle development during the juvenile period is also stimulated by FSH, other pituitary hormones (prolactin and growth hormone), as well as neurotransmitters produced by neurons that innervate the ovaries. One of the more significant consequences of this increased follicular development is an increase in production of estradiol by the ovaries. During the juvenile period, an estradiol-LH positive feedback system has begun to develop. This means that estradiol (produced by the ovaries) feeds back on the hypothalamus and to further enhance GnRH release. This results in the appearance of "mini-surges" of LH during the afternoon. These mini-surges of LH further enhance production of estradiol by the ovaries.

The third and final activational period marks the transition between the juvenile and peripubertal periods, and involves maturation of the estradiol-LH positive feedback system. During the juvenile period, a population of GnRH neurons begins developing the capacity to release increased amounts of GnRH in response to elevated concentrations of estradiol, causing minisurges of LH. Once these neurons become fully responsive to estradiol, they gain the capacity to elicit a full surge of LH in response to elevated estradiol concentrations. By the time this occurs, ovarian follicles have become fully developed and are maximally responsive to gonadotropins. The massive increase in LH that characterizes the LH surge induces rupture of pre-ovulatory follicles and release of oocytes.

In addition to inducing a pre-ovulatory surge of LH, the rise in estradiol caused by follicle maturation induces estrus behavior. In this way sexual receptivity is synchronized with ovulation, thereby enhancing the chance of a fertile mating.

Before we discuss puberty in other mammalian species, it is important to mention that the negative feedback actions of ovarian steroids do not seem to play an important role in the sexual development of rodents. The increase in LH secretion that is pivotally important in pubertal development in rats is attributed to changes in neuronal inputs that activate and synchronize activity of GnRH neurons. In domestic ungulates the prepubertal increase in LH secretion is attributed to a decrease in response to the negative feedback actions of estradiol. The female rat expresses a similar change in response to estradiol negative feedback, but this occurs after (not before) first ovulation.

Domestic Ungulates

Much of what has been learned about the endocrine mechanisms governing puberty onset in rodents also applies to domestic ungulates. In each case, onset of puberty depends on four necessary conditions: 1) the ability of the hypothalamic-pituitary unit to produce high basal levels of LH (i.e., high-frequency pulses), 2) the ability of the ovaries to develop pre-ovulatory follicles and produce high levels of estradiol in response to elevated LH secretion, 3) the ability of the hypothalamic-pituitary unit to elicit a pre-ovulatory surge of LH in response to high levels of estradiol, and 4) the ability of pre-ovulatory follicles to ovulate in response to an LH surge. Of these four conditions, the first is the last to be achieved, and therefore appears to be the event that ultimately determines the timing of puberty onset. As noted in the previous discussions, the prepuberal rise in basal LH secretion in rats is due primarily to steroid-independent mechanisms, in particular removal of the central restraint that suppresses GnRH release. In domestic ungulates, steroid-dependent mechanisms play a major role in keeping LH pulse frequencies low during the prepubertal period. Specifically, the hypothalamic-pituitary unit becomes less sensitive to estradiol negative feedback within the last few weeks of the prepubertal period, allowing LH pulse frequencies to increase and stimulate follicle growth to the pre-ovulatory stage.
BOX 8-1 Focus on Fertility: The Gonadostat Hypothesis

The so called gonadostat hypothesis is the earliest
attempt to explain onset of puberty in the rat. It
was developed during the 1930s and gained wide
support until it was refuted in the early 1980s.
Ironically, the hypothesis has been proven to be
applicable to species other than the one in which
it was originally developed.

According to the gonadostat hypothesis, the
increase in LH pulse frequency that is necessary for
gonadal maturation results from a resetting of the
hypothalamic-pituitary system (the gonadostat) to
the negative feedback actions of gonadal steroids
(testosterone in males and estradiol in females).
The earliest evidence supporting this idea comes
from observations regarding age-related changes in
response to gonadodectomy in rats. Removal of the
gonads results in formation of "castration cells" in
the anterior pituitary gland. Castration cells reflect
the removal of the negative feedback actions of
gonadal steroids on pituitary cells that produce
gonadotropins. Formation of castration cells is
prevented if animals are provided with injections of
gonadal steroids. The fact that the dose of estradiol
required to prevent formation of these cells in
immature female rats is only 1 percent of that
required to produce the same response in adults
was interpreted to mean that the young animal is
much more sensitive to the negative feedback actions
of estradiol on the pituitary gland. Research
in the 1960s and 1970s confirmed that the sensitivity
of the gonadostat to the negative feedback
actions of testosterone and estradiol decreased as
rats approached puberty (Figure 8-7). However, a
careful analysis of LH patterns in developing rats
revealed that the decrease in response to negative
feedback occurs after onset of puberty. The prepubertal
increase in LH in rats appears to be due to
removal of a gonadal steroid independent (most
likely centrally mediated) inhibition of GnRH
release.

[FIGURE 8-7 OMITTED]

In spite of the fact that the gonadostat
hypothesis proved to be inadequate to explain
onset of puberty in rats, it did provide a useful
conceptual framework for studying puberty in a
variety of mammals. As it turns out, the hypothesis
appears to be valid for sheep, cattle, and pigs,
but not for primates. The history of the gonadostat
hypothesis illustrates that a scientific hypothesis
can be wrong but extremely important in advancing
our understanding of a phenomenon.


[FIGURE 8-8 OMITTED]

The heifer is a good model for understanding puberty onset in domestic ungulates because the physiologic events associated with sexual maturation have been thoroughly characterized and this information has been used to manipulate age at puberty in production of beef and dairy cattle (Figure 8-8). Sheep and swine have also been used extensively in studies of puberty onset. The time course of events leading to the onset of puberty is well characterized in heifers. A similar pattern of developmental events applies to the ewe lamb and gilt, but the ages at which these events occur vary according to how rapidly the animal develops sexually.

Antral follicles first appear on the ovaries of calves before birth and become responsive to gonadotropins between 2 and 4 weeks of age. Exogenous LH and FSH have been shown to induce development of pre-ovulatory follicles by 4 weeks of age, and injections of LH that mimic the LH surge induce ovulation of such follicles. The hypothalamic-pituitary unit of cattle is intact and functional by the first few weeks of life. In calves the hypothalamus releases GnRH in a pulsatile manner by 2 weeks of age. Moreover, pulses of LH have been detected in peripheral circulation by this age. The ability to respond to the stimulatory feedback action of estradiol appears to be fully developed by 5 to 6 months of age. Based on this evidence it seems that the heifer calf has the potential to become pubertal by 6 months of age. How is it that most heifers do not reach puberty until much later (12 months)? The answer to this question can be developed by understanding the regulation of pulsatile LH release in the developing heifer.

The pattern of pulsatile LH in calves changes between birth and puberty. During the infantile period (0 to 2 months), LH pulses begin to appear in the circulation and the number begins to increase. This may be due to organization and activation of GnRH-secreting neurons and the pituitary gland gaining the ability to respond to GnRH. The frequency of LH pulses increases and then declines during the early prepubertal period (2 to 5 months), and remains low throughout the late prepubertal period (5 to 10 months). The increase in LH may be due to a lack of feedback inhibition by the ovary. At this stage of development, ovarian follicles are beginning to develop and produce very little estradiol. The subsequent decline in LH concentrations is likely due to the negative feedback actions of estradiol which is being produced by developing follicles. This negative feedback prevails throughout the late prepubertal period and sustains a low-frequency pattern of LH secretion. During the peripubertal period (between 10 months of age and puberty), LH pulse frequency increases to a level exceeding that of the early prepubertal period. This has been attributed to a decrease in sensitivity to the negative feedback actions of estradiol.

The conclusion that the low frequency pattern of LH during the prepubertal period is attributed to a high sensitivity of the hypothalamic-pituitary unit to estradiol negative feedback is based on two important observations. First, ovariectomy of prepubertal heifers results in an increase in LH pulse frequency. Second, administration of estradiol prevents the effects of ovariectomy on pulsatile LH secretion. The conclusion that the prepubertal increase in pulsatile LH release is due to a loss of sensitivity to estradiol negative feedback is based on the observation that ovariectomized heifers given estradiol exhibit an increase in pulsatile LH secretion at about the time of puberty onset in intact heifers. These observations do not exclude the possibility that a steroid-independent mechanism (similar to removal of central restraint) might also contribute to the prepubertal increase in pulsatile LH secretion in heifers and other ungulates.

What are the consequences of the escape from estradiol negative feedback? The resulting increase in LH pulse frequency sets into motion a series of events that culminate in estrus and ovulation. In order to understand how this works it is necessary to keep in mind that the ovaries of prepubertal animals are expressing waves of follicular growth. In other words, proliferative pools of follicles develop to various stages. Some of these may become tertiary follicles, but they ultimately undergo atresia rather than develop into pre-ovulatory follicles. However, if a large tertiary follicle encounters a high-frequency pattern of LH, it develops into a pre-ovulatory follicle. The details of this process will be discussed in the next two chapters. The pre-ovulatory follicle produces high levels of estradiol and causes circulating concentrations of this steroid hormone to increase. At a particular threshold concentration, estradiol induces estrus as well as an LH surge. The LH surge induces ovulation of the pre-ovulatory follicle.

There is little doubt that the escape from estradiol negative feedback is an important prerequisite for onset of puberty in heifers. However, this physiologic change does not appear to be a developmental event as much as a means by which various environmental cues influence reproductive activity. Changes in sensitivity to estradiol negative feedback also mediates the effects of season, nutrition, and lactation on reproductive activity of domestic ungulates. Under certain circumstances (e.g., high plane of nutrition), heifer calves attain puberty as early as 6 months of age. Thus it appears that the inhibition of LH release by estradiol negative feedback can be overcome. Such a mechanism may serve as a means to allow the female to reproduce when environmental conditions are favorable.

Primates

Unlike rodents and many other mammals, primates experience a long interval between birth and puberty. For example, in human females, puberty isn't initiated until the second decade of life. Another important difference between most primates and other mammals is the fact that in the vast majority of primate species, females do not express a heat period (estrus). Although there may be fluctuations in sexual activity in these females they appear to be sexually receptive at all times. Whereas first estrus is useful in estimating age at puberty in non-primate species, first menstruation (menarche) is the most noticeable external change associated with sexual maturation in female primates. Unlike estrus, menstrual flow is not tightly coupled with ovulation. Ovulation occurs approximately 14 days after the initiation of menstruation during the normal menstrual cycle of adults.

[FIGURE 8-9 OMITTED]

Figure 8-9 summarizes the major events leading to onset of puberty in the female primate. The key to understanding the onset of puberty in the females of these species is the fact that an increase in the pulsatile release of LH is an important necessary condition that sets into motion a cascade of events which lead to menarche and ovulation. In fact, this is similar to what occurs in female rodents. Recall that in the female rat, the occurrence of mini-surges of LH during the afternoon stimulates follicle growth to the pre-ovulatory stage. Another similarity between rats and primates is that prior to the prepubertal increase in LH, GnRH secretion is held in check by a central restraint.

Ovarian development in humans and other primates begins early in gestation. By 16 to 20 weeks of pregnancy the number of germ cells in the primate ovary reaches a peak. Primordial follicles appear at this time and soon give rise to primary follicles. Such development is not dependent on gonadotropins. Later in gestation (after the second trimester), the fetal ovaries develop FSH receptors. This permits FSH to induce development of primary follicles into antral follicles. Although the fetal and prepubertal ovaries contain antral follicles, they undergo atresia rather than develop into pre-ovulatory follicles. The size of the ovaries increases between infancy and adulthood, primarily due to an increase in number of antral follicles as well as an increase in mass of the medullary stromal tissue. Steroid hormone production by the ovaries parallels follicular development. By 8 to 10 years of age, production of estradiol by the human ovaries is comparable to that of adult women, and induces development of secondary sex traits (e.g., pubic hair, and breast development). By 12 to 13 years of age, most girls undergo menarche, which is indicative of the fact that the ovaries have produced sufficient amounts of estradiol and progesterone to induce proliferation of the uterine endometrium. The female primate is rarely fertile at menarche. In most cases, first ovulation doesn't occur until at least 6 months after first menstruation. Regular, fertile menstrual cycles may not occur until several years later in humans.

In primate females, attainment of puberty appears to be dependent on development of a high-frequency pattern of pulsatile gonadotropin secretion. The hypothalamic-pituitary portal system develops early in pregnancy allowing GnRH to stimulate release of LH and FSH. Concentrations of these gonadotropins in fetal blood increase throughout the first half of gestation, and then decline by the end of gestation. In humans, circulating concentrations of LH and FSH increase to adult levels during the first 2 years of life, but then decline until late in the prepubertal period. This period of low gonadotropin secretion is known as the quiescent period of gonadal development, or the prepubertal hiatus in gonadotropin secretion. In humans this occurs between 4 and 11 years of age. The low concentrations of LH and FSH prevent ovarian follicles from developing to the pre-ovulatory stage.

The physiologic basis of low gonadotropin secretion during the prepubertal period of primates has been elucidated by several important experiments. As noted earlier, suppression of gonadotropin release can be attributed to steroid-dependent and steroid-independent mechanisms. In the case of primates, steroid-independent mechanisms appear to be more important. The strongest evidence for this conclusion is the fact that removal of the ovaries at 1 week of age in rhesus monkeys failed to abolish the prepubertal hiatus in gonadotropin secretion. This is consistent with the idea that the inhibition of gonadotropin secretion during this period is due to inhibitory inputs that do not depend on actions of ovarian steroids.

There is evidence to suggest that steroid-dependent mechanisms play a role in prepubertal regulation of gonadotropin secretion. It is clear that the negative feedback actions of estradiol develop by the end of fetal development and are likely present throughout the prepubertal period. Although such effects cannot account for the prepubertal hiatus in LH and FSH secretion, they may be of significance before development of the central restraint as well as after removal of this steroid-independent inhibition.

Late in the prepubertal period (11 to 12 years of age), the hypothalamic-pituitary unit "re-awakens" and gonadotropin secretion increases. This response is diurnal in nature, consisting of a nocturnal increase in the pulsatile release of LH and FSH. In humans, the increase in pulsatile release of LH is associated with rapid-eye movement (REM) sleep. There is consensus that this increase in gonadotropin secretion is due to a decline in central inhibition of GnRH as well as a decreased sensitivity to the negative feedback actions of estradiol.

The consequence of increased gonadotropin secretion is enhanced development of ovarian follicles. The increase in pulsatile LH secretion is associated with appearance of large, antral follicles and elevated release of estradiol by the ovaries. As noted earlier, this increase in estradiol induces development of secondary sex traits and enhances growth of the genital organs. At the same time, the estradiol-LH positive feedback system within the hypothalamus becomes mature. The extremely high levels of estradiol produced by a pre-ovulatory follicle induce and LH surge, which in turn can induce ovulation. The first LH surge typically fails to induce a fertile ovulation. In most cases, the ovulated follicle is not completely luteinized resulting in a short menstrual cycle. Nevertheless, the abrupt decline in estradiol and progesterone following the first LH surge results in sloughing of the uterine endometrium (menarche).

Regulation of Puberty in Males

Compared to the female, our understanding of puberty onset in the male is limited. Whereas puberty in females involves abrupt changes in activity of the reproductive system (estrus, LH surge, and ovulation), the physiologic changes associated with sexual maturation in males can be best described as subtle and gradual. The primary event that sets into motion the onset of puberty in the male appears to be an increase in the pulsatile secretion of LH. The immediate consequence of this rise in LH secretion is development of steroidogenic pathways within the testes. This results in an increase in testosterone production which is the primary stimulus for spermatogenesis. These principles are best understood for the bull calf (Figure 8-10).

The sexual maturation of bull calves can be divided into four stages: infantile, prepubertal, transitional, and pubertal. During the infantile (birth to 3 months of age) stage, the testes contain cells that are precursors for Leydig and Sertoli cells. As in the heifer calf, frequency of LH pulses is low, but begins to increase by 2 to 3 months of age. This increase in LH release has been attributed to initiation of pulsatile GnRH release along with increased pituitary responsiveness to GnRH. During the prepubertal period (3 to 6 months of age), LH pulse frequency continues to increases, but then declines. The drop in LH concentrations coincides with an increase in testosterone secretion by the testes. The increase in testosterone production is due to LH-induced development of Leydig cells. The inverse relationship between LH and testosterone is due to the negative feedback effects of testosterone on LH release. Concentrations of FSH are also elevated during the prepubertal period, due to a lack of negative feedback actions of testicular hormones. FSH induces the development of Sertoli cells, which produce estradiol and inhibin. As concentrations of these two testicular hormones increase, they feed back negatively on the pituitary gland to suppress FSH release. Therefore, FSH levels decline during the prepubertal period. The development of Sertoli cells and the production of testosterone by Leydig cells mark the transition of the testes from the prepubertal to the pubertal state. The presence of Sertoli cells and testosterone initiates spermatogenesis. During the transitional stage (6 to 12 months of age), pulsatile secretion of LH remains low and stable and reflects the negative feedback relationship between testosterone and LH. Concentrations of testosterone increase gradually during this period, reflecting a gradual maturation of the testes. Functionally speaking, the endocrine relationships between the testes and the hypothalamic-pituitary unit are mature by the end of the prepubertal period. The characterizing feature of the transitional period is the gradual maturation of the testes, culminating in an adult pattern of spermatogenesis; that is, sperm production sufficient for impregnating a female.

[FIGURE 8-10 OMITTED]

TIMING OF PUBERTY ONSET

Having reviewed the major theories describing how puberty onset occurs, it now seems appropriate to consider one of the more fundamentally important questions regarding reproductive biology: How is the age at puberty determined? In other words, what mechanisms control the timing of events that lead to onset of puberty, or what determines when the puberty alarm sounds? The bulk of research addressing this question has been done with females. The previous discussion of puberty onset in females highlights the importance of an increase in the pulsatile release of LH in determining age at puberty. In light of this important concept, our question about the timing of puberty onset becomes one of what regulates the timing of the prepubertal increase in LH secretion. To address this question, we turn to our earlier consideration of thermodynamics and reproduction. Recall that reproduction is an energy-dependent process. Thus it should be no surprise that the mechanisms controlling onset of puberty are also energy dependent. There is an abundance of information to support this claim. In the 1950s, animal scientists first noted an inverse relationship between prepubertal growth rate and age at puberty. Similar observations have been documented in numerous species including humans. Today it is generally accepted that the timing of puberty onset is largely dependent on the generation of metabolic signals that indicate that the animal has attained a metabolic status that will support successful reproduction.

SUMMARY OF MAJOR CONCEPTS

* Puberty can be defined as attainment of the ability to reproduce, and includes all of the morphologic, physiologic, and behavioral changes associated with this ability.

* Age at puberty is a major determinant of the lifetime reproductive success of an individual, but there are significant biological costs associated with early sexual maturation.

* Theoretically speaking, the process of sexual maturation can be viewed as involving a "developmental clock," that governs the sequential expression of key regulatory genes that lead to onset of puberty. The rate at which this process occurs is genetically predetermined, but whether or not expression of these genes culminates in onset of puberty depends on permissive signals that convey information about the animal's internal and external environments.

* Of the genes regulating sexual maturation, those controlling the pulsatile secretion of LH appear to be particularly important. Onset of a high-frequency mode of pulsatile LH secretion initiates a cascade of events that culminates in full maturation of the gonads.

* The prepubertal increase in pulsatile LH secretion is attributed to both steroid-independent (loss of central restraint) and steroid-dependent (escape from negative feedback actions of gonadal steroids) mechanisms. The relative importance of these two types of mechanisms varies with species.

DISCUSSION

1. Bruce, age 12, is the only boy in his seventh-grade class to sport a mustache and sideburns. Would it be correct to conclude that Bruce has reached puberty? Why or why not? Explain, in theoretical terms, why Bruce's male classmates lack an adult pattern of facial hair.

2. The feral Soay sheep inhabit the islands of the St. Kilda archipelago off the coast of Great Britain and live under extremely harsh environmental conditions. The Soay sheep are seasonal breeders; rutting season and mating occurs during the autumn, just before the onset of harsh winter weather, whereas lambing occurs during the milder weather of the spring. During rut, males reduce their feeding time and increase their physical activity in an attempt to find and secure mates. This behavior limits opportunities to build up stores of metabolic fuel that are vital to survival during the winter months. Under these circumstances, one might hypothesize that natural selection would favor a slow rate of sexual maturation so that rams would not engage in rut as juveniles. Interestingly, males typically attain puberty by 7 months of age (at the onset of the rutting season), when they are only one-third of their adult size. The risks of such a strategy are readily apparent. The mortality rate among Soay males is extremely high during the winter months that follow rut; sometimes reaching 99 percent. Explain how such a presocial sexual maturity ensures reproductive success of individual rams in the face of such environmental conditions?

3. Imagine that you are the first reproductive biologist to study sexual maturation in the female alpaca. You already know when these animals attain puberty, but you know nothing about the hormonal control of sexual maturation in this species. Based on your knowledge of puberty in other female mammals, what are some of the most important research questions you would seek to address for this species?

4. Describe an experiment that would allow you to distinguish between steroid-dependent and steroid-independent inhibition of LH secretion in a prepubertal female mammal.

5. Describe several ways (treatments) that would induce early puberty onset in male and female mammals. Describe how these treatments would work to induce puberty.

REFERENCES

Andrews W.W., J.P. Advis and S.R. Ojeda. 1981. The maturation of estradiol negative feedback in female rats: evidence that the resetting of the hypothalamic "gonadostat" does not precede the first preovulatory surge of gonadotropins. Endocrinology 109:2022-2031.

Day, M.L. and L.H. Anderson. 1998. Current concepts on the control of puberty in cattle. Journal of Animal Science 76 (Suppl. 3):1-15.

Foster, D.L. 1994. Puberty in the sheep. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., Second Edition. New York: Raven Press, pp. 411-451.

Ojeda, S. R. and H.F. Urbanski. 1994. Puberty in the rat. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., Second Edition. New York: Raven Press, pp. 363-409.

Plant, T.M. 1994. Puberty in primates. In E. Knobil and J.D. Neill, The Physiology of Reproduction Vol. 2., Second Edition. New York: Raven Press, pp. 453-485.

Ramirez, V.D. and S.M. McCann. 1963. Inhibitory effect of testosterone on testicular growth in rats. Endocrinology 76:412-417.

Ramirez, V.D. and S.M. McCann. 1963. Comparison of the regulation of luteinizing hormone (LH) secretion in immature and adult rats. Endocrinology 72:452-464.

Schillo, K.K., J.B. Hall, and S.M. Hileman. 1992. Effects of nutrition and season on the onset of puberty in the beef heifer. Journal of Animal Science 70:3994-4005.

Sisk, C. and D.L. Foster. 2004. The neural basis of puberty and adolescence. Nature Neuroscience 7:1040-1047.

Steele, R.E. and J. Weisz. 1974. Changes in sensitivity of the estradiol-LH feedback system with puberty in the female rat. Endocrinology 95:513-520.

Keith K. Schillo, PhD

Department of Animal and Food Sciences

University of Kentucky

Lexington, Kentucky
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Author:Schillo, Keith K.
Publication:Reproductive Physiology of Mammals, From Farm to Field and Beyond
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Date:Jan 1, 2009
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