Pubertal neuroendocrine maturation: Early differentiation and stages of development

Adolesc Pediatr Gynecol (1988) 1:3-12

Adolescent and Pediatric Gynecology © 1988 Springer-Verlag New York Inc.

Mini Reviews

Pubertal Neuroendocrine Maturation: Early Differentiation and Stages of Development Peter A. Lee, M.D., Ph.D. Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania

Abstract. The neuroendocrine maturation of the hypothalamic-pituitary-gonadal axis is described as a process which appears to be mature and functional in the fetus. There is dynamic activity during the neonatal period followed by a prolonged period of quiescence during childhood. Puberty then is a resurgence of a previously active process rather that the development of total new physiologic phenomena. Episodic release of gonadotropin releasing hormone and consequent episodic release of gonadotropins are an inherent part of this process. A variety of hormones, neurotransmitters, and other factors effect this episodic release. The driving force for the onset of pubertal gonadotropin secretion eminates from the eNS and involves much more that a readjustment of negative feedback setpoints. The dynamics of the fetal and neonatal period are key to overall differentiation. The period of relative quiescence of childhood is marked by diurnal differences in gonadotropin activity, dynamic changes of ovarian follicles, and growth of the ovaries.

Key Words. Puberty-Fetal endocrinology-Pituitary gonadotropins-Neonatal endocrinology

The phase of development that involves the maturation of the genital organs and the development of secondary sexual characteristics, which result in the capability of mature sexual function and reproduction, is called puberty. This represents the last stage of the growth and developmental process. From the prospective of the development and differentiation of the hypothalamus-pituitary, gonad, and other sexual-reproductive organs, the phases can be considered as: 1) fetal-a period of in utero differentiation of reproductive organs, the pituitary and the hypothalamus; 2) neonatal-a period of increased

hormonal activity and a transition phase from the fetal environment to a period of quiescence; 3) childhooda phase of hypogonadotropism, a relatively prolonged interval in humans compared with most other mammals between the newborn period and the attainment of reproductive capacity; and 4) puberty.l.2 Puberty is characterized by evident physical and psychosocial characteristics resulting from the effects of increased gonadal sex steroid production. The obvious changes of puberty are preceded by increased hormonal secretion. The gonad begins secreting increased amounts of sex steroid because of increased gonadotropin stimulation, this elevation resulting from increased gonadotropin-releasing hormone (GnRH) stimulation from the hypothalamus. For years it has been perceived that the stimulus to tum on puberty must proceed from the central nervous system because it had been demonstrated that both the gonads and the pituitary from the prepubertal individual were capable of adult function. Studies demonstrating the potential of the prepubertal organs in animals included the transplantation of an immature pituitary beneath the median eminence of a hypophysectomized adult, with resumption of adult function 3 and the assumption of function after transplantation of prepubertal gonads into castrated adults.4 Further evidence for the role of the central nervous system is sexual precocity, which is known to occur with increased incidence in association with central nervous system (eNS) abnormalities such as tumors in or near the hypothalamus, chronically increased intracranial pressure and hydrocephalus, after encephalitis or meningitis, and in association with congenital eNS malformations or anomalies. 5 Control of Gonadotropin Secretion in Adults

Address reprint requests to: Peter A. Lee, M.D., Division of Endocrinology, Children's Hospital of Pittsburgh, One Children's Place, 3705 Fifth Avenue at DeSoto Street, Pittsburgh PA 15213, USA.

In the adult, the stimulus for gonadotropin secretion to the pituitary comes from the eNS (Fig. 1). This

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stimulation is by intennittent secretion of GnRH, which is delivered from the hypothalamus to the pituitary gonadotropes (pituitary gonadotropin-producing cells) by the hypophyseal portal system. This GnRH stimulates the synthesis and release of gonadotropins. 6.7 Critical to normal pituitary gonadotropin secretion is the intermittent pattern of GnRH stimulation (Fig. 2).8-10 If GnRH, a decapeptide, is not secreted in a pulsatile fashion, normal secretion of gonadotropins, which also occurs in a similar pulsatile pattern, does not occur. The amplitude and frequency pattern of the episodic release of GnRH governs pituitary gonadotropin secretion. 11. 12 The control of the secretion of GnRH is not understood. GnRH-secreting neurons are dispersed within the hypothalamus with areas of clustering. There is evidence that secretion of GnRH is under the control of a variety of neurotransmitters. Catecholamines are involved; alpha-adrenergic agents stiqlUlate GnRH release. I •3 Endogenous opioid peptides-endorphins and enkephalins-inhibit GnRH pulse frequency. With naloxone blockage of opiate receptors, luteinizing hormone (LH) pulses are more frequent. 14.15 The drive for the episodic release has been theorized to reside within a so-called pulse generator or oscillator that lies within the hypothalamus. 16 However, it is not known whether the intermittent secretion is the result of influences upon the GnRH-secreting cells from some other location or the episodic release is an innate property within the cells themselves so that they somehow synchronize their episodic release. Thus, it is unclear whether this pulse generator, which controls intermittent secretion, should be conceived of as within a cluster or clusters of GnRH-secreting neurons or as a physically separate control center. The pattern of amplitude and frequency of gonad-

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Twenty-minute Intervals Fig. 2. Hypothetical patterns of episodic release of LH during a 3-hour period at various phases of development and the menstrual cycle.

otropin release changes with varying amounts of sex steroid. 17-20 Moreover, the frequency of GnRH stimulation affects the total secretion of LH and folliclestimulating hormone (FSH). Generally, more frequent release results in relatively greater circulating levels of LH than FSH.I1.l2 This is consistent with the previous concept of negative-feedback control. The regulation of the total secretion as well as the pattern of secretion has long been known to be due in part to the negative feedback by gonadal sex steroids. Absence of gonads and therefore lack of sex steroids results in so-called castrate levels

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of LH and FSH with marked hypersecretion. 21 The control of the negative feedback may be directly upon the pituitary gonadotropins and their response to GnRH or upon the actual secretion of GnRH or both. Despite the elevation of the level of gonadotropin secretion in primary hypogonadal states, there is a persistence of the pattern of episodic release. 22 The pattern of episodic release is hourly and appears to reflect the innate drive unaffected by feedback of sex steroids. 16.23 The variation of the pattern of gonadotropin secretion in the adult female during the menstrual cycle (Fig. 2) depends largely upon the feedback of ovarian sex steroids. 2 During most of the menstrual cycle, gonadotropin secretion is regulated by the negative feedback action of estradiol. When at the end of the follicular phase estradiol levels attain concentrations of about 200 pg/ml or greater, the positive feedback effect is seen. A surge of gonadotropin secretion occurs, resulting in the midcycle peak that precedes and leads to ovulation.

Onset of Neuroendocrine Activity of Gonadotropins Fetal A mature hypothalamic-pituitary pattern resulting in control and secretion of gonadotropins occurs within the first trimester of gestation. GnRH 24- 27 and pituitary LH and FSH 27- 30 are detectable in the fetus by 10 weeks of gestation. GnRH can be demonstrated by immunoreactive techniques within hypothalamic nuclei and GnRH can be extracted from the hypothalamus. 25,26 The fetal pituitary is capable of response to GnRH stimulation. 24 Based on evidence from sheep, LH is secreted in a pulsatile manner in the fetus. 31 The hypophyseal portal system is intact in the human by 14 weeks postconception,32 so the anatomic vascular communicating structures are intact for normal mature control of gonadotropin secretion. Thus, available evidence suggests that fetal gonadotropin se-

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cretion is the result of intermittent GnRH stimulation with mature control mechanisms (Fig. 2). Hypothalamic GnRH and pituitary LH and FSH secretion and circulating levels of LH and FSH progressively increase until after midgestation (Fig. 3).25,27-30 Subsequently LH and FSH levels decline and at term low levels are present. 27 A concept to explain this pattern is that during the first half of gestation there is progressive differentiation and maturation of the hypothalamus and pituitary, with the resulting ability to secrete progressively greater amounts of gonadotropins in an adult fashion. This then is followed by a maturation of the neuroendocrine control, with a balance of inhibiting and stimulatory factors, which brings suppression of the markedly elevated (castrate) levels that occur by midgestation because of negative feedback of placental hormones. There is a significant difference in gonadotropin physiology between the female and male fetus. 27-30 GnRH, FSH, and LH secretion is greater in the female. Male secretion is probably less because of suppression by testicular steroidogenesis, which is far more active than ovarian steroidogenesis during fetal life. While these differences do not indicate differences in the distinctions of the male and female hypothalamic-pituitary unit, they do strongly suggest that feedback mechanisms are intact by the second half of gestation. Furthermore, the FSH:LH ratios are greater in the female fetus than in the male. The ratios and patterns of pulse frequency in mature individuals suggest that this could be due to relatively less gonadal sex steroid with less negative-feedback effects in the female when compared with the male. 33 Diminished feedback appears to result in less frequent GnRH pulses in the female than in the male. These more infrequent pulses of GnRH result in relatively greater circulatory concentration of FSH than LH. This is only partly because FSH has a half-life of hours rather than 1-2 hours, as for LH. Neonatal During the latter weeks of gestation, circulating LH and FSH concentrations decline probably because the negative-feedback mechanisms have matured and sex steroids cause negative feedback. Steroids of placental source contribute significantly to this feedback. Immediately after birth, there is an acute rise and fall of circulating levels of hormones of anterior pituitary source, including LH and FSH. 34 The fall occurs within hours of birth. The circulating gonadotropin and sex steroid levels, which are largely of placental source, drop dramatically over the fIrst few days of life.34 Over the ensuing few weeks of life there is a dramatic rise of plasma LH and FSH concentrations (Fig. 3).35-37

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This is consistent with the pattern expected with a mature differentiated hypothalamic-pituitary unit. The rise of gonadotropins occurs as the sex steroid levels wane because their primary source, the placenta, has been abruptly cut off. In male infants, the rising gonadotropin concentrations are accompanied by a marked rise in testosterone to levels that approach or reach adult male levels. 38 There is also less dramatic evidence for increased ovarian steroidogenesis at this age. 36 .39 For a short time then, from about 6 weeks to 3 months of age, the hypothalamic-pituitary-gonadal control mechanisms appear to operate in a manner similar to that of the adult. This evidence, plus the evidence from late gestation, suggests that neuroendocrine mechanisms are fully differentiated and mature. At this age, individuals with primary gonadal failure, such as patients with Turner's syndrome or males presenting with bilateral cryptorchidism, have markedly elevated circulating levels of gonadotropins. 21 ,40 These levels are comparable to the "castrate" levels found during and after the usual age of pubertal development and are actually diagnostic of gonadal failure. Data from primate studies further substantiate the concept of fully developed and functional mechanisms at this stage. In mature individuals, pituitary gonadotropin synthesis and release can be suppressed by continually exposing the pituitary to high levels of GnRH. This down regulates pituitary GnRH receptors and eventually abolishes LH and FSH release to a superimposed acute GnRH stimulus. Analogues of the GnRH molecule that have a prolonged half-life can be used to continually expose the pituitary to high levels of GnRH and down regulate the mature pituitary so that synthesis, secretion, and plasma-circulating levels of LH and FSH are reduced to those found in hypogonadotropic individuals. Such suppression can be caused in the neonatal primate in much the same way that it occurs in the adult primate and in humans. Additional evidence that the neonate has a fully differentiated hypothalamus and pituitary is the adult-like postcastration rise of gonadotropin levels, which follows gonadectomy in animals. 42 In castrated newborn animals, LH secretion is episodic (Fig. 2) and exhibits an hourly pulse frequency pattern characteristic of the mature pattern when uninfluenced by sex steroid secretion. Sleep-related release is also evident. 43 Thus, the evidence not only suggests a fully developed feedback pattern but also a mature pattern of periodic GnRH secretion and gonadotropin release. Childhood Subsequent to the neonatal period, gonadotropin levels begin to fall (Fig. 2) both in the normal juve-

nile35 -37 and in those with gonadal failure and lack of negative feedback.40 Levels among patients with Turner's syndrome or bilateral testicular failure fall to a range that for individual discernment is not different from other children of similar age, although mean levels for groups of hypogonadal patients is recognizably greater than those for normal children. The decreased circulatory levels mark the phase of quiescence, the physiological hypogonadotropic state of childhood. The occurrence of this phenomenon in gonadal patients suggests that this occurs as a result of decreased drive from the eNS rather than as a result of an increased sensitivity of negative feedback. Thus, the model to explain this phase should probably be conceived of as involving greater inhibition of GnRH secretion-not an increased sensitivity with very low levels of sex steroids, which more strongly suppress gonadotropin secretion. Thus, the concept of a gonadostat with variable sensitivity over time as a primary determinant of the quiescence of childhood and the resurgence of hormonogenesis of puberty is untenable. Gonadotropin dynamics during childhood, although less dramatic (Fig. 2), demonstrate a pulsatile and sleepenhanced secretion pattern.44-46 However, naloxone administration, given to block opiate receptors, does not result in an increase of pulse frequency or amplitude during childhood. 47 This failure to cause release does not indirectly demonstrate inhibition of gonadotropin release by endogenous opioids, as in the mature individual. The mechanism of gonadotropin inhibition during childhood is apparently different. Based on data from the observations of normal development, which clearly demonstrate that gonadotropin secretion wanes dramatically during this phase, it is apparent that augmented sensitivity of negative feedback by gonadal steroids or other messengers cannot account for the restrained hypothalamic-pituitary activity. Furthermore, a reversal in this sensitivity, resulting in a setpoint that progressively becomes diminished, cannot be used as an encompassing theory to explain the onset and progression of pUberty. The basis for the development of the gonadostat concept of pubertal control resulting from decreased feedback sensitivity evolved from animal data. These demonstrated that postcastration hormonal and physical changes could be prevented in the immature animal with doses of sex steroids that are lower than those used in the adult. 48,49 Similar evidence from children indicating gonadotropin suppression with treatment at lower steroid dosages likewise suggested a change in sensitivity to steroid feedback at various developmental stages. 50,51 But because the agonadal state during childhood is not marked by dramatically elevated gonadotropins and castration is not followed by an abrupt onset of hypersecretion of gonadotropins,

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the gonadostat hypothesis cannot be postulated to be responsible for either the hypo gonadotropic state of childhood or the dramatic onset of gonadotropin secretion at puberty. Like the fetal and neonatal phases, plasma FSH levels are higher in females than males during childhood years 35 .36 and the response of FSH to GnRH stimulation is greater in prepubertal females than in males. 52-54 This could be related to gonadal feedback and could be responsible for the continual ovarian growth and ongoing but limited follicular development that occur during childhood.

Puberty The rise of gonadotropin secretion increases activation of the gonads, which results in pubertal development. The evidence for this is vast. Abnormally early pubertal development, which includes early onset of ovulation and spermatogenesis, is marked by increased gonadotropin secretion. 5 Treatment of sexual precocity, which suppresses the physical progression of puberty and gametogenesis, involves the restraint of gonadotropin secretion. 55 Conversely, pubertal development in patients, with an abnormal delay in onset of puberty but with gonads having potentially normal function, can be stimulated with gonadotropin or GnRH administration. 5 Pituitary gonadotropin levels as measured by radioimmunoassay of plasma levels have documented the impression from earlier urinary gonadotropin bioassays. The onset of puberty in both males and females is characterized by a progressive increase in circulating FSH and LH concentrations (Fig. 3).36.37.56.57 These data reflect a progressive increase in pituitary gonadotropin secretion. The pattern of gonadotropin release is episodic (Fig. 2).58 Since there is evidence of episodic release during fetal and neonatal life, and in a more subdued fashion during childhood, the change that heralds the onset of pubertal development is a resurgence of an increased amplitude of episodic release with a progressive and characteristic pattern of increased frequency of release. The first evidence of this reestablished pattern, which is the earliest chemical evidence of puberty, is the sleep-related release of LH. 59 ,6Q This episodic secretion can initially be identified during the first hours after the onset of sleep. This pattern is characterized at this point in the sleep-wake cycle during the months before puberty and while the first physical signs of puberty are appearing. Progressively, the intermittent episodic release throughout puberty becomes an established pattern. The release occurs at regular intervals through more and more of the sleep period and eventually throughout the 24-hour period. The interval between bursts is affected by sex steroid levels so the

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release pattern changes in a describable fashion through the menstrual cycle. 17,61 All gonadotropin secreted during the acute release constitutes the major part of a circulating gonadotropin pool and the increase of mean levels that occurs with pubertal progression is reflective of greater amplitude and frequency of episodic release. Initially, mean levels are greater at night, particularly for LH because of its more rapid metabolism. The episodic release of pituitary gonadotropins is reflective of the episodic release of GnRH, which causes this release. The physiology of gonadotropin release involves periodic discharge rather than a continual response. For ongoing, continued pubertal secretion of physiologic amounts of gonadotropins, the stimulation with GnRH at intervals is obligatory. The gonadotropin response to an acute bolus of exogenous GnRH is followed by a rise of LH and FSH of a magnitude commensurate with the stage of pubertal development and level of GnRH priming. 1.53.62.63 These differences are more dramatic for LH than for FSH (Fig. 4). The prepubertal child has lower baseline levels and a smaller incremental rise after stimulation. Both the basal levels and magnitude of response after stimulation become greater as the system is gradually turned up. The continuous infusion of GnRH over a severalhour period also results in a gonadotropin response that is reflective of the extent of matured function. 64,65 The gonadotropin response may have a biphasic pattern, which has been interpreted to represent in the fIrst phase the previously synthesized "readily-releasable" pool of gonadotropin. The second phase is believed to reflect the synthesis and release stimulated by GnRH. The magnitude of response of both these phases is proportional to the extent of endogenous GnRH priming of the pituitary gonadotrope. This priming effect is consistent with the view that the pituitary is ready to secrete gonadotropin when stimulated to do so. The response in the prepubertal individual is less than in the pubertal individual because the pituitary has not been primed-there is a 150

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Fig. 4. Schematic representation of release of LH and FSH after exogenous GnRH stimulation at time 0 in prepubertal and pubertal females. The lower line for each represents the prepubertal state. With maturity, rise of LH is more dramatic than that of FSH.

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lack of significant physiologic stimulation during recent hours and days. Patients with hypogonadotropic hypogonadism have variable responses after the first stimulation with GnRH, the response almost always being less than that in normal adults and comparable with that seen in prepubertal children. 66- 68 The response to repeated GnRH stimulation, given in frequencies ranging from once daily to hourly, leads to successively greater gonadotropin release, the induction of puberty, and, in some instances, attaining the normal adult response. IO •69 ,70 Most individuals with hypogonadotropic hypogonadism have hypothalamic and not pituitary defects and these individuals are the ones who have the potential of normal adult pituitary function. Those without gonadotropin response probably have pituitary defects. The response generated by intermittent GnRH stimulation is further evidence that puberty is stimulated and generated from the eNS. Key to the priming and generation of greater release is intermittent GnRH stimulation with a frequency similar to physiologically occurring intermittent GnRH release. This generates GnRH receptors in the pituitary gonadotropes, which in tum cause gonadotropin release and synthesis. Over time, more frequent or continuous stimulation with GnRH results in a downregulation of receptors, decreased synthesis and release, and a depletion of stored gonadotropins. Thus, while the usage of the GnRH analogues that have a prolonged physiologic effect first causes a stimulatory response with elevated LH and FSH, after 5-7 days continuous stimulation results in a decrement of release and circulating levels of LH and FSH. With continued usage, levels are repressed into the hypogonadotropic range. This overall suppressive effect upon gonadotropin secretion and thereby on gonadal sex steroid secretion and gametogenesis by GnRH analogues is the basis for the treatment of sexual precocity. 55,71,72 With treatment using analogue at an adequate dosage, gonadotropin levels are suppressed after an initial stimulatory phase.

Ovarian Function Fetal There is progressive growth of the ovary from the time of fetal organogenesis to adulthood. 73 Primordial germ cells migrate to the gonad and begin mitotic division by the sixth week of gestation and this process continues so that by midgestation there are several million oogonia. 74 The first stages of meiotic division has begun with the formation of oocytes. Degeneration of oogonia has begun, as well, but also some oocytes have become surrounded by granulosa cells and thus primary follicles are recognizable by the end of the second trimester of gestation. 75 Development contin-

ues throughout the final trimester so that by the time of birth, primary oocytes and antral follicles as well as atretic follicles are present. It is apparent that there is a direct relationship between gonadotropin stimulation and ovarian development. The rate of germ cell division appears to be related to FSH levels. The female fetus has higher gonadotropin levels than the male fetus. 27- 3o These levels do not appear to be suppressed by sex steroids or other ovarian feedback because ovariectomy does not result in a further rise of gonadotropins, as does orchidectomy in males. While the steroidogenic cells of the ovary do not respond to gonadotropin stimulation with a dramatic secretion of sex steroids, it may well be that gonadotropin stimulation of ovarian development (in terms of development of the ovarian and follicular formation) is a critical phase of normal differentiation requiring the greater secretion and stimulation that is characteristic of the developing female embryo. Neonatal Ovarian development may need the stimulation from gonadotropin levels, which rise to peak mean levels between 2 and 4 months of life. These increased levels, when compared with males, persist during the first 2 years of life and, to a lesser degree, between 2 and 4 years. 35- 37 During these years, both LH and FSH circulating levels are higher in females than in males. There are relatively greater concentrations of FSH than LH. Mean plasma estradiol concentrations are greater during infancy than later in childhood. 39 This implies greater ovarian steroidogenesis at this age. The anatomy of the ovary reflects this increased stimulation; there are a greater number of pre antral and antral follicles seen and follicular cysts may be present. Childhood Throughout the years of childhood there is growth and regression of ovarian follicles, as well as a progressive increase in ovarian size,76 in contrast to the testes, which grows very slowly and almost imperceptibly until the prepubertal years. The enlarging size of the ovary is due to the increase in the number and size of ovarian follicles, as well as to an expansion of the mass of ovarian stroma. Follicles grow to the antral stage but do not progress to graafian follicles during childhood. The typical picture is of various-sized antral follicles. Cysts may develop and regress. 5 The development of cysts may occur during childhood or concomitantly with the onset of puberty. 77 Changes-including breast budding, a clear mucous vaginal discharge, and increased cornification of the vaginal mucosa-may begin. However, if these changes are due to temporary ovarian cyst hormone production and not to pubertal maturing hormone secretion, they regress. Such changes

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can be considered a variation of normal childhood development. At presentation, the differential diagnosis includes sexual precocity. However, the demonstration of ovarian cysts by examination, ultrasound, computerized tomography or magnetic resonance imaging does not differentiate a temporary phenomenon from the beginning of sexual precocity. Both presumably result from gonadotropin stimulation, probably FSH in particular. This stimulation may be either within the broad range of childhood normal physiology or accompanied by evidence of greater maturation. To understand why this may occur during childhood, it is important to remember that FSH has been believed to have major follicular growth-stimulated properties, that puberty in girls is marked by a much less dramatic rise of mean levels of FSH, and that the incremental rise of FSH after exogenous GnRH stimulation does not change much with pubertal maturation. Thus, this information is consistent with a considerable difference in neuroendocrinology between female and male puberty. The greater gonadotropin stimulation, more so for FSH than LH, may be necessary for the maturation of ova and follicles during fetal, neonatal, and childhood years. Puberty Ovarian follicular growth occurs more dramatically during the first half of puberty than during previous years. However, full follicular maturation and, hence, ovulation does not occur until an average of 2 or more years after the physical changes of puberty begin. Thus, until ovulation begins, puberty in females is marked by progressively greater ovarian sex steroid production and ovarian follicular growth and regression. This change occurs as a result of progressively greater gonadotropin stimulation. This stimulation results in increasing mean concentrations of estradiol (in individuals the levels may fluctuate considerably over time). The increased estradiol levels are accompanied by the early and subsequent estrogen-stimulated changes of puberty. These changes include breast development, genital maturation, and growth of the uterus and adnexal structures. Other changes of puberty that are androgen-mediated-such as the development of pubic and axillary hair, acne, and body odor-may not occur concomitantly with increased ovarian steroidogenesis. While the ovary secretes androgens and contributes to the overall pubertal development of these characteristics, the onset and progression of such development may result from increased adrenal androgen production, which is a normal change of pubertal hormone production. This is referred to as "adrenarche"; its etiology and neuroendocrinology is not understood. Adrenarche generally begins concomitantly with the onset of increased ovarian steroidogenesis, but may precede

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or follow it. In about 10% of females, the onset of pubic hair (pubarche) is preceded by the onset of breast development (thelarche). Rarely, axillary hair may appear before pubic hair. In these instances adrenarche apparently precedes the onset of pubertal ovarian sex steroid production (gonadarche). The lack of full follicular maturation and ovulation during the first 2 or more years of pubertal development is probably because the balance of stimulation of pituitary gonadotropins and ovarian sex-steroid response does not set up a pattern comparable with the follicular phase with progressive elevation of LH, FSH, and estradiol secretion, which leads to full Graafian follicle maturation and ovulation. Menarche in the average girl occurs at age 12-13 years and is the most dramatic event of puberty. Menarche only indicates the shedding of the endometrium and most often is not the result of ovulation. It is usually the result of inadequate hormonal effect; the previously stimulated proliferation of the uterine endometrium is not maintained. This may occur if estradiol levels acutely drop, or because the growth of the endometrial lining has been so stimulated over a prolonged or relatively short time period that the hormonal milieu can no longer maintain it. The shedding may have a pattern of normal menstruation in terms of interval, duration, and intensity, or may occur irregularly, be prolonged, or be marked bv intermittent spotting. Ovulation has been documented to occur before menarche. 57 Such is probably the exception rather than the rule. In these instances menarche is truly menstruation. The endometrial shedding occurs about 2 weeks after ovulation. A corpus luteum develops with progesterone production and a true luteal phase, culminating in endometrial sloughing, occurs after the classical drop in hormonal levels. However, most evidence suggests that ovulation does not occur or occurs only irregularly for several months or years after menarche and that menstrual periods may not indicate a real menstrual cycle. 78 Generally, regular menstrual cycles probably mean ovulation is occurring. Short cycles may indicate short luteal phases or withdrawal bleeding because of hormonal fluctuation without ovulation. Prolonged cycles may be due to prolonged follicular phases followed by a normal luteal phase, but are more likely due to lack of proper synchrony of hormonal control of the cycle with sporadic irregular hormonal secretion and withdrawal bleeding. Controlling regularity of menstrual bleeding with exogenous estrogen and progesterone has not been shown to effect the maturation of the hypothalamicpituitary-ovarian axis or to establish a synchrony for this cycling. Thus, the indication for prescribing such medication should be to cause regular cycling rather than to cause hypothalamic-maturation.

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Summary

The development of the capacity for reproduction can be considered by phases from in utero development through pubertal development. During the first phase, fetal-stage gonadotropin secretion progressively increases, with a pattern of secretion and circulating levels that can be compared with the onset and first half of puberty. Gonadal steroidogenesis increases more dramatically in males than females. Differentiation of the hypothalamus, pituitary, and gonad occurs indicating that episodic release of gonadotropins and the negative feedback mechanisms are functional. Available data suggest that the organs and intercommunication mechanisms are capable of functioning at an adult level by the time of birth. Puberty then is an upregulation of this system. The second phase is the neonatal. During this time hormonal secretion is greater than during the remainder of childhood. Secretion of gonadotropins and sex steroids increase after the first few days of life. For a period of a few weeks, secretion seems to persist at pubertal or adult levels, but without stimulating the physical changes that would be expected with such hormonal stimulation during childhood. The third phase, childhood, begins with a downregulation resulting in a decrement of circulating levels to those found in hypogonadotropic hypogonadism in the adult. Such low levels characterize childhood. During these years, gonadotropin levels drop even among agonadal individuals and the pituitary and the ovary or testes are capable of adult function when properly stimulated. Thus, the low levels of secretion are a function of decreased hypothalamic stimulation, which is under eNS control. The final phase of development is puberty. It is marked by a resurgence r:ather than the initiation of gonadotropin and sex steroid secretion. This secretion begins with abrupt release of pituitary gonadotropins in pulses coincident with sleep. With maturation, this pulsatile pattern becomes more regularly episodic and progresses from being characteristic of progressively more of the sleep period to waking times to the entire 24-hour period.

References 1. Lee PA: Neuroendocrine maturation. Pediatric and Adolescent Obstetrics and Gynecology. Edited by JP Lavery, JS Sanfilippo. New York, Springer-Verlag, 1985, pp 12-26 2. Marshall JC, Kelch RP: Gonadotropin-releasing hormone: Role of pulsatile secretion in the regulation of reproduction. N Engl J Med 1986; 315:1459 3. Harris GW, Jacobson D: Functional grafts of the an-

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