Disorders of Puberty: Take a Good History!

Puberty is the process through which reproductive competence is attained. This process represents the culmination of events that began during early embryonic life with the birth of GnRH neurons in the olfactory placode. The GnRH neurons then migrate in close association with olfactory neurons through the cribriform plate. Upon arrival within the forebrain, the GnRH neurons become diffusely distributed in both the preoptic area and medial basal hypothalamus with extensive projections to the median eminence. These projections have been termed “dendrons” because they have properties characteristic of both axons and dendrons (1, 2). Humans and nonhuman primates demonstrate a distinctive “on-off-on” pattern of GnRH pulse generator activity. During fetal development and in early infancy, GnRH pulse generator activity is evidenced by gonadotropin secretion; the lack of Sertoli cell androgen receptor expression and limited gonadal responsivity prevent premature germ cell maturation at these ages (3). Subsequently, the GnRH pulse generator is held in check, resulting in the hypogonadotropic state of the prepubertal years. Despite the major role of the GnRH neurons in the hypothalamic-pituitary-gonadal axis, the GnRH neurons, pituitary, and gonads of juvenile primates are not limiting to the onset of puberty (3).

The onset of puberty depends on the appropriate balance of afferent inputs and removal of restraints of the neuroendocrine mechanisms governing activity of the GnRH neuronal network. In addition to neuronal afferents, GnRH neurons maintain close physical contact with glial cells (4). Kisspeptin, neurokinin B, dynorphin, leptin, insulin, IGF-1, ghrelin, fibroblast growth factor 21, sex steroids, orexigenic peptides, anorexigenic peptides, other hormones and neurotransmitters, and paracrine interactions provide signals that are integrated to modulate GnRH secretion, influence pubertal maturation, and govern ongoing reproductive function (3, 5–8). Recent evidence emphasizes the fundamental role of transcriptional repression by zinc finger motif proteins such as makorin-3 encoded by the MKRN3 gene in the neurobiological mechanisms regulating puberty (9). Environmental factors such as nutritional status, stress, and environmental chemicals may also affect the timing of puberty.

Why has there been a long-standing interest in investigating ages at the onset of puberty? One obvious reason is to elucidate the molecular attributes of the timing mechanisms governing puberty and reproduction (10). One practical reason relates to the challenges in the evaluation of patients with disorders of pubertal timing. In some instances, associated features such as anosmia, midline facial defects, renal agenesis, concurrent chronic disease, or skeletal anomalies point to specific disorders associated with hypothalamic hypogonadism (HH) (11). Yet, accurately discriminating individuals with constitutional delay of growth and puberty from those with HH remains problematic (12). The association between constitutional delay of growth and puberty and HH in some families further confounds this dilemma (13).

Another justification is that the age at onset of puberty is associated with long-term health consequences. For females, earlier menarche connotes a lengthier period of exposure to estrogen with increased risks for obesity, breast cancer, endometrial cancer, type 2 diabetes mellitus, and cardiovascular disease (14–19). Menarche at older ages is associated with increased risks for osteopenia and osteoporosis (20). Using a Mendelian randomization approach with a derived genetic risk score for pubertal development in males, later age for pubertal development was associated with decreased risk for prostate cancer (21). Thus, adopting the concept of developmental origins of disease, pubertal timing may foreshadow risks for diseases in adulthood (22).

Another impetus to investigate the age at onset of puberty is the observation of a secular trend to decreased age at menarche dating from the early part of the 20th century (23). Although attributed to better nutrition, several studies involving girls of differing ethnic, racial, and socioeconomic backgrounds have suggested a more complex relationship between nutrition and age at menarche (24–30). Nevertheless, better understanding of the genetic basis of puberty would potentially clarify the complex relationship between pubertal timing and environmental influences.

Despite considerable between-individual variability for the age at onset of puberty, family and twin studies indicate that genetic factors account for approximately 50% of the variation in age at menarche (31, 32). Investigation of families with multiple members with disordered pubertal timing led to identification of single gene mutations associated with HH and central precocious puberty. Phenotypic heterogeneity, variable penetrance, and oligogenicity, reflecting digenic genetic variants that interact, occur (33, 34). Common genetic factors appear to influence body mass index (BMI) and age at menarche (35).

Genome-wide association studies have identified additional loci associated with the timing of puberty, timing of menarche, and BMI (36). Some genome-wide association study signals associated with age at onset of menarche are located near genes associated with known rare disorders of puberty (37, 38). Some loci are mapped to imprinted genomic regions and manifest parent-of-origin effects (39). Nevertheless, identified genetic variants account for < 5% of the variance associated with age at menarche.

To test their hypothesis that genetics plays a role in the ages at onset of puberty, Wohlfahrt-Veje et al (40) followed a cohort of normal Danish children. The mothers of these children were recruited during early pregnancy between 1997 and 2003. Subsequently, 672 girls and 846 boys were followed longitudinally and evaluated for pubertal status. Mothers and fathers of subjects were asked to complete questionnaires regarding their age at puberty before a routine study examination. Parents were asked to recall whether their pubertal development was early, average, or late. These data provide the first systematic inquiry regarding the influence of paternal age at puberty on the timing of puberty in their children.

The longitudinal design enabled evaluation at multiple landmarks of puberty such as onset of gonadarche, onset of pubic hair development, and menarche in females and transition between pubertal stages. Tanner staging for breast development was evaluated by palpation to avoid misclassifying breast tissue as lipomastia. Testicular volume was assessed by palpation and measured with an orchidometer. Tanner staging for male genital development and pubic hair was assessed by inspection. Pubertal development was judged per Marshall and Tanner criteria (41, 42). Probit analyses were utilized to assess the impact of parents' pubertal timing. Combinations of parental pubertal timing were not randomly distributed in that late-maturing fathers were often partnered with late-maturing mothers.

In boys, the onset of gonadarche was defined as testicular volume > 3 mL or ≥ 2 genital development according to Tanner; onset of pubarche was defined as ≥ 2 pubic hair development. For girls, onset of gonadarche was defined as ≥ 2 breast development, and onset of pubarche was defined as ≥ 2 pubic hair development. Early parental pubertal timing was significantly associated with earlier milestones in their sons and earlier menarche in their daughters. Significant interactions between parental pubertal timing were noted for onset of pubarche in boys and menarche in girls. No sex-specific effects of parental pubertal timing were identified. Age at menarche showed a greater correlation with parental puberty timing than did breast or pubic hair development for the girls. Not surprisingly, more boys had delayed puberty than girls.

Although maternal age at menarche was correlated with the daughter's age at menarche, the girls experienced menarche significantly earlier (12.99 ± 1.16 years) than their mothers (13.17 ± 1.32 years). Maternal age at menarche was associated with all pubertal milestones, for both daughters and sons, with the exception of pubic hair development in the girls. The authors suggested that the regulatory mechanisms governing female gonadarche and adrenarche are distinct. In comparison with studies performed in the same geographic region approximately 20 years ago, pubertal onset, especially breast development, was earlier in this cohort (43). The authors concluded that their data are consistent with the secular trend to earlier pubertal maturation and hypothesized a role for environmental influences.

The authors meticulously evaluated pubertal development but did not report the weights or BMI values for the children and their parents. Studies have indicated that BMI at age 7 years predicts age at pubertal growth spurt (44). Familial obesity, food behaviors, lifestyle choices, environmental influences, and genetic factors may impact BMI. Timing of puberty, weight status, and genetic variation are entangled. Wohlfahrt-Veje et al (40) have clearly demonstrated that parental timing of puberty predicts age at onset of puberty in their offspring. Nevertheless, one can query whether the correlations in pubertal timing reflect genetic variations governing puberty and/or weight status. The challenge will be to dissect the neurobiological pathways governing timing of puberty and regulation of body weight.

Comparison of human studies suggests both earlier onset of initial pubertal stages and older chronological ages at the final pubertal stages. It has been speculated that these trends reflect the influences of environmental disruptors, epigenetic changes, and energy balance (45). The particulars of prenatal environment, postnatal nutrition, dietary macronutrients, maternal obesity, childhood adversity, psychosocial stress, and environmental exposures likely modulate the specific consequences of these factors (46, 47). Epigenetic changes are plastic, can occur relatively rapidly allowing for responses to the environment, affect chromatin structure, modify gene expression, and may influence pubertal timing (48, 49).

Much remains to be elucidated regarding the role of genetic variants, noncoding RNA, epigenetic modifications, environmental exposures, nutritional status, and cell-specific gene expression patterns in the timing and regulation of puberty and reproduction. At the current time, the data reported herein are not surprising. These data emphasize the importance of obtaining a thorough medical history of pubertal timing in parents and other extended family members to help with clinical decision-making and management for disorders of pubertal timing. With family studies and continuing development of novel bioinformatic tools, the neurobiological timing mechanisms that govern pubertal development may ultimately be illuminated.

Acknowledgments

I express my deep gratitude to Tony M. Plant and Luigi Garibaldi for their thoughtful editing and many discussions about puberty.

This work supported in part by National Institutes of Health Grant 3R01DA026312-05S1.

Disclosure Summary: The author has nothing to declare.

Abbreviations

 
• BMI

  body mass index

 
• HH

  hypothalamic hypogonadism.

References