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Special Articles: Hormones and Reproductive Health |
Division of Endocrinology, Department of Medicine (M.R.P.), Children’s Hospital, Boston, Massachusetts 02115; and Reproductive Endocrine Unit (M.R.P., P.A.B.) and Pediatric Endocrine Unit (P.A.B.), Massachusetts General Hospital, Boston, Massachusetts 02114
Address correspondence and requests for reprints to: Paul A. Boepple, M.D., Reproductive Endocrine Unit, Bartlett Hall Extension 5, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114.
Abstract
Human puberty begins with the reemergence of GnRH secretion from its relative quiescence during childhood, activating a cascade of pituitary-gonadal maturation. This transition begins across a wide range of ages, and the rate of subsequent sexual maturation can be quite varied. The factors that regulate the hypothalamic-pituitary-gonadal axis and modulate the timing of puberty remain elusive, but it is clear that some regulation is under genetic control. Here, we discuss how new advances in genetic research may provide the tools to help unravel this long-standing mystery.
HUMAN PUBERTY BEGINS with the reemergence
of GnRH secretion from its relative quiescence during childhood,
activating a cascade of pituitary-gonadal maturation. The transition
from childhood to the reproductive competency of adulthood occurs
across a wide range of ages in normal, healthy adolescents. Using
clinical assessments and milestones as indices, the timing of puberty
in humans approximates a normal or gaussian distribution. Several
pathological states that influence the timing of puberty either
directly or indirectly contribute to this splay (Fig. 1
), and it is the first priority of the
physician to consider such entities when faced with a child presenting
with disordered puberty. However, the great majority of the variance in
pubertal timing cannot be attributed to any clinical disorder, even
after extensive investigation. Here, we review variations in the timing
of human puberty and then discuss how new advances in genetics may
further our understanding of the biology underlying different patterns
of sexual maturation.
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Although disorders of puberty may occur secondary to abnormalities
at any level of the reproductive endocrine axis, variations in the
timing of pubertal onset most commonly stem from differences in the
maturational program of GnRH secretion (Fig. 2; reviewed in Refs. 1 and
2). After a period of robust GnRH secretion during
infancy, the reproductive axis usually enters a long period of
relative, but not absolute, quiescence until late childhood when
pubertal maturation occurs. Over the last decade, studies have shown
that the transition from the childhood quiescence to the adolescent
pattern of GnRH secretion is gradual rather than abrupt. Animal models
that permit direct assessments and human studies using peripheral
levels of LH and FSH as indices of GnRH activity suggest that
hypothalamic neurons are actively synthesizing and secreting GnRH
throughout childhood. Using supersensitive immunoassays, small pulses
of GnRH-induced LH and/or FSH secretion have been detected in normal
children as young as 4 yr of age. Throughout childhood, LH and FSH
levels undergo small but progressive increases until the onset of
puberty, when secretion is greatly accentuated. During puberty, the
levels of LH and FSH increase markedly, with predominant nighttime
secretion of early puberty expanding into the daytime hours as well.
The increased mean LH and FSH levels stem from increased pulse
amplitude and possibly from increased pulse frequency, although the
latter change is debated and may be method dependent (for example see
Refs. 3, 4, 5, 6, 7, 8 and review Ref. 9). The
mechanism(s) underlying the relative suppression and the subsequent
pubertal activation of hypothalamic GnRH secretion is unknown but of
critical importance. Further understanding of the maturation of GnRH
secretion and pituitary responsiveness is vital to understanding the
mechanism(s) behind the broad variation in the timing of puberty.
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Given that the great majority of children who begin to show signs of puberty at a young age have no discernable underlying pathology, the determination of what constitutes a "normal" or "precocious" puberty must be based on statistical considerations and, therefore, cannot escape of an element of arbitrariness. This determination is now more difficult than ever in light of the recently published data about the timing of pubertal maturation in American girls (10). According to these data, 27% of African-American girls and 7% of white girls show some secondary sexual characteristics by age 7 yr, an age that has clearly qualified in the past as being "precocious" for puberty.
When puberty in a young child is driven by activation of hypothalamic
GnRH secretion, it is designated "central" or "true" precocious
puberty (CPP) (Fig. 2
). In a minority of patients, CPP arises in the
setting of a central nervous system (CNS) lesion
(e.g. hypothalamic hamartoma, neurofibromatosis,
hydrocephalus, CNS infection, and intracranial neoplasm with or without
radiation therapy). CNS lesions seem to predispose males and females
equally to early central puberty; that is, the sex ratio among patients
with neurogenic CPP approximates unity. However, among children with
CPP in whom there is no underlying pathology (idiopathic CPP), there is
a striking sex difference, with the female to male ratio approaching
10:1 in most series. Although the reason for this female predominance
in idiopathic CPP remains to be elucidated (as does the reason for the
male predominance of constitutional delay of puberty; see below),
genetic studies may provide insights not previously available through
physiologic investigations.
Whereas the entities that underlie neurogenic CPP clearly fall outside
the distribution due to physiologic variation (Fig. 1), they may
provide a glimpse of the factors that can modulate GnRH neuronal
function in both normal and pathological states. Neurogenic CPP, with
the possible exception of that arising from hypothalamic hamartomas, is
thought to be due to the early activation of the normal complement
of hypothalamic GnRH neurons. The presence of GnRH- containing
vesicles within some hamartomas of the tuber cinerium raises the
possibility that these lesions may act as ectopic GnRH pulse
generators. Alternatively, it has been suggested that hypothalamic
hamartomas as well as some mechanisms of brain injury may initiate
puberty through increased local production of transforming growth
factor 
, stimulating GnRH neurons through epidermal growth
factor receptors on their cell surface (11).
Although it is by no means clear that this pathway is operative in
triggering normal puberty, one can conceive of physiological models to
examine such a role.
In contrast to the classical patient with CPP who undergoes the normal crescendo of sexual maturation once the first signs of puberty are evident, some young children exhibit evidence of a staccato pattern of pituitary-gonadal maturation that precedes more progressive pubertal development by many years. It is interesting to note that a similar pattern of punctuated hypothalamic maturation has been observed in male rhesus monkeys during longitudinal studies performed at the pubertal transition (12). Other children who begin puberty at an early age exhibit steady progression, but at a pace that is much slower than most adolescents or the typical patient with CPP. These two groups, patients with intermittent and slowly progressive CPP, are often difficult to distinguish from each other and may actually overlap (for example see Refs. 13, 14, 15, 16, 17). The fact that some siblings have shared such a pattern of pubertal development suggests that it may have a genetic basis.
Typically, children with CPP experience development of secondary sexual characteristics along with dramatic acceleration in linear growth and progressive bone age advancement compared with age-matched peers. Diagnostic confirmation relies on the demonstration of pubertal levels of gonadotropin and sex steroid secretion (reviewed in Refs. 1 and 2). Although newer, more sensitive immunoassays may succeed in reliably discriminating prepubertal from pubertal levels of baseline LH secretion, the diagnosis of CPP is traditionally made by assessing the gonadotropin response to a challenge with exogenous natural sequence GnRH. Patients with "classical" CPP exhibit a dramatic LH rise following GnRH stimulation, which is 2- to 3-fold higher than the prepubertal response and which far exceeds the relative rise in FSH. Patients with slowly progressive variants of CPP, on the other hand, occupy an intermediate position between prepubertal children and patients with classical CPP with respect to the effects of sex steroids on linear growth and skeletal maturation and their gonadotropin responses to GnRH administration (14).
Late or absent pubertal development and its variants
Delayed puberty is defined as the failure to have manifest the
initial signs of sexual maturation by an age that is more than 2–2.5
SD above the mean for the population (
13 yr in girls and
14 yr in boys). Although a variety of disease processes can lead to
delayed or absent puberty, it is also true at this end of the spectrum
that the great majority of adolescents presenting in this fashion have
no underlying pathology. In the subset of patients with delayed puberty
who are found to have CNS, gastrointestinal, or other systemic
disorders, the sexes seem to be fairly equally represented. However,
among those patients without an underlying clinical problem
(constitutional delay of growth and maturation), the gender ratio is
similarly dramatic to that found in early puberty, but in this instance
males far outnumber females (Fig. 1; reviewed in Ref. 2).
It is interesting to note that most boys and girls destined to enter
puberty late have a family history of later pubertal development and
follow a characteristic program of linear growth throughout childhood,
suggesting that variations in the "tempo" of growth and puberty may
well represent the unfolding of a complex mixture of genetic
variables.
Some of the genetic factors that regulate the function of the reproductive axis have become evident through the study of patients with hypogonadotropic hypogonadism (HH) who classically present with a failure to undergo sexual maturation at the usual time of puberty. In some instances, patients exhibit phenotypic features that permit the diagnosis to be made earlier in life. For example, the finding of microphallus and or undescended testes in a male infant warrants an evaluation of putative deficits in androgen production or action. If such an evaluation is undertaken in the first several months of life, one may take advantage of the normal period of active hypothalamic-pituitary-gonadal (HPG) function to document HH, which foreshadows a failure to enter puberty years later.
There are several clinical syndromes characterized, at least in part, by HH. However, many (e.g. Prader-Willi syndrome) include other features that represent evidence of more widespread hypothalamic-pituitary dysfunction. As such, single gene defects that result in HH in isolation are likely to yield the most insight into those factors that modulate the timing of a normal puberty. The first of these to be elucidated, KAL, encodes anosmin, a cellular matrix protein required for normal migration of olfactory processes and GnRH neurons from their common site of origin, the olfactory placode. KAL defects result in the X-linked form of Kallmann’s syndrome, characterized by anosmia and HH [the molecular bases of HH have been recently reviewed in detail (18, 19, 20)].
Another form of X-linked HH, that associated with adrenal hypoplasia congenita, is due to defects of DAX1 (dose-sensitive sex reversal AHC-associated gene on the X chromosome). DAX1 encodes a novel transcription factor that seems to play key developmental roles in the hypothalamus, pituitary, and gonad as well as adrenal cortex.
Pedigree analysis and direct sequencing of both KAL and DAX1 have confirmed that X-linked forms of HH are in the minority. Thus far, defects in the gene encoding the GnRH receptor (GnRHR) represent the only known autosomal basis for isolated forms of HH, with the clinical phenotype varying with the extent to which GnRH binding and signaling is disrupted. An additional autosomal disorder, a defect in prohormone convertase (PC1), has been shown to disrupt GnRH processing and results in HH along with obesity and impaired processing of insulin and pro-opiomelanocortin.
In addition to gene defects that result in a failure of pubertal maturation by impinging directly on GnRH activity through disruption of neuronal migration (KAL), hypothalamic-pituitary development (DAX1), GnRH processing (PC1) or its signaling (GnRHR), other defects have revealed indirect effects on the hypothalamic-pituitary-gonadal (HPG) axis. The interactions between reproduction and nutritional or metabolic homeostasis have been underscored by the fact that HH is a component of the human phenotype caused by defects in leptin or its receptor (for example and review see Refs. 19, 20, 21). It remains to be seen whether less severe disruptions of these and other gene products in the same pathways help to explain the normal variations in the timing of puberty. The striking family history of delayed puberty in some probands with complete HH suggests that this may be the case (22).
Variation in the timing of puberty: how genetics may provide insights
The factors that regulate the onset of puberty remain elusive (9). Certainly environmental and metabolic factors are critical regulators of the HPG axis and the timing of puberty, but their influence is superimposed on significant genetic control. We have already discussed some hints of genetic modulation. More direct evidence for genetic regulation of the timing of puberty is provided by data demonstrating a correlation between the ages at which a mother and her son or daughter attain pubertal milestones (23). Population studies demonstrating that the timing of puberty varies among racial groups, while subject to socioeconomic influences, are also suggestive of genetic modulation (10, 24). Finally, twin studies have revealed that skeletal maturation during childhood, age of growth spurt, age of menarche, and Tanner staging during puberty all display greater concordance between monozygotic than dizygotic twins (25, 26, 27, 28). The calculated measures of heritability in these various studies suggest that up to 50–80% of the variance in pubertal onset may be genetically controlled.
Because of this genetic regulation, the sequencing of the human genome and the rapid advances in genomics provide exciting opportunities to increase our understanding of the maturation and modulation of the human reproductive endocrine axis. Much has already been learned from the single defects that lead to HH (19, 20), and new insights are sure to derive from identification of additional genes that underlie HH. However, in the general population, the genetic modulation of a trait, such as the age of puberty whose variance approximates a gaussian distribution, most likely arises from the additive effect of multiple genes (29). Thus, the timing of puberty is unlikely to exhibit classic Mendelian inheritance that is attributable to a single locus; rather, it is likely to be a complex genetic trait that is modulated by variations in multiple genes (for example see Refs. 30 and 31).
Identification of genes that regulate the timing of puberty presents a new opportunity to enhance our understanding of the factors that modulate the HPG axis in humans. The identification of allelic variants of candidate genes that are associated with variations in the timing of puberty is an attractive genetic strategy for such investigation. Association studies are particularly suited for this endeavor because, unlike linkage studies, they do not rely on either families with multiple generations of affected members or the existence of several affected pairs of siblings. Linkage analysis is not well-suited for families with only a single affected member and often lacks sufficient power to detect the weaker, potentially additive genetic effects that may underlie polygenic traits (32).
Association studies also have weaknesses, although these disadvantages are rapidly becoming less problematic. An analysis designed to test whether a particular allele occurs at a higher frequency among affected than unaffected individuals can be confounded by population admixture. If "cases" and "controls" in such a design are drawn from genetically distinct populations, one is at risk of finding spurious associations (33). In fact, any allele that is more common among the affected group will show positive association with any trait that is also more common among that group. In the study of pubertal onset, this issue is of paramount concern because African-Americans and Hispanics are known to enter puberty earlier than whites, and, therefore, the simple study of early vs. late maturing children would be confounded by the different ethnic make-up of the two groups. Fortunately, the development of transmission disequilibrium testing provides one way to overcome this difficulty by using data from trios (an affected individual and his/her parents), thus relying on internal rather than unrelated controls (34, 35).
Other disadvantages of association studies are also becoming more surmountable. First, because these studies rely on candidate genes, the gene(s) (candidates) involved in regulating the HPG axis must be tentatively identified before the tests can be performed. This limitation is diminishing with the sequencing of the human genome and the continued, rapid identification of its composite genes. Second, the logistical pressures to select only a small number of candidates for study are diminishing as new high-throughput technologies such as hybridization to high-density oligonucleotide arrays (DNA chips), denaturing high-performance liquid chromatography, and single base extension sequencing facilitate the querying large numbers of genes (for example see Refs. 36, 37, 38).
Association studies could explore the genetic factors that regulate the timing of puberty by focusing on patients with either CPP or constitutional delay, generating a comprehensive list of candidate genes, determining which of these genes harbor common sequence variants, genotyping a large set of trios for the particular allelic variants, and then testing whether any of the variants associate significantly with early or late puberty. Other scenarios could be envisioned that would also allow identification of allelic variants that associate with the diverse patterns of pubertal onset.
It is our hope that the ongoing identification of genes that lead to pathological failure of the HPG axis (e.g. hypothalamic hypogonadism) and those that underlie the normal variation in the timing of puberty will help to solve the long-standing mystery underlying the regulation of the onset of puberty. Such insights would surely expand our understanding of human reproduction and its disorders.
Received February 9, 2001.
Revised March 19, 2001.
Accepted March 21, 2001.
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