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Normal and Abnormal Puberty

, M.D. and , M.D.

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Last Update: August 8, 2015.

ABSTRACT

Puberty is the period of life that leads to adulthood through dramatic physiologic and psychological changes. Clinically, the onset of puberty is announced by the appearance of secondary sex characteristics, in particular the appearance of breast in females, testicular enlargement in males, and pubic/axillary hair in both sexes. Puberty is initiated by gonadotropin-releasing hormone release from the hypothalamus followed by a complex sequence of endocrine changes and is controlled by multiple, interconnected regulatory pathways that respond to numerous endogenous and environmental signals. The aim of this chapter is to summarize recent developments in the field of puberty control, focusing on the genetic, epigenetic, environmental, neuroendocrine, and metabolic components of the complex and coordinated process of puberty. In addition, the main diagnostic and therapeutic aspects of variations of normal pubertal development such as premature pubarche and thelarche and constitutional delay of growth and puberty are also summarized. For complete coverage of this and related areas in Endocrinology, visit the free online textbook, www.endotext.org

CLINICAL FEATURES

Puberty is the period of life that leads to adulthood through dramatic physiologic and psychologic changes. Clinically, the onset of puberty is announced by the appearance of secondary sex characteristics, in particular the appearance of breast in females, testicular enlargement in males, and pubic/axillary hair in both sexes. These features evolve from appearance to adulthood and are rated into 5 stages according to Tanner's criteria (1).

Breast development in females may be unilateral for several months and begins with an elevation of the breast and papilla, and a slight enlargement of the diameter of the papilla (stage 2) defined as breast bud. The breast and the areola enlarge then further (stage 3) until the areola and the papilla form a secondary mound above the level of the breast (stage 4). The mature stage (stage 5) occurs at the end of puberty or with a first pregnancy and is characterized by the projection of the papilla only, due to a recession of the areola to the contour of the breast (Fig. 1A). Pubic hair in females appears as sparse, long, slightly pigmented and curly mainly along the labia (stage 2). It becomes progressively darker, coarser, and curlier and progressively spreads over the junction of the pubes (stage 3), covering a smaller area than in an adult (stage 4). In the adult stage the hair is distributed as an inverse triangle and spreads to the medial surface of the thighs (stage 5) (Fig.1B). Pubarche is usually preceded by the appearance of the breast bud.

Figure 1. (Left) Stages of breast [B] development. B-1: pre-pubertal; B-2: breast bud; B-3: enlargement of beast and areola with no separation of the contours; B-4: projection of areola and papilla to form a secondary mound above the level of the breast; B-5: recession of the areola to the general contour of the breast with projection of the papilla only. (Right) Stages of pubic hair [Ph] development in females. Ph-1: pre-pubertal; Ph-2: sparse growth of long slightly pigmented hair usually slightly curly mainly along the labia; Ph-3: the hair is darker, coarser, and curlier and spreads over the junction of the pubes; Ph-4: the hair spreads covering the pubes; Ph-5: the hair extends to the medial surface of the thighs and is distributed as an inverse triangle.

Figure 1

(Left) Stages of breast [B] development. B-1: pre-pubertal; B-2: breast bud; B-3: enlargement of beast and areola with no separation of the contours; B-4: projection of areola and papilla to form a secondary mound above the level of the breast; B-5: recession of the areola to the general contour of the breast with projection of the papilla only. (Right) Stages of pubic hair [Ph] development in females. Ph-1: pre-pubertal; Ph-2: sparse growth of long slightly pigmented hair usually slightly curly mainly along the labia; Ph-3: the hair is darker, coarser, and curlier and spreads over the junction of the pubes; Ph-4: the hair spreads covering the pubes; Ph-5: the hair extends to the medial surface of the thighs and is distributed as an inverse triangle.

In males, the penis and pubic hair usually mature simultaneously, as both processes depend on circulating androgens. The stages of development, however, are rated independently to establish potential disorders of the testes and adrenal glands (Fig. 2). The onset of puberty in boys is marked by testicular enlargement and defined as testicular volume >3 ml, established by comparison with ellipsoids of know volume (Prader’s orchidometer). The penis, measured in the stretched flaccid state, increases from an average length of 6.2 cm in pre-puberty to 12.4±2.7 cm in white adults and to 14.6 cm in black and 10.6 cm in Asian men (2). Pubic hair in boys usually appears initially on the scrotum and at the base of the penis and develops to the adult stage progressively as in females, with a final distribution as an upright triangle. Furthermore, during puberty, the membranous and cartilaginous components of the vocal cords lengthen, facial hair appears initially on the corners of the upper lip and the upper cheeks and spreads to the rest of the face and chin after Tanner stage 5.

Figure 2. Stages of genital [G] and pubic hair [Ph] development in the male. G-1, Ph-1: pre-pubertal; G-2: the testis and scrotum enlarge, and the skin of the scrotum shows some reddening and change in the texture. Sparse growth of pigmented hair usually slightly curly, mainly at the base of the penis (Ph-2); G-3: Testis and scrotum enlarge further, the penis grows mainly in length but also in breadth. The hair is darker, coarser and curlier and spreads over the junction of the pubes (Ph-3); G-4: Scrotum, testis, and penis grow further with development of the glans, and further darkening of the scrotal skin. The hair spreads covering the pubes; G-5: adult stage with spreading of the hair to the medial surface of the thighs (Ph-5).

Figure 2

Stages of genital [G] and pubic hair [Ph] development in the male. G-1, Ph-1: pre-pubertal; G-2: the testis and scrotum enlarge, and the skin of the scrotum shows some reddening and change in the texture. Sparse growth of pigmented hair usually slightly curly, mainly at the base of the penis (Ph-2); G-3: Testis and scrotum enlarge further, the penis grows mainly in length but also in breadth. The hair is darker, coarser and curlier and spreads over the junction of the pubes (Ph-3); G-4: Scrotum, testis, and penis grow further with development of the glans, and further darkening of the scrotal skin. The hair spreads covering the pubes; G-5: adult stage with spreading of the hair to the medial surface of the thighs (Ph-5).

In both sexes, the appearance of comedones, acne, and seborrhoea of the scalp are due to the increase in adrenal and gonadal steroids. The mean age at onset of pubertal characteristics in young girls has been revised in 1997 in an extensive population of 17,000 girls evaluated in a cross-sectional study (3) and shown to vary with race, ethnicity, geographical location, environmental and nutritional conditions. The study highlighted the secular trend of puberty, showing that in the mid-1990s pubertal development appeared to begin up to one year in advance in white and up to 2 years in African-American girls with respect to previous reports (1,4). In Tanner's original report (5), white girls had a mean age at onset of breast development and pubic hair of 11.2 and 11.7 yr, respectively. In more recent studies, breast stage 2 is reported to occur in white girls at 9.96±1.82 yr (mean±SD) with upper and lower limits of 7 and 13 years, and in African-American at 8.87±1.93 yr with limits between 6 and 13 years. Pubic hair would occur at 10.51±1.67 and 8.78±2.00 yr in white and African-American girls, respectively. In summary, white girls would begin puberty by 10 years of age on average, and African-American between 8 and 9 years. In boys, the timing of puberty does not seem to have changed over time and is considered normal when it occurs after 9 and before 13.5 years of age (2,6,7).

The age of menarche seems anticipated with respect to the data by Tanner in white British girls (13.5 yr) (4,5) and is reported to occur at 12.88±1.2 yr in white and 12.16±1.2 yr in African-American girls, generally at Tanner stage 4. A variety of environmental and genetic factors are involved in the regulation of menarche. Twin analyses indicated that 53-74% of the variation in age of menarche may be attributed to genetic effects (6). Among these, polymorphisms of the estrogen receptor α (6), insulin growth factor I (8), and CYP17 genes (9) have been suggested as potential genetic determinants of the age of menarche. Obesity and endocrine-disrupting chemicals have been debated as environmental factors associated to the secular trend of puberty (10-12). Studies on genetic regulation of pubertal timing in humans show that there is a genetic overlap between age at menarche and BMI, consistent with the epidemiological association between earlier menarche and higher BMI (13). Among endocrine-disrupting compounds, pesticides, phthalates, bisphenol A, and plant-derived phytoestrogens are able to anticipate or delay the timing of puberty, depending on age at exposure as well as other associated factors such as obesity (14,15).

Pubertal growth spurt occurs during stages 3 to 4 of puberty in most boys and is completed by stage 5 in more than 95% of them. In girls, pubertal growth spurt occurs during stages 2 and 3. In males, growth velocity can be as low as 3.5 cm/year before puberty and increases from 5 cm/yr on average to 7 cm/yr during the first year of puberty, reaching approximately 9 cm/year during the second year. Females do not show such a low growth velocity as males before puberty and increase their growth velocity to 6 cm/yr during the first year of puberty, and 8 cm/year on average during the second year (6) (Fig. 3A, 3B).

Figure 3. (A) - The sequence of events during puberty in girls. Breast bud appearance is usually before pubic hair growth; in the meantime growth velocity increases reaching the peak at Stage 4 of puberty. At this time menarche may appear. (B) - The sequence of events during puberty in boys. Pubertal development usually begins with enlargement of the testis followed by growth of pubic hair and growth of the penis. Peak height velocity is attained on average 2 years later than in girls.

Figure 3

(A) - The sequence of events during puberty in girls. Breast bud appearance is usually before pubic hair growth; in the meantime growth velocity increases reaching the peak at Stage 4 of puberty. At this time menarche may appear. (B) - The sequence of events during puberty in boys. Pubertal development usually begins with enlargement of the testis followed by growth of pubic hair and growth of the penis. Peak height velocity is attained on average 2 years later than in girls.

ENDOCRINOLOGY OF PUBERTY

The onset of puberty is preceded by an increase in the androgen levels secreted by the adrenal glands. Adrenal androgens (androstenedione, dehydroepiandrosterone - DHEA, and dehydroepiandrosterone-sulfate - DHEAS) are secreted in small amounts during infancy and early childhood, and their secretion gradually increases with age, paralleling the growth of the zona reticularis (7).

The onset of DHEA and DHEA-S production from the adrenal zone reticularis leads to the phenomenon of adrenarche. The latter occurs only in human beings and some Old World primates, such as the Chimpanzee (16), and in order to occur, a specific cell type able to synthesize DHEA must differentiate in steroid-secreting cells within the zona reticularis of the adrenals. The mechanisms by which this zone develops with age and the regulation of its secretion are not fully known. During this process, plasma concentrations of the adrenal androgens increase, whereas those of cortisol remain stable, suggesting that factors other than corticotropin are involved. A role for Corticotrophin releasing hormone (CRH) has also been proposed in the regulation of DHEA production, particularly in the human foetal adrenal (17), but it is not the only candidate. Many others factors, both local and circulating, play a role in adrenal growth and adrenarche. The GH – IGF-1 axis and hormones related to body mass, such as insulin and leptin, have been suggested as modulators of this multifactorial event (18).

A programmed shift in the production of intra-adrenal regulatory factors, associated with differentiation of adrenal cells and changes in steroid biosynthesis, is called “adrenal cortex zonation” and is modulated by extra- and intra-adrenal factors regulating proliferation, migration, and differentiation of zone reticularis cells (19). Steroidogenesis is driven by the concerted action of specific Cytochromes P450 such as CYP11A, CYP17, and SULT2A1. CYP11A performs the first committed step common to all cells that synthesize steroid hormones: the conversion of cholesterol to pregnenolone, and it is considered the quantitative regulator of steroidogenesis. CYP17 catalyses the 17-hydroxylation of both pregnenolone and progesterone and the 17,20-lyase reaction on their 17-hydroxy derivatives. The 17-hydroxylase activity is necessary for cortisol biosynthesis from human adrenal zona fasciculata, and both 17-hydroxylase and 17-20 lyase activities are needed for C19-steroid production from adrenal zona reticularis, human foetal adrenal, Leydig, and theca cells of the gonads. Therefore CYP17 is recognized as one of the principal qualitative regulators of steroidogenesis (20). The 17-hydroxylase reaction requires the flavoprotein P450 oxidoreductase (POR) to transfer electrons from reduced nicotinamide adenine dinucleotide phosphate (NADPH) to the P450 heme moiety, and POR performs this function for all microsomal cytochromes P450 in the adrenal, testis, liver, and other tissues. The 17,20-lyase reaction, in contrast, is much more efficient in the pregnenolone pathway than the progesterone pathway (21). The 17,20-lyase reaction also requires POR, but in addition, the presence of roughly one molar equivalent of cytochrome b5 (b5) (22). The mechanism of b5 action remains unclear, although electron transfers to and from b5 are probably not involved (21), and b5 residues E48 and E49 are critical for this action (23). Genetic evidence supports the need for all three proteins for normal 17,20-lyase activity, as isolated 17,20-lyase deficiency can be caused by mutations in the genes encoding P450c17 (24,25), POR (26), or b5 (27). An important feature of adrenarche is the increased conversion of 17-hydroxypregnenolone to DHEA that results from an increase in the 17,20-lyase activity of CYP17. SULT2A1 (DHEA-sulphotransferase) catalyses the final step in the biosynthesis of DHEA-S and requires 3′-phosphoadenosine-5′-phosphosulfate (PAPS) as sulfate donor for catalytic activity (28). In adrenal and gonads, 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2) irreversibly transforms Δ5-steroids into their Δ4-congenors. While 3β-HSD2 activity is essential to the genesis of aldosterone and cortisol in the glomerulosa and fasciculata, 3β-HSD2 expression in the reticularis negatively impacts DHEA biosynthesis. Infants younger than 5 years old exhibit a poorly developed adrenal reticularis that expresses 3β-HSD2. At adrenarche, the zona reticularis begins to expand, and 3β-HSD2 content falls, restricting steroidogenesis to the Δ5-pathway. This process is associated with detectable increases in circulating DHEA and DHEA-S. The content of 3β-HSD2 protein in the reticularis remains low throughout adulthood, maintaining DHEA-S production. Taken together, these data support the hypothesis that balance and coordination of SULT2A1 and CYP17 activities, together with increased expression of b5 and reduced expression of 3β-HSD2 in the developing adrenal reticularis are key determining factors driving DHEA-S production during adrenarche (19,29).

The increase in androgen levels occurring in childhood is responsible for the appearance of body odour, and pubic and axillary hair. Although the temporal relation between adrenarche and the onset of puberty suggests that adrenal androgens might have a regulatory influence on the timing of puberty, it is now evident that the two events are independent processes.

Gonadotropin releasing-hormone (GnRH), a decapeptide secreted by approximately 1000 neurons located in the basal forebrain and extending from the olfactory bulbs to the mediobasal hypothalamus, is responsible for the gonadotropin secretion by the pituitary gland. Based on cell size, labeling density, and location, three morphological subtypes of GnRH neurons have been described in humans (30). It is not clear whether all these distinct functional subgroups of GnRH neurons are involved in reproduction. In fact, many of GnRH neurons other than type I occur at sites not closely related to reproduction and have shown a negative immunoreaction for GnRH, meaning that these neurons are unlikely to fully process the prohormone to the mature GnRH decapeptide (31). GnRH neurons I originate in the embryonic period and exhibit an endogenous secretion very early in development. After birth their activity is "turned-off" by the low circulating levels of androgens/estrogens released by the gonads, by means of a negative feed-back mechanism. At puberty, the reactivation of this "gonadostat" is independent of the effect exerted by the steroids and is related to a reduced sensitivity to their action (32).

GnRH induces the release of LH and FSH from the pituitary which in turn stimulates the gonads. LH and FSH have negative feedback effects on the hypothalamus, whereas testosterone (T) and Androstenedione (A) produced by the testis, and Estradiol (E2) produced by the ovary inhibit both the hypothalamus and the pituitary gland. Inhibin, activin, and follistatin have also feedback effects at both levels. GnRH secretion by the hypothalamus is under the control of a plethora of central and peripheral signals: excitatory aminoacids and other neurotansmitters such GABA, gonadal sex steroids, adrenal and thyroid hormones, the GH-IGF-1 axis, nutrition, and energy-related hormones such as insulin, leptin, and ghrelin (Fig.4).

Qualitative and quantitative changes in LH secretion resulting from pulsatile GnRH secretion, occur approximately 2 years before the appearance of secondary sexual characteristics. At puberty, LH pulsatile secretion is characterized by a 28-fold increase in pulse amplitude, whereas pulse frequency increases only 1.8-fold. During prepubertal years both LH and FSH secretions are preponderant during nighttime. In the peripubertal period the gonadotropin secretions increase during sleep, and stimulation with exogenous GnRH shows an enhanced release of LH from the pituitary gland that may be useful in differentiating a pubertal from a pre-pubertal response. Throughout puberty then, gonadotropin pulses further increase becoming apparent during daytime also. In girls, FSH levels increase during the early stages, and LH levels during the later stages of puberty with a 100-fold increase in hormone concentrations. In boys, FSH levels rise progressively through puberty with an increase in amplitude only, whereas LH levels increase in early puberty reaching shortly a plateau.

Central signals regulating GnRH secretion

The neuroendocrine control mechanisms regulating GnRH release are represented by:

1.Upstream control of genes expression

Some transcriptional factors such as Oct-2, TTF-1, and EAP-1, have been identified as potential regulators of the cell network which controls the GnRH secretion. They regulate the expression of genes involved in cell function and cell-cell communication.

Oct-2 is a transcriptional regulator of the POU-domain family of homeobox-containing genes (33), that is more expressed in astrocytes than in neurons (34). Hypothalamic Oct-2 mRNA levels increase in the mammalian during juvenile development in a gonad-independent manner, while blockade of its synthesis via antisense oligodeoxynucleotides reduces astrocytic TGFα synthesis and delays the age of the first ovulation. In the mammalian, hypothalamic lesions that induce sexual precocity activate both Oct-2 and TGFα expression in astrocytes near the lesion site (35), suggesting that TGFα is one of Oct-2 targets.

TTF-1 (thyroid transcriptional factor-1), also termed Nkx2.1, is a homeodomain-containing transcription factor playing a role in the organogenesis of some hypothalamic structures (36). After birth, it remains expressed in selected neuronal and glial population of the hypothalamus. At the onset of puberty, TTF-1 enhances GnRH (36), erbB2, and KiSS-1 gene transcription but inhibits preproenkephalin promoter activity (37).

EAP1 (enhanced at puberty 1, earlier known as C14ORF4) transactivates the promoter of genes involved in facilitating the advent of puberty and in reproductive function (such as GNRH1) while suppressing the expression of inhibitory genes regulating pubertal and reproductive processes (such as preproenkephalin) (38). Knocking down hypothalamic EAP1 expression causes delayed puberty and disrupted estrous cyclicity, both in rats and monkeys (38,39). Incresead hypotalamic expression of EAP1 at puberty is independent of ovarian steroids actions, suggesting a central regulation of EAP1 expression (40).

The existence of an hypothalamic gene network composed of genes situated at different, but interactive, hierarchical levels is consistent with the idea that the onset of puberty is genetically determined and depends on the contribution of more than one gene in a remarkable redundancy system (13,41,42).

Recently, an epigenetic mechanism of transcriptional repression regulating initiation of puberty has been described (43). In the ARC of female rats, the Polycomb group – PcG (a protein complex) exerts a repressive state on the expression of KISS1, a puberty-activating gene. Before puberty, methylation of two key PcG genes (Eed and Cbx7) increases, their expression decreases, and in turn KISS1 expression rises. The overexpression of the PcG transcriptional silencing complex leads to blunted pulsatile GnRH release, delayed puberty, and compromised fertility, suggesting a direct causal relationship between polycomb­mediated inhibition and puberty onset (44).

2. Kisspeptin system: director of central functional network and peripheral signals

Since 2003, when a genetic inactivation of GPR54 was associated in vivo with hypogonadotropic hypogonadism (45,46), increasing interest has been focused on the KISS1/GPR54 or kisspeptin system. In the last decade, genetic, physiological, and clinical data strongly indicate that the KiSS-1/GPR54 system is not merely one more element in the cascade of signals controlling the gonadotropic axis, but an essential gatekeeper of GnRH function, which allows for the integration of central and peripheral inputs, thereby playing a pivotal role in the control of reproductive function (47).

Kisspeptins (Kp) are a family of structurally related peptides, encoded by the KISS1 gene, with ability to bind and activate the G protein-coupled receptor GPR54, recently renamed KISS1 receptor (KISS1R) (48-50). The main peptide of the Kp family is a 54-amino-acid-peptide (kisspeptin-54), also known as metastatin because of its capacity to inhibit tumor metastasis (51,52). The 10 C-terminal amino acids of the sequence (termed kisspeptin-10), originated by a proteolitic cleavage of the primary KISS1 protein, is sufficient to exert biological actions, although all know kisspeptins are able to bind and activate KISS1R (53). Kp neurons are located in discrete neuronal subsets of the antroventral periventricular nucleus (AVPV), the arcuate nucleus (ARC), the periventricular nucleus (PeN), and the anterodorsal preoptic nucleus (ADP) (54-56). KISS1R-expressing cells are diffusely distributed (54,57), including GnRH neurons and the adenohypophysis (58,59). Surprisingly, KISS1 and KISS1R have been colocalized in the same immortalized gonadotrope cell line, suggesting both a paracrine and autocrine regulation of the Kp system at the pituitary level (56). KISS1 is also widely expressed in peripheral tissues and organs, such as liver, lung, gonads, prostate, endocrine pancreas, adipose tissue, and cardiovascular system (56).

KiSS-1 is an extraordinary potent elicitors of LH and FSH release, acting on GnRH neurons. These releasing effects were observed both after central (intracerebroventricular) and systemic (intravenous, intraperitoneal and subcutaneous) KISS1 administration of the peptide (54,55,57,60-64) and represent a unique feature of this neuropeptide.

Both in rats and in primates, a marked increase in KiSS-1 and KISS1R mRNA levels coincide with the onset of puberty (54,61). Moreover the sensitivity of GnRH system to kisspeptin is dramatically enhanced in adult versus juvenile mice (65). Thus, the developmental activation of the GnRH axis by KiSS-1 at puberty reflects a dual phenomenon involving not only the increase of Kp tone, but also the enhancement of its efficiency to activate GnRH neurons, probably through post-transcriptional changes in KISS1R signalling (65).

Hypothalamic Kp system also plays an essential role in relaying the negative feedback input of sex steroids onto GnRH neurons. Indeed, both in male and female rats, bilateral gonadectomy evoked a consistent increase in KiSS-1 mRNA at the hypothalamus. In primates and humans, negative feedback action of sex steroids on gonadotropin secretion has been documented in the ARC (66). In contrast, in the anteroventral periventricular nucleus (AVPN), KiSS-1 mRNA decreases after gonadectomy and increases after sex steroid replacement (67,68). ERα appears to mediate the estrogen regulation of KISS1 expression, while ERβ is not involved in this process (56). Considering that the increasing E2 levels in the pre-ovulatory phase stimulate KISS1 expression in Kp neurons of the AVPV, the Kp system is considered to be involved in the generation of the pre-ovulatory gonadotropin surge, via positive regulation of GnRH secretion (53). Moreover E2 seems to enhance the GnRH neurons responsiveness to KISS1 during the peri-ovulatory period (53). Thus, the steroid-sensitive Kp neurons, converting steroids feedback signals to GnRH neurons, represent an essential downstream element in both negative and positive feedback loops controlling gonadotropin secretion (69).

The complexity of the Kp system is further increased by the identification of a new subpopulation of neurons in ARC, coexpressing, in addition to KISS1, also neurokinin B (NKB) and Dynorphin (DYN) (70). This neuronal subpopulation, named KNDy cells, seems to have a role in the fine-tuning of the HPG axis (53). The reproductive function of NKB is confirmed by the discovery that a mutation in the gene encoding the NKB receptor (NK3R or TACR3) is associated with hypogonadotropic hypogonadism in humans (71). DYN is an endogenous opioid peptide that mediates progesterone negative feedback on GnRH neurons (70) and suppresses GnRH release by inhibiting KNDy neuronal activity; it may be responsible for interrupting GnRH secretion during the interpulse intervals of Kiss1/GnRH secretion (72,73). In contrast, NKB stimulates KNDy activity. Thus, DYN and NKB are auto-regolatory signals for Kp neurons. In a number of species a stimulatory role of NKB on LH release is observed and likely mediated by autosynaptic inputs of NKB on KNDy neurons to induce GnRH secretion in a kisspeptin-dependent manner (74). This process is coordinated by other neuroendocrine factors, such as DYN, glutamate, or GABA. It has been proposed a model in which NKB feeds back to the KNDy neuron to shape the pulsatile release of Kp, and hence GnRH, in a mechanism also dependent on the sex steroid level (74). NKB is part of the Tachykinins family including substance P (SP) and neurokinin A (NKA), whose role in reproduction has recently emerged. In addition to NK3R, the other Tachykinins receptors are represented by NK1R for and NK2R for NKA. In the presence of Kp-KISS1R signaling, a potent regulation of gonadotropin release by the SP/NK1R and NKA/NK2R systems is observed, indicating that they may be involved in the control of GnRH release, at least in part through actions on Kiss1 neurons (75). Patients with NKB or NK3R mutations fail to undergo puberty due to decreased GnRH secretion. Despite this pubertal delay, many of these patients achieve activation of the HPG axis in adulthood, a phenomenon termed ‘reversal’, indicating that NKB signaling may play a more critical role for the timing of pubertal development than adult reproductive function (76). This is also supported by the observation that in mice the absence of the NKB ligand delays puberty, whereas the reproductive axis is able to compensate for the absence of the NKB receptor likely through other tachykinin receptors (76). It has been proposed that NKB may act upstream of kisspeptin to promote LH release and initiate puberty, driving KNDy neurons to temporarily outweigh the E2-dependent inhibition of Kiss1 expression (77). Then, upon maturation, both Kiss1 and NKB work to sustain pulsatile GnRH secretion and mediate the sex steroid-dependent feedback control of GnRH secretion (77).

Besides feedback control, compelling evidence indicates that hypothalamic Kp system may participate in delivering information regarding the nutritional status of the organism to GnRH-neurons, thereby contributing to the link between energy stores and fertility. In rats LH responses to kisspeptin in vivo and GnRH responses in vitro were significantly augmented in fasting conditions, suggesting that a decrease in central KISS1 tone occurs during negative energy balance, which may in turn cause inhibition of the gonadotropic axis and sensitization to the effects of exogenous kisspeptin (78). Repeated administration of KISS1 in a model of under-nutrition of immature female rats was sufficient to restore vaginal opening (as external index of puberty) in a significant number of animals and induced robust gonadotropin and estrogen responses in all rats treated with kisspeptin. Since the permissive actions of leptin on the reproductive axis are mediated through modulation of GnRH secretion, and KISS1 but not GnRH neurons express leptin receptors (79), kisspeptins can be considered plausible candidates for ultimately conveying leptin signal onto GnRH neurons. In summary, the Kp system controls GnRH and gonadotropin secretion and functions as essential integrator for peripheral inputs, including gonadal steroids and nutritional signals (80).

Although our knowlegde of the physiology of Kp system has increased greatly over the last decade, several key aspects remain unclear. For instance, the nature and hierarchical position of KiSS-1 neurons within the complex network controlling the GnRH pulse generator are yet to be completely defined. Whether the Kp system is the trigger for puberty and/or KISS1 and KISS1R may operate as integrator like subordinate genes under the control of upstream regulators (80), whose protein products operate as trans-synaptical regulators of GnRH neurons (81), must be investigated.

3.Functional integration of neuronal and glial networks

GnRH neurosecretion appears to be under the control of many neurotransmitters and neuropeptides which participate in the excitatory and inhibitory control of GnRH neurons. This control is exerted trans-synaptically or via glia-to-neuron communication.

A functional integration of neuronal and glial networks acting on GnRH neurons is the first control level of GnRH neurosecretion. It was early established that the major excitatory trans-synaptic event prompting the initiation of puberty, is an increase in glutaminergic neurotransmission (82,83). Glutamic acid directly stimulates GnRH neurons while indirectly activates glial cells and KiSS neurons.

The inhibitory control of GnRH neurons is determined by opioid neuronal systems (such as enkephalin- and dynoprhin-containing neurons) and by GABAergic neurons. This explains the pubertal delay observed in epileptic boys treated with Valproic Acid, a drug with GABAergic activity (84). In contrast to the inhibitory action in the adult brain, the action of GABA on many neuronal systems in the developing embryonic brain is excitatory (85). While the switch in GABA action in the Central Nervous System of rodents occurs postnatally, in primates it is expected to occur prenatally. Thus, if GnRH-1 neurons in higher primates manifest this developmental switch, the action of increased GABA release during prepubertal development to restrain pulsatile GnRH release could be accounted for by a direct action of the neurotransmitter on GnRH-1 neuron. Conversely, if GnRH-1 neurons in the postnatal primate brain remain “embryonic” and are excited by GABA, then an indirect action of GABA on inhibitory afferents of the GnRH-1 network, such as neuropeptide Y (NPY), would have to be invoked (86).

GnRH neurons and glial cells share an intimate morphological and functional association (87-89). This relationship depends upon growth factors, such as TGF-β1, IGF-1, bFGF, TGFα, and neuregulins (NRGs). TGF binds to erbB1 receptors located on astrocytes and tanycytes whereas NRGs are recognized by erbB4 receptors expressed only in astrocytes. Both receptors recruit the co-receptor erbB2 for signalling, and in both cases, a major outcome is the release of chemical messengers, such as PGE2, that act directly on GnRH neurons to stimulate GnRH secretion (90,91).

4.Other central mechanisms regulating GnRH

In 2000 a neuropeptide with inhibitory action on gonadotropin secretion was identified and isolated in quail and named Gonadotropin-inhibitory hormone (GnIH) (92,93). As in birds, mammalian GnIH homologs act inhibiting gonadotropin release in several species, according to the hypothesis that GnIH has an evolutionarily conserved role in controlling vertebrate reproduction. In birds and mammals GnIH has been shown to operate also on gonads as an autocrine/paracrine regulator of steroidogenesis and gametogenesis (92).

In mammals GnIH appears to be involved in the regulation of seasonal reproduction, stress, and food intake through a mammalian orthologue of GnIH named RFamide-related peptide (RFRP). In humans two GnIH homologs were isolated from the hypothalamus: human RFRP-1 (MPHSFANLPLRF-NH2) and human RFRP-3 (VPNLPQRF-NH2) (94).

GnIH actions are mediated by binding to GPR147, a novel G protein-coupled receptor, expressed by hypothalamic GnRH neurons and gonadotropin cells in the pituitary. GnIH-neurons in the paraventricular nucleus show axonal projections to GnRH neurons in the preoptic area (POA), as well as to the median eminence, consistent with the role for GnIH in the inhibitory regulation of both GnRH neurons by neurosecretion and gonadotropin pituitary cells by secretion into hypophyseal portal system (92).

Melatonin secreted by the pineal gland is involved in stimulating the expression and release of GnIH via melatonin receptors expressed by GnIH neurons (92).

Furthermore GnIH secretion seems to have a reciprocal interplay with the Kp system. In fact, KISS and GnIH levels increase and decrease, respectively, in conditions of maximal activation of HPG axis, such as seasonal breeding (66).

In female Syrian hamsters, GnIH homolog RFRP-3 secreting neurons, located in the dorsomedial hypothalamus, receive close appositions from suprachiasmatic nuclus (SCN)-derived vasopressinergic and vasoactive intestinal peptide (VIP)-ergic terminal fibers (95). The majority of RFRP-3 cells do not coexpress either of the VIP receptors, VPAC1 or VPAC2, suggesting that SCN VIP-ergic signaling inhibits RFRP-3 cells indirectly. The timing of this VIP-mediated disinhibition is further coordinated via temporally gated responsiveness of RFRP-3 cells to circadian signaling (95). These findings reveal a novel circadian hierarchy of control coordinating the preovulatory LH surge and ovulation.

In humans, GnIH homolog RFRP-3 plays some role in the negative regulation of reproduction by direct action within the ovary. RFRP-3 is expressed in human granulosa cells in which it acts via GPR147 to inhibit gonadotropin signaling, reducing gonadotropin-stimulated progesterone accumulation and StAR expression (96). RFRP-3 may be an important autocrine regulator of ovarian steroidogenesis, but it is unclear whether it is involved in the corpus luteum formation, progesterone production, or regression (96). Overall, human RFRP-3/GPR147 signaling could contribute to normal ovarian function.

In conclusion, although GnIH and its homologs have been shown to play a key role in controlling vertebrate reproduction, further studies are needed to evaluate their role in the human physiopathology. Moreover, since GnIH has the potential of an alternative drug to inhibit gonadotropins and steroid hormones, future perspectives of GnIH application could be the treatment of hormone-dependent diseases or contraception (97).

Recently, Abreau et al. suggested MKRN3, a protein mediating ubiquination, to be involved in puberty onset. In contrast with kisspeptin and neurokinin B, which stimulate the commencement of puberty, MKRN3 seems to inhibit puberty as its mutation, predicted to cause loss of function of the protein, causes central precocious puberty (98). In healthy girls, circulating MKRN3 levels decline prior pubertal onset and through puberty, as MKRN3 concentrations are lower in early maturing girls than in age-matched prepubertal girls (99). Similarly in mice, increased levels of Mkrn3 mRNA were found at young ages in the arcuate nucleus of male and female mice, with a striking reduction in levels immediately before puberty and low levels in adulthood. The arcuate nucleus is considered to play a key role in puberty control in mice, and the pattern of Mkrn3 mRNA expression correlates with an inhibitory effect on the initiation of puberty in these animals corroborating the view that transcriptional repression is a core component of the neuroendocrine circuitry that regulates the timing of puberty. The structural features of this gene and its pattern of expression in the developing hypothalamus suggest that MKRN3 might function much like polycomb group proteins as silencers of downstream genes that activate puberty, such as KISS1, and represents the first example of gene that controls puberty by potentially repressing downstream targets instead of activating the GnRH neuronal network (44).

Peripheral signals regulating GnRH secretion

Leptin, a 16-kDa peptide secreted by adipocytes, was shown to play an important role in reflecting the amount of body energy stores involved in triggering the neuroendocrine mechanisms controlling the onset of puberty.

Leptin, binding to specific transmembrane receptors, regulates the action of hypothalamic neuropeptides involved in the control of neuroendocrine functions and energy intake and expenditure. It is supposed to signal to the brain the critical amount of fat stores necessary for LHRH secretion, which in turn activates the hypothalamic-pituitary-gonadal axis (100). Leptin does not act directly on GnRH neurons but operate through indirect regolatory pathways. The Kp system seems to be an indirect mediator of leptin central signalling, which may occur in intermediate neuronal pathways originating from the ventral premmamilary nucleus with capacity to modulate Kp cell function (101).

Leptin was also shown to suppress neuropeptide Y (NPY) expression in the arcuate nucleus. Since NPY stimulates appetite, has an inhibitory effect on the gonadotropin axis, and is involved with the inhibition of puberty in conditions of food restriction, it has been hypothesized that leptin might exert its effects by acting on NPY. Under favourable nutritional conditions, the rise in leptin levels would suppress NPY, and in turn release the inhibitory effect of NPY neurons on the GnRH-LH/FSH axis, allowing the initiation of puberty (102). In addition to the central effects, in vitro (103) and in vivo (104) data indicate a direct negative effect of leptin on gonadal function through inhibition of the steroidogenic enzymes. Thus, leptin seems to exert a positive central effect on the hypothalamic-pituitary-gonadal axis and a negative peripheral one on the gonads.

Subjects with mutations in the human leptin receptor gene have no pubertal development, while obese patients who are known to have an increased rate of infertility (105) and recurrent spontaneous abortion (106), exhibit high serum leptin levels. Dietary treatment of obese individuals is accompanied by an improvement of endocrine and ovarian function and a concurrent fall in plasma leptin concentrations (107,108).

During starvation, in subjects with anorexia nervosa, and in strenuously exercising athletes with amenorrhea, leptin and E2 levels fall concomitantly. In boys with constitutional delay of puberty, leptin levels are low for the corresponding body mass indexes indicating a potential role of leptin in the initiation and progression of pubertal development (109,110). In humans and animals, leptin blood concentrations rise with the onset of puberty and normal levels are necessary for the maintenance of menstrual cycles and normal reproductive function. No gender differences were detected in the relationship between leptin serum levels and fat mass in pre-pubertal and early pubertal subjects, while differences were significant in late puberty. At Tanner stages IV and V, in fact, the serum hormone concentrations decrease in males and increase in females. Furthermore, a significant negative correlation between circulating concentrations of testosterone and leptin was described in males only (100). In adolescents of both sexes, the gradual rise in serum leptin levels before puberty together with a decline in circulating levels of soluble leptin receptor suggest that these changes may serve as one of the signals to the central nervous system that metabolic conditions are adequate to support pubertal development and trigger puberty (111).

Overall, the effects of leptin on puberty onset are predominantly permissive and mainly driven at central/hypothalamic levels, but the primary sites and mechanisms of action are not fully clear (112). It has been suggested that the Kp system operates as key sensor of the metabolic state and relay system for the reproductive effects of leptin, but it is debated whether the putative actions of leptin on the Kiss1 system are actually indirect and/or may primarily target Kiss1-independent pathways (112). Additionally, extra-hypothalamic or peripheral actions of leptin have to be considered, including direct gonadal effects on steroidogenesis modulation (113), which may contribute to the metabolic control of reproduction in extreme body weight conditions (112).

Ghrelin (GRLN), a gastroenteropancreatic hormone, is a potent orexigenic factor stimulating food intake and modulating energy expenditure, and the natural ligand of the GH secretagogue (GHS) receptor-1a (GHS-R1a). In fact, GRLN displays strong GH-releasing activity however its action is not specific for GH, exhibiting other neuroendocrine activities such as inhibition of LH. In animals, intracerebroventricular injection of GRLN decreases LH concentration and frequency of pulsatile LH secretion (114,115). In healthy young males a prolonged infusion of acylated GRLN inhibits LH concentration and pulsatility but not FSH secretion (116). In contrast with in vitro data showing that GRLN reduces the LH response to GnRH in rodents (117), in humans the LH response to GnRH is not modified by the exposure to acylated GRLN, suggesting that GRLN does not play any direct inhibitory role on pituitary gonadotropic cells. Moreover, increased ghrelin levels observed in young amenorrhoeic athletes have been associated with decreased LH pulsatility(118), supporting the hypothesis that GRLN represents an important link between metabolism and reproduction. In addition to the central effects of GNRL on the HPG axis (114,115,117,119), partly mediated by by the down-regulation of KISS1 expression in the AVPV (113), GRLN seems to play an inhibitory role also at the gonadal level, as it reduces Leydig cell proliferation, testosterone secretion, luteal function and progesterone release (113).

Nesfatin-1, one of the products of the gene NUCB2, is an anorectic neuropeptide that likely signals energy sufficiency, probably operating in a leptin-independent manner, and it seems to be involved in puberty onset (120). Nesfatin-1 mRNA and protein levels increase in the hypothalamus at puberty (120), and central injection of nesfatin-1 increases LH secretion in pubertal male and female rats (120). Conditions of metabolic stress that delay puberty reduce the hypothalamic mRNA and protein expression of esfatin-1 (120). At last, suppression of hypothalamic levels of nesfatin-1 delays the timing of puberty and moderately reduces Kiss1 expression in rodents (120).

Insulin has not only multiple roles in peripheral and central energy homeostasis but also reproductive effects. Stimulatory roles for insulin have been observed at both hypothalamic level, particularly with an increase in LH pulse in women, and gonadal level (113). Current evidence suggests a permissive action by insulin on hypothalamic GnRH neurones via leptin, POMC and NPY neurones (113).

Other hormones have been shown to undergo significant changes at puberty (121). Growth hormone (GH), IGF-1, and its major binding protein, IGFBP-3, normally rise at puberty. The increase in growth hormone and IGF-1 concentrations is probably responsible for most of the metabolic changes observed during puberty, including insulin-resistance, increased β-cell response to glucose, and growth spurt. Data in boys with constitutional delay of puberty treated with either testosterone alone or testosterone in combination with letrozole, a P450-aromatase inhibitor, suggest that GH, and not androgens, directly affects insulin sensitivity regulating the glucose-insulin homeostasis at the time of puberty (122). Circulating levels of adiponectin, an adipocytokine with antidiabetic and antiatherogenic effects, were shown to progressively decline in parallel with pubertal development in boys, being inversely related to serum testosterone and dehydroepiandrosterone sulfate levels (123).

Inhibin, activin, and follistatin are also involved in the modulation of the hypophyseal-gonadal axis function, as inhibin and follistatin inhibit and activin stimulates the expression, biosynthesis, and secretion of FSH. These hormones are synthesized mainly in the gonads (2,124). Inhibin, a heterodimeric glycoprotein, is a member of the TGF-b superfamily produced by the Sertoli cells in the testis and by ovarian granulosa cells. It is composed of an α, and one or two β subunits which form two different products, inhibin A and B, respectively. FSH stimulates the synthesis and secretion of inhibins by the gonads, which in turn are involved in the feedback regulation of FSH secretion. In girls, inhibin A concentrations increase between stage 2 and 3 of puberty, remain constant throughout stages 4 and 5, and correlate positively with bone age, inhibin B and estradiol serum levels (125,126); in boys, serum levels are undetectable at any pubertal age (127,128). Inhibin B blood concentrations, in girls, increase similarly to inhibin A levels, reaching a plateau at 12 to 18 years, and correlate with estradiol (125,126) and FSH serum levels (129). In boys, hormone concentrations increase from stage 1 and peak at stage 3, decreasing thereafter and correlate with testicular volume (125). In males, this dimer is produced exclusively by the testis and it is considered a valuable index of spermatogenesis (130). Blood levels of activin A were shown both to increase from stage 1 to 3 of puberty (126), and to remain unmodified in females (131). In boys, changes in activin A serum concentrations were not described during pubertal development (129).

Blood concentrations of follistatin decrease slightly from stage 1 to 4 and 5 of puberty in girls (126), whereas no pubertal variations were described to date in males.

In conclusion, at puberty the concentrations of two negative regulators of FSH secretion, inhibin and follistatin, change in opposite directions (126), whereas the blood levels of a positive regulator, activin A, increase, at least in females. All together, these alterations in serum concentrations of FSH-regulatory peptides lead to an increase in FSH secretion.

The role of melatonin in puberty is questioned. In fact, while the marked increase in LH amplitude observed in early puberty at night occurs at precisely the same time of melatonin secretion, precocious puberty associated with pineal tumors and due to ectopic secretion of gonadotropins is independent of melatonin (32).

Figure 4. Multiple levels of GnRH neurosecretory control of the onset of puberty. In purple, the three central hierarchical levels of GnRH secretion control: 1° upstream controlling genes; 2° Kisspeptin system; 3° functional integration of neuronal and glial network. Upstream controlling genes (Oct2, TTF1, EAP1 et others) are transcriptional regulator of subordinate genes required for cell function and cell-cell communication of neurons and glial cells which compose a functional network. Kisspeptin system directs this network and also connects it to the peripheral systems (gonads and nutritional status). Positive and negative effects on GnRH secretion are indicated in red and blue, respectively.

Figure 4

Multiple levels of GnRH neurosecretory control of the onset of puberty. In purple, the three central hierarchical levels of GnRH secretion control: 1° upstream controlling genes; 2° Kisspeptin system; 3° functional integration of neuronal and glial network. Upstream controlling genes (Oct2, TTF1, EAP1 et others) are transcriptional regulator of subordinate genes required for cell function and cell-cell communication of neurons and glial cells which compose a functional network. Kisspeptin system directs this network and also connects it to the peripheral systems (gonads and nutritional status). Positive and negative effects on GnRH secretion are indicated in red and blue, respectively.

VARIATIONS OF NORMAL PUBERTAL DEVELOPMENT

Premature pubarche

Premature pubarche refers to the precocious appearance of pubic hair without other signs of puberty or virilization (132,133). The age limit until recently has been considered 8 years in girls and 9 years in boys. However, the results of a large cross-sectional study carried out in 1997, suggest that the appearance of pubic hair in girls may be considered normal when it occurs after 7 years of age in white subjects, and after 6 years of age in African-Americans (3,134). Axillary hair, apocrine odor, and acne may or may not be present. Growth velocity may be increased, and slightly advanced bone maturation usually well correlated with the height age, is often present. The transient acceleration of growth and bone maturation has no negative effects on the onset and progression of puberty, and on final height (135,136). Height-adjusted bone mineral density is similar to age-matched controls, with evidence for a higher body fat mass (137) which appears to be directly associated with premature pubarche and other clinical signs of androgen action (138). Premature pubic or axillary hair and other clicnical signs of androgen action such as adult-type body odor, acne, oily hair are more common in girls than in boys (26.1% vs 10.0%) probably because of higher peripheral androgen precursor conversion to more active androgens in girls (138).

The precise etiology of premature pubarche is not known. Generally, it has been attributed to an early maturation of the zona reticularis of the adrenal cortex leading to an increase of adrenal androgens to levels normally seen in early puberty and, in turn, to the premature appearance of pubarche (139,140). Because half of premature pubarche patients have normal androgen levels, a hypersensitivity of the hair follicle to steroid hormones has also been proposed. (Fig.5)

Figure 5. Etiology of premature pubarche

Figure 5Etiology of premature pubarche

The diagnosis of premature pubarche is based on the exclusion of true precocious puberty and the nonclassic forms of congenital adrenal hyperplasia (Fig. 6). The incidence of defective steroidogenesis in children with PA is extremely variable, ranging from 0% in some reports (135) to 40% in others(136), probably due to the varying ethnic background of the populations studied. A high incidence of molecular defects of the CYP21 gene was reported in Greek children with premature pubarche, the majority of whom were heterozygotes for 9 different molecular defects (139). Whether this finding has any general clinical relevance, only long-term prospective studies will be able to establish it. Recently, Type II 3beta hydroxysteroid dehydrogenase gene mutations were also identified in patients with premature pubarche and elevated 17-hydroxypregnenolone ACTH-stimulated plasma levels (141).

Since idiopathic precocious puberty is generally characterized by pubertal progression of the hypothalamic-pituitary-gonadal axis function, it can usually be clinically distinguished from premature pubarche. The plasma concentrations of DHEA, DHEA-S and D4-A as well as the levels of the 17-ketosteroids and their urinary metabolites, are increased for age in children with premature pubarche, and similar to those normally found in children with Tanner stage II of pubertal development (7,142). ACTH stimulation test rules out nonclassic congenital adrenal hyperplasia but not the carrier state (7,143). Gonadotropin levels are in the prepubertal normal range both at basal state and after stimulation with gonadotropin-releasing hormone. Free IGF-1 (144) and plasminogen activator inhibitor 1 plasma levels are increased (145) while IGF binding protein-1 levels are decreased (144). Recently, mildly increased blood erythrocyte count was reported in prepubertal girls with premature adrenarche compared with their healthy peers with serum IGF-I, DHEAS, and testosterone concentrations associated with hemoglobin levels, suggesting that the relatively small increases in androgen concentrations during adrenarche may be able to stimulate erythropoiesis, and IGF-I could be involved in this effect (146).

Once precocious puberty and nonclassic congenital adrenal hyperplasia are ruled out, no treatment is needed. However, a long-term follow-up of these patients is warranted (Fig. 6). Recent data, in fact, indicate that girls with premature pubarche may not have a benign outcome. Forty percent of postpubertal girls diagnosed with premature pubarche during childhood have an increased frequency of functional ovarian hyperandrogenism (147). Furthermore, hyperinsulinemia is a common feature in adolescent patients with premature pubarche and functional ovarian hyperandrogenism, and is directly related to the degree of androgen excess (96-98) (144,148-150). Although the mechanisms interlinking the triad of hyperinsulinemia, premature pubarche, and ovarian hyperandrogenism remain enigmatic, this frequent concurrence may result, at least in part, from a common genetic or early origin, as the result of in utero growth retardation (149). In fact, programming of the endocrine axes is known to occur during critical phases of fetal development and can be affected by intrauterine growth retardation. Some authors reported, in a population from a specific part of Spain, a significantly lower birth weight in girls with premature pubarche and ovarian hyperandrogenism (150). It was concluded that girls with premature pubarche born small for gestational age are at a higher risk of getting polycystic ovary syndrome. However, French, Finnish, and Scottish girls presenting with PP did not have significantly lower birth weight than controls (151-153). In contrast, an association between low birth weight and PP in girls has been found in three different study samples from France, Italy, and Australia (154-156). Data from Finnish and British birth cohort studies indicate no correlation between the occurrence of PCOS and low birth weight (157,158). Two studies on pre-pubertal PP girls measured anti-Mullerian hormone (AMH), a marker of ovarian function that is increased in PCOS (159). In a cross-sectional study in Scottish PP girls, AMH levels were increased above the sex- and age-specific reference ranges (152) whereas a case–control study found normal AMH levels in Finnish PA girls (160). A high prevalence (21.2%) of patients with premature pubarche born small for gestational age was recently reported in a Brazilian cohort, accompanied with a high prevalence of obesity compared with the reference population but not of hyperinsulinemia (161). In a Dutch population of short children born small for gestational age, only 2.2% of the 90 girls examined had premature pubarche (162). This is comparable with the incidence of premature pubarche in the normal population, in which the incidence in white girls is 2.8% (3). Moreover, in a smaller group of Italian patients with premature pubarche all girls had birth weights appropriate for gestational age (154). It was also shown in a cohort of French young women that intrauterine growth retardation predisposes to insulin resistance but not to hyperandrogenism. It is therefore plausible that there are two distinct forms of premature pubarche, one characterized by the association of premature pubarche with low birth weight, hyperinsulinism, and hyperandrogenism, and one by premature pubarche alone in the absence of other clinical and/or biochemical abnormalities. The prevalence of these distinct forms of premature pubarche may vary in the different populations. The pathogenetic mechanisms underlying the two forms of premature pubarche may also be different. In children with premature pubarche and low birth weight, hyperandrogenism, and hyperinsulinism the concurrence of these clinical and biochemical features may result from a common origin as an effect of early exposure of the fetus to poor nutrition leading to permanent changes in insulin metabolism and body fat deposition, according to the thrifty phenotype hypothesis. These are the patients most probably at higher risk of developing PCOS and the metabolic syndrome in adulthood and deserve a careful follow-up. Recent short-term studies suggested that an insulin-sensitizing therapy in these patients may prevent the progression from premature pubarche to PCOS (163,164). However, since no data regarding safety of long-term use of insulin-sensitizers in children and adolescents, and no long-term studies to document acceptable risk-benefit profile are available, the use of such agents in children with premature pubarche is not recommended outside of experimental clinical trials.

In patients with isolated premature pubarche in the absence of biochemical and metabolic abnormalities, a hypersensitivity of the pilosebaceous unit to androgens as a result of increased androgen receptor activity may be responsible for the isolated precocious appearance of pubic hair (165). These are patients who most probably are not at risk of developing endocrine or metabolic abnormalities in adulthood and the families should be informed about the usually benign nature of the condition. However, since data on the outcome are not available, a long-term follow-up of these patients is also warranted to ascertain the benign outcome of the disease.

Figure 6. Algorithm for diagnosis and follow-up of premature pubarche. DHEAS: dehydroepiandrosterone sulfate, Δ4A:androstenedione, 17OHP: 17-hydroxyprogesterone, T: testosterone, Glu/Ins: Glucose/Insulin, OGTT: oral glucose tolerance test, GI: glucose intolerance, GT:glucose tolerance, NC: nonclassic, BA: bone age, CA: chronological age

Figure 6

Algorithm for diagnosis and follow-up of premature pubarche. DHEAS: dehydroepiandrosterone sulfate, Δ4A:androstenedione, 17OHP: 17-hydroxyprogesterone, T: testosterone, Glu/Ins: Glucose/Insulin, OGTT: oral glucose tolerance test, GI: glucose intolerance, GT:glucose tolerance, NC: nonclassic, BA: bone age, CA: chronological age

Premature Thelarche

Premature thelarche refers to the precocious appearance of breast development in girls with no other signs of sexual maturation, accelerated growth velocity, or bone age advancement. It is most common during the first 2 years of life, and its incidence in nursery children from Northern Italy was reported as high as 36.6%. The etiology of premature telarche is still unknown, although different pathogenetic mechanisms have been suggested. Some authors postulated that an increase in breast sensitivity to estrogen might be responsible for the premature development of breast tissue. Others, using an ultrasensitive recombinant cell bioassay, showed that girls with premature thelarche exhibit higher estradiol levels than those of normal pre-pubertal girls (166). Transient estrogen secretion from ovarian follicular cysts (105), increased production of estrogens from adrenal precursors, and transient partial activation of the hypothalamic-pituitary-gonadal axis with increased secretion of FSH, were also claimed as possible causes of premature telarche (167,168). An increased prevalence of detectable ovarian microcysts at ultrasound was also reported, but the presence or absence of these cysts did not correlate with basal gonadotropins or estradiol levels (169). Recent studies identified activating mutations of GNAS1 gene in some patients with chronic fluctuating and/or exaggerated thelarche, without other classic signs of McCune-Albright syndrome (170). BMI was also shown to be associated with occurrence of premature thelarche in 4- to 8-year old girls (171), supporting a previous observation that the prevalence of premature thelarche can be affected by BMI (172).

In the last years great attention was paid to the effects on pubertal development of the so-called endocrine disruptors. A growing list of chemicals were shown to influence the endocrine system either in vitro or in vivo, but only a few were associated with altered pubertal development. The outbreak of epidemics of premature telarche in some geographical areas was suggested to be linked to exposure to endocrine disruptors. Phthalates were suspected in Puerto Rico, whereas in Michigan polybrominated biphenyls were associated with advanced breast development in children of exposed mothers. Thus, possible exposure to endocrine disruptors should be borne in mind in the diagnostic work-up of premature telarche (173).

Premature telarche is usually a self-limited condition that undergoes spontaneous regression during the first 2-3 years of life. However, in some cases the outcome of premature thelarche is not always entirely benign. It has been observed that when its onset occurs after 2-3 years of age, a certain percentage of patients develop central precocious puberty (174), but onset of thelarche under 2 years of age does not assure a transient course (175). In fact, progression to PP is not associated with age at presentation of thelarche or clinical course, meaning that girls presenting with thelarche at birth have the same risk of developing true PP as girls presenting at an older age (176). In an initial Italian series, 14% of girls diagnosed with premature thelarche at a mean age of 5.1 years, progressed to precocious or early puberty (174). In a following retrospective multi-center study on 119 girls, only 60% of the patients who presented with premature breast development before 2 yr of age showed a complete regression during the follow-up period (177). In 40% of these girls the breast size was unmodified at a follow-up period of 134 months, and 7/38 (18.4%) patients developed central precocious puberty. Furthermore, another subgroup was identified (28.5%) which included patients showing an accelerated height velocity and/or bone maturation at diagnosis but did not develop precocious puberty (177). In premature thelarche patients who developed precocious or early puberty, final height was unaffected and normal for mid-parental height, so that the sexual precocity was interpreted as a reflection of early maternal menarcheal age (178).

The observation of IGF-1 serum concentrations and IGF-1/IGFBP-3 values intermediate between those detected in prepubertal children and in central precocious puberty suggests that premature thelarche could be considered a very early stage of puberty (179). Also, children developing premature thelarche in late childhood exhibit a pubertal response to GnRH stimulation test one year after breast development (180), supporting the hypothesis that precocious thelarche may represent a decreased juvenile inhibition of the hypothalamic-gonadotropic-gonadal axis.

Identifying clinical or laboratory parameters predictive for progression into precocious puberty is a crucial process. For example, in premature thelarche girls younger than 2 years, growth velocity value of >1 SDS or a basal LH level ≥0.3 IU/L have been suggested as indicators for close follow-up (175). Conversely, in girls younger than 3 years of age, no laboratory parameters were identified able to predict progression into precocious puberty (181). Elevated FSH and LH peak responses to GnRH are frequently observed in infancy and early childhood, and they are not related with the clinical progression to true precocious puberty. Even though a peak LH/FSH ratio >1 could represent a good marker of progression, its sensitivity is low in the early phases of pubertal activation. The combined measurement of both basal LH levels and longitudinal diameter of the uterus may represent a reliable screening approach to identify the subjects at risk of true precocious puberty who should undergo GnRH testing (181).

In addition to clinical and hormonal assessments, pelvic ultrasound might be useful to distinguish premature thelarche from precocious puberty. In fact, while no significant differences in uterine and ovarian ultrasound measurements were detected between children with premature thelarche and controls, significant differences in pelvic ultrasound parameters were reported between healthy girls and age-matched girls with central precocious puberty. Uterine transverse diameter ("'width"'), uterine length, fundal anteroposterior diameter, uterine volume, ovarian length, ovarian circumference, and mean ovarian volume are all increased in girls with central precocious puberty. The calculated cut-off values to predict precocious puberty by ultrasound vary among studies. Haber et al. found that a uterine volume >1.8 ml, uterine length >3.6 cm, and ovarian volume >1.2 ml were highly predictive for precocious puberty (182). Herter et al. reported that the best cut-off points were uterine length 4.0 cm, uterine cross-sectional area 4.5 cm2, uterine volume 3.0 cm3, and ovarian volume 1.0 cm3 (183). Comparing 30 girls with precocious puberty and 21 with premature thelarche in whom peak luteinizing hormone was <5 mIU/ml on the GnRH stimulation test, De Vries et al. found significant differences in uterine width, fundus diameter, uterine volume, and ovarian circumference (184). The Authors suggest that increased uterine and ovarian measurements may be an early and sensitive sign of precocious puberty (Tab. 1) and that pelvic ultrasound may give the clinician a complementary indication to the GnRH test in distinguishing isolated premature thelarche from early-stage precocious puberty in girls with early breast budding.

Table 1

Cut-off values to predict precocious puberty by ultrasound and their sensitivity and specificity (modified from de Vries et al. Ref. 18)

ValueSensitivity %Specificity %
Uterine volume (cc)>2.088.889.4
Uterine length (cm)>3.480.257.8
Uterine transverse diameter (cm)>1.567.9100
Fundus (cm)>0.882.576.4
Presence of endometrial echo57.3100
Ovarian circumference (cm)>4.566.685.5

The measurement of baseline estradiol blood concentrations may also be helpful in distinguishing premature thelarche from precocious puberty, although the differential diagnosis is based on the results of the classic gonadotropin releasing-hormone (GnRH) stimulation test (100 mg LH-RH as i.v. bolus). Baseline LH and FSH plasma levels are often higher, and peak LH levels are significantly and constantly elevated in precocious puberty than in premature thelarche patients, whereas peak FSH levels may not be significantly different in the two groups. A stimulated LH/FSH ratio greater than 1, is suggestive of precocious puberty (185). In recent years, the stimulation with an LH-RH analogue such as leuprolide acetate, was proved to be particularly useful in the differential diagnosis of pubertal disorders. Peak LH was shown to be significantly higher and consistently >8 IU/l in pubertal in contrast to pre-pubertal subjects (185). Moreover, the gonadal response, which is maximal 24h post-stimulation, was also discriminating between pre-pubertal and pubertal conditions (estradiol in females >150 pmol/L, and testosterone >3.15 nmol/L in males) (185). Other Authors reported a 100% sensitivity and 84% specificity for a peak LH/FSH ratio >0.24 (186). Breast ultrasound alone has limited ability to distinguish precocious puberty from premature thelarche (187).

New markers for the differential diagnosis of premature thelarche and precocious puberty have been investigated. Particularly, serum kisspeptin, leptin, and neurokinin B were reported to be higher in patients with central precocious puberty and premature thelarche compared to controls (188) (189,190). However, these markers are not able to differentiate patients with central precocious puberty from premature thelarche (188,190).

Constitutional Delay of Growth and Puberty

Constitutional delay of growth and puberty (CDGP) is defined as a delay of growth occurring in otherwise healthy adolescents with stature reduced for chronological age, but generally appropriate for bone age and stage of pubertal development, both of which are usually delayed. It is more frequent in boys than in girls with a 10:1 ratio and is the most common cause of delayed puberty (80-90%). A family history of delayed puberty is seen in half of the CDP cases and strongly suggestive of CDP (191) (192), but patients with CDP can also be seen in pedigrees of families with isolated HH. The prevalence of CDGP in girls may be underestimated, as evidenced by equal numbers of female and male family members with pubertal delay in CDGP patients with a familial background (192).

The characteristically retarded linear growth occurs during the early years of life and is followed by regular growth paralleling the normal growth curve throughout the rest of prepubertal years. Pubertal growth spurt is attenuated and occurs after the usual expected time. Bone age is usually delayed by more than 2 years and results in normal predicted adult height (Fig.7). This latter, however, is often in the lower part of the parental height range, with few patients exceeding the target height. When CGDP occurs in the context of familial short stature, it results in short final height (193). Because of the paucity of female CDGP patients in pediatric endocrinology clinics, there are only a few studies addressing CDGP characteristics in girls and indicating that a proportion of CDGP girls do not attain AH consistent with their TH.

Correct classification of boys with pubertal delay is essential, not only in prepubertal boys who have reached 14 years of age, but also in older boys with delayed pubertal progression. The stage line diagram was recently introduced and offers an alternative to the classical criteria by providing status (in SD) and tempo (in SD/y) of pubertal development based on Dutch boys (194,195). These Dutch data have been implemented in the UK growth charts, which allow clinical use of nomograms in daily clinical practice (www.growthcharts.rcpch.ac.uk).

Bone mineral density can be compromised by the low serum steroid concentrations (196,197). Specifically, the attainment of peak bone mass may be impaired, although recent data do not indicate significant changes in volumetric bone mineral density in young men with previous CDGP compared with appropriate controls (198).

Figure 7. Growth curve of a boy with constitutional delay showing slower growth in the peripubertal time and then achievement of the normal range by the end of the growth process. The growth velocity curve is shown with a more attenuated and lower increase at puberty.

Figure 7

Growth curve of a boy with constitutional delay showing slower growth in the peripubertal time and then achievement of the normal range by the end of the growth process. The growth velocity curve is shown with a more attenuated and lower increase at puberty.

As a consequence of inadequate production of gonadal steroids, acute provocative tests may show a GH response consistent with partial GH deficiency (199). Pre-treatment with gonadal steroids, however, results in the normalization of the GH responses. Serum IGF-1 and IGF binding protein-3 levels are normal for bone age, as is the overnight spontaneous GH secretion when the levels in CDGP children are matched with those of appropriate controls (200,201). The sleep-related increase in LH concentrations that characterizes the onset of puberty, is normally present in CDGP children. The LH response to leuprolide acetate, an LH-RH analogue, is intermediate between that of hypogonadal patients and normal pubertal children and is therefore useful in differentiating CDGP from hypogonadotropic hypogonadism (202).

Treatment of CDGP children is controversial. CDGP is a paraphysiologic condition and as such does not require any specific therapy. Supportive care is most often enough to reassure children that they will achieve a normal adult height and full functional sexual maturation. However, the psychological and social problems faced by CDGP children sometimes force physicians to treat them. In males, testosterone treatment to induce puberty is recommended only if the bone age is greater than 12 years to avoid the risk of inappropriately bone age advancement and thus compromised adult height. Androgen therapy may consist of a 4-6 months course of 50 mg im testosterone enanthate monthly (203). Oral testosterone administered in increasing doses starting with 40 mg once daily rapidly increasing to 40 mg twice daily and subsequently 80 mg twice daily, was recently reported to be safe and followed by pubertal induction and progression and short-term growth without compromising final height (204). The combination therapy of testosterone and aromatase inhibitors has been also suggested to reduce estrogen synthesis and action at the growth plate site (205). Hero et al. reported an improvement in the near-final height of 17 boys with CDGP treated with testosterone and letrozole for 12 months (206). Near-final height of subjects treated with letrozole + testosterone did not differ from their target height, while the near-final height was found to be lower than target heigth in boys treated with testosterone + placebo. However, the amount of height gained as well as the optimal timing, dose, and duration of therapy with aromatase inhibitors remain uncertain. Moreover, potentially adverse effects, especially impaired development of trabecular bone and vertebral-body deformities, which were observed in boys with idiopathic short stature who were treated with letrozole, must be considered.

In girls, estrogen therapy is recommended only after statural considerations have been carefully taken into account. The administration of estrogen, in fact, even in small amounts, leads to progressive skeletal maturation, and ultimately to epiphyseal fusion. Anabolic steroids might also be used to stimulate growth. Oxandrolone is one anabolic compound that may be used, as it was shown to accelerate growth without causing rapid bone maturation or compromising adult height if administered in appropriate dosage (207). Growth hormone was also reported to transiently improve height velocity. However, given the high costs of GH and the lack of any definite evidence that GH treatment has any beneficial effect on adult height, the use of such growth-promoting agent is not recommended (208-210).

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