Normal and Abnormal Puberty

ABSTRACT

Puberty is a biological process that represents the development of secondary sexual characteristics and attainment of reproductive capacity, influenced by genetic, metabolic, environmental, ethnic, geographic, and economic factors. Pubertal onset is characterized by the increased kisspeptin and neurokinin B secretion leading to re-emergence of pulsatile gonadotropin releasing hormone signaling from the hypothalamus which stimulates increased pituitary secretion of luteinizing hormone and follicle stimulating hormone, which in turn stimulate gonadal sex hormone production. Precocious puberty refers to secondary sexual development occurring earlier than the lower end of normal age and delayed puberty refers to secondary sexual development occurring later than the upper end of normal age for the onset of puberty. These changes may represent a serious underlying condition or signify a common variation of normal for which treatment may not be necessary. Clinical evaluation should include a detailed history and physical examination, including anthropometric measurements, calculation of linear growth velocity, and evaluation of secondary sexual characteristics. This chapter summarizes the physiology of pubertal development, variations in pubertal development, and recent developments regarding human puberty. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Puberty is the process through which reproductive competence is achieved (1). Physical characteristics associated with this process include the development of secondary sex characteristics, acceleration in linear growth velocity, and the occurrence of menarche in women and spermatogenesis in men. The sex chromosome karyotype of the embryo, XX or XY, determines the trajectory for differentiation of the gonads and development of the internal and external genital structures. This complex process, beginning in utero, depends on neuroendocrine signaling and gonadal components. Ultimately, integrated communication between the reproductive and metabolic systems is critical for timely pubertal development (2).

Pubertal development and neuroendocrine system maturation involve the ontogeny, activity, and interactions of the gonadotropin releasing hormone (GnRH) neurons. The onset of puberty is accompanied by increased kisspeptin and neurokinin B secretion causing the GnRH neurons to secrete GnRH in a pulsatile manner. Increased GnRH secretion stimulates pulsatile pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) secretion (3). LH and FSH stimulate gonadal sex steroid secretion which promotes development of secondary sex characteristics and influences hypothalamic-pituitary function via negative feedback inhibition. This chapter summarizes the physiology of pubertal development, variations in pubertal development, and recent developments regarding human puberty.

CLINICAL FEATURES OF NORMAL PUBERTAL DEVELOPMENT

Children typically demonstrate a predictable sequence of physical changes during pubertal maturation. Within the chronologic age ranges for pubertal development, individual variations regarding age at onset and tempo of pubertal development are expected.

In humans, two physiological processes, gonadarche and adrenarche, govern pubertal transition. Gonadarche reflects the reactivation of the hypothalamic GnRH pulse generator which has been quiescent since late infancy. Increasing pulsatile GnRH secretion stimulates pulsatile gonadotropin secretion which, in turn, stimulates the growth and maturation of the gonads and gonadal sex steroid secretion. Increased estrogen secretion promotes breast development, cornification of the vaginal mucosa, and uterine growth in girls. Increased testosterone secretion promotes penile enlargement. The increased HPG axis activity culminates in folliculogenesis, ovulation, and menses in the female and spermatogenesis in the male.

In addition to gonadal sex steroid secretion, humans experience adrenarche signifying adrenal pubertal maturation. Adrenarche typically begins prior to the first visible physical manifestation of gonadarche, breast development, or testicular enlargement. Pubarche, the physical manifestation of adrenarche, is characterized by the development of pubic hair, axillary hair, apocrine odor, and acne. Adrenarche indicates increased adrenal cortical zona reticularis activity and is accompanied by increased secretion of dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), androstenedione, and 11-hydroxyandrostenedione (4, 5). These so-called “adrenal androgens” are C19 steroids which do not bind directly to the androgen receptor and can be peripherally converted to more potent androgens. Circulating concentrations of two adrenal 11-oxyandrogens, 11-hydroxyandrostenedione and 11-ketotestosterone increase with adrenarche. Whereas 11-hydroxyandrostenedione has minimal androgenic activity, 11-ketotestosterone is almost as potent as testosterone. During adrenarche, 11-ketotestosterone appears to be the major bioactive adrenal C19 steroid and may be responsible for the physical changes associated with pubarche (6).

Gonadarche and adrenarche are dissociated such that the absence of adrenarche does not prevent gonadarche or the attainment of fertility (7). Curiously, the phenomenon of adrenarche appears to be limited to humans and a few species of non-human primates (8, 9). The factors that drive the dynamic changes within a strictly defined zona reticularis within the adrenal cortex, are still poorly defined. How adrenarche and increased adrenal C19 steroids impact brain development during human adolescence is indeterminate (10). Urinary steroid hormone profiling suggest that adrenarche may be a gradual process that likely begins earlier than previously believed (11).

STAGING OF PUBERTY

Tanner and colleagues followed the pubertal development of children living in an orphanage in the UK. Their five-stage classification system continues to be commonly utilized for clinical assessments (12, 13, 14). For girls, Tanner staging is used to describe breast and pubic hair development (See Figure 1). For boys, Tanner staging is used to describe testicular volume, penile development, and pubic hair development (See Figure 2). Tanner and his colleagues also described that the tempo of puberty varies between individuals.

Figure 1.

Tanner Staging for pubertal development in girls. In girls, breast development is rated from 1 (preadolescent) to 5 (mature), and stage 2 (appearance of the breast bud) marks the onset of pubertal development. Pubic hair stages are rated from 1 (preadolescent, no pubic hair) to 5 (adult), and stage 2. Although pubic hair and genital or breast development are represented as synchronous in the illustration, they do not necessarily track together and should be scored separately. Figure 1 Adapted with permission from Carel JC, Léger J. Clinical practice. Precocious puberty. N Engl J Med. 2008;358(22):2367 and Klein DA, Emerick JE, Sylvester JE, Vogt KS. Disorders of Puberty: An Approach to Diagnosis and Management. Am Fam Physician. 2017 Nov 1;96(9):590-599. PMID: 29094880.

Figure 2.

Tanner Staging for pubertal development in boys. In boys, genital development is rated from 1 (preadolescent) to 5 (adult); stage 2 marks the onset of pubertal development and is characterized by an enlargement of the scrotum and testis and by a change in the texture and a reddening of the scrotal skin. Pubic hair stages are rated from 1 (preadolescent, no pubic hair) to 5 (adult), and stage 2 marks the onset of pubic hair development.Although pubic hair and genital or breast development are represented as synchronous in the illustration, they do not necessarily track together and should be scored separately. In normal boys, stage 2 pubic hair develops at an average of 12 to 20 months after stage 2 genital development. Figure 2 Adapted with permission from Carel JC, Léger J. Clinical practice. Precocious puberty. N Engl J Med. 2008;358(22):2367 and Klein DA, Emerick JE, Sylvester JE, Vogt KS. Disorders of Puberty: An Approach to Diagnosis and Management. Am Fam Physician. 2017 Nov 1;96(9):590-599. PMID: 29094880.

Girls

The typical first clinical sign of puberty in girls is the appearance of breast tissue with elevation of the breast and papilla; this is considered to be Tanner Stage 2 (Figure 1). Initially, breast development (thelarche) may be unilateral. Many girls complain of mild breast tenderness or discomfort during this stage that subsequently resolves. Tanner stage 3 breast development is considered to be additional enlargement of the breast and areola. During Tanner stage 4, the papilla forms a secondary mound above the breast; this stage is often very rapid. Tanner stage 5 represents mature breast development due to recession of the areola to the contour of the breast. Palpation of the breast is obligatory to differentiate breast tissue from lipomastia. In children with obesity without breast development, a palpable depression beneath the nipple in the center of the areola when examined in the supine position gives the impression of a donut and is referred to as the ‘donut’ sign. Breast ultrasound correlates reasonably well with Tanner staging by palpation and can detect breast development slightly earlier than physical exam (15). In most instances, breast development is evident before pubic hair development. Typically, the pubertal growth spurt in girls occurs concurrently with the onset of breast development with only 4-6 cm of linear growth occurring after menarche, however this may be variable.

The appearance of sexual hair including pubic hair (pubarche) signifies the onset of adrenarche. In girls, Tanner stage 2 pubic hair is characterized by sparse, coarse, lightly pigmented hairs along the labia majora. For Tanner stage 3, pubic hair becomes progressively darker, coarser, and spreads over the mons pubis. For Tanner stage 4, pubic hair continues to extend to become an inverse triangle, with spread to the medial aspects of the thighs being considered Tanner stage 5.

With the onset of ovarian estrogen secretion, the vaginal mucosa changes from shiny bright red to pale pink appearance due to cornification of the vaginal mucosa. Increased estrogen secretion promotes uterine growth and causes physiologic leukorrhea, a thin, white, non-foul-smelling vaginal discharge that typically begins 6 to 12 months before menarche. Menarche occurs, on average, 2 to 2.5 years after the onset of breast development (See figure 3A). During the first-year post-menarche, menses are usually irregular and anovulatory. These early years are characterized by inconsistent ovulation and varying lengths of follicular and luteal phases. Ultimately, coordinated maturation of the hypothalamic, pituitary, and ovarian components occurs culminating in cyclic monthly ovulation (16). Although full HPG axis maturation generally occurs over several years, by three years post-menarche, most cycles are between 21-35 days.

Figure 3A and 3B.

Average ages and sequence of pubertal development. Panel A: girls; Panel B: boys.

Boys

For boys, increased testicular volume is the first physical finding indicating onset of gonadarche (See Figure 2 and Figure 3B). Palpation of the testes and use of a Prader orchidometer is essential for accurate assessment. A Prader orchidometer is a collection of 3-D ellipsoids ranging in volume from 1 to 25 mL (See Figure 4). During gonadarche, testicular volume increases, and the penis increases in length and diameter. Flaccid penile length can be measured using a straight edge on the dorsal surface from the pubic ramus to the tip of the glans while compressing the suprapubic fat pad and applying gentle traction to stretch to penis.

Figure 4.

Prader Orchidometer.

Increased testicular volume represents Sertoli cell proliferation, differentiation, and eventually, the initiation of spermatogenesis. The onset of puberty is defined as a testicular volume ≥ 4 ml and a testicular length ≥ 2.5 cm. The volume of mature human testis is approximately 20-25 ml. Spermatozoa (spermaturia) can be found in early morning urine samples beginning during genital stage 3 (16). Nocturnal sperm emissions may also begin around this time.

For boys, Tanner stage 2 pubic hair consists of downy hairs at the base of the penis. During pubic hair stage 3, the hair becomes longer, darker, and extends over the junction of the pubic bones. For pubic hair stage 4, the extent of hair has increased, but has not yet achieved the adult male escutcheon with spread to the medial aspects of the thighs that would be considered Tanner stage 5. Additional features include axillary hair, increased size of the larynx, voice break with deepening of the voice, increased bone mass, and increased muscle strength. Terminal hair develops in androgen-dependent regions on the face and trunk approximately three years after appearance of pubic hair. The distribution and density of beard, chest, abdominal, and back hair varies among individuals.

Peak height velocity is both age and sex-dependent. It occurs earlier in girls, between Tanner breast stages 2 and 3, and later in boys, between Tanner testis stages 3 and 4.

Approximately 50% of boys experience pubertal gynecomastia (17). Typically, pubertal gynecomastia is transient and most prominent in mid-puberty when the ratio of circulating estradiol to testosterone concentrations is relatively higher.

DISCOVERY OF THE HYPOTHALAMIC-PITUITARY-GONADAL (HPG) AXIS

Since ancient times, it was known that castration of animals and humans interfered with development of secondary sex characteristics and fertility (14). In 1935, Ernst Laquer and colleagues isolated testosterone from several tons of steer testes (18). Later that year, Adolf Butenandt, Gunter Hanisch, Leopold Ruzicka, and A. Wettstein published the chemical synthesis of testosterone (19, 20). After showing that follicular fluid obtained from a sow ovary was able to induce cornification of vaginal mucosa, Edgar Allen and Edward Doisy isolated the active substance, estrone (21). Donald MacCorquodale, Stanley Thayer, and Edward Doisy isolated estradiol from 8000 pounds of sow ovaries in 1935 (22). Philip Smith, Bernhard Zondek, Hermann Zondek, H.L. Fevold and colleagues, and Geoffrey Harris established the functional relationships involved in HPG axis function (23, 24, 25, 26). Roger Guillemin and Andrew Schally engaged in a vigorous competition to identify hypothalamic releasing hormones including GnRH (27, 28, 29). Ernst Knobil and his colleagues identified that pulsatile GnRH secretion was essential for sustained pituitary gonadotropin secretion (28, 30). Fred Karsch and Ernst Knobil independently developed the concept of the “GnRH pulse generator” (31). In the 1970s, Melvin Grumbach and colleagues measured circulating gonadotropin concentrations in the human fetus (32). Around the same time, Charles Faiman and Jeremy Winter also reported gonadotropin concentrations in normal and agonadal children (33). Their collective findings led to recognition of early postnatal HPG axis activity followed by quiescence of the HPG axis during childhood until resumption of GnRH pulse generator activity at the onset of puberty.

MINI-PUBERTY

Facilitated by the availability of more sensitive hormone assays, Forest and her colleagues described a transient period of increased HPG axis activity in early infancy (83, 84). Following the low gonadotropin concentrations at birth, gonadotropin concentrations were found to rise in both boys and girls within weeks of birth (85). This period of transient gonadotropin secretion has been designated as “minipuberty”. Gonadotropin concentrations in the immediate neonatal period are likely low due to in-utero suppression by placental estrogen. With removal of the placental estrogen suppression, the HPG axis is functional. Relevantly, physical findings typical of pubertal sex steroid secretion are absent with the rare exception of vaginal bleeding attributed to decreased exposure to placental estrogen.

Over the first few years of life, sexual dimorphism in gonadotropin concentrations occurs (86) Boys have higher LH concentrations which peak between 2-10 weeks of age and decline by 4-6 months of age. Girls have higher FSH concentrations which may remain elevated until 2-4 years of age.

In boys, LH stimulates testicular testosterone secretion with testosterone concentrations typically peaking around 1 month of age followed by a decline to prepubertal concentrations by 7-12 months of age. During this phase, the number of germ cells and Sertoli cells increase and penile size increases (87, 88). The proliferation of Sertoli cells leads to a transient increase in testicular volume (89). Sertoli cells secrete Anti-Mullerian Hormone (AMH) and inhibin B. Since Sertoli cells do not express androgen receptors during this stage, spermatogenesis does not occur and AMH secretion remains high (90, 91). A temporary increase in the number of Leydig cells also occurs, but subsequent fetal Leydig cell apoptosis reduces fetal Leydig cell number (92). Longitudinal data obtained from healthy boys suggests a temporal dissociation of Leydig and Sertoli cell activity during minipuberty (93). These data suggest that single blood sample may be insufficient to assess HPG axis activity during early infancy and that obtaining several consecutive samples may be more informative. Curiously, gonadotropin and testosterone concentrations are higher among preterm boys. In addition, increases in testicular volume and penile length are greater in preterm boys compared to full term boys essentially enabling catch-up for testicular volume and penile length (94). Some small studies have documented an exaggerated physiologic hormonal response in extremely premature infants (95).

In girls, the gonadotropins promote granulosa cell proliferation and ovarian estrogen and AMH secretion (96). As would be anticipated, AMH concentrations remain much lower in girls compared to boys (97). A longitudinal study involving healthy full-term infant girls demonstrated two gonadotropin peaks in early infancy with one peak occurring around days 15 to 27 and a later peak occurring at days 164-165 (98). Again, collecting several consecutive samples may be more informative than a single blood sample to assess for minipuberty in infancy.

This transient time period of an active HPG axis, provides an opportunity to diagnose individuals with differences/variants of sex development (DSD/VSD). In a series including both healthy infants and infants with DSD, testosterone measured by LC-MS/MS, AMH concentration, and LH/FSH ratio provided the best discrimination between sexes. The cut-point for LH/FSH ratio was 0.32. Inhibin B and AMH levels were higher in boys with minimal overlap in girls (99). Infants with Turner Syndrome usually have elevated FSH concentrations. Surprisingly, gonadotropin concentrations are typically not elevated in patients with complete androgen insensitivity.

This brief interval of HPG axis activity can also help diagnose congenital hypogonadotropic hypogonadism in boys who present with micropenis accompanied by low gonadotropin and testosterone concentrations (100). Testosterone, LH, FSH, AMH, and inhibin B concentrations may provide information regarding the functionality of testicular tissue in infant boys (101).

As noted above, the human HPG axis displays an “on-off-on” pattern. The biological basis and rationale for transient post-natal HPG axis activity during the first few months of life are enigmatic. At birth, the brain is still plastic with ongoing development. Most axon and synapse formations are completed during the first year of life. Does this transient HPG axis activity imprint specific areas in the brain? Does minipuberty influence future patterns for female and male reproductive function with cyclic gonadotropin patterns in females and not in males? Are gonadal hormones during infancy able to affect future fertility, gender identity, sexual orientation, behaviors, and risk for autism spectrum dysfunction? Data are accruing regarding patterns of hormone secretion during the first six months of life. However, the factors that initiate and terminate this transient period of HPG axis activity and maintain the quiescence of the HPG axis until the onset of puberty are still unknown.

SECULAR TRENDS REGARDING PUBERTY

Over the past few decades, several studies have observed that puberty is beginning at a younger age. Clinical studies examining ages of the onset of puberty depend on the criteria used to denote puberty. Onset of breast development and age at menarche are the conventional indicators of puberty in girls. Prospective observations and retrospective questioning of parents and young girls through in-person questioning has been used to record age at menarche; shorter recall intervals provide the greatest accuracy regarding the details of menarche (102, 103). For boys, age at voice change has been used as a surrogate marker because accurate ascertainment of pubertal onset in boys requires testicular exams using an orchidometer, thus, effectively excluding large-scale epidemiologic clinical studies (104).

During medieval times, available evidence suggests that puberty began around 10-12 years of age. However, the tempo of puberty was slow with menarche occurring closer to 15 years in rural areas and 17 years in London (105). Presumably, undernutrition, increased infections, and greater physical exertion impacted both the timing and tempo of puberty during medieval times (106). The age of menarche declined from 16 to 17 years in the early 19^th century to 13 years of age in the late 20^th century in Europe and North America. Similarly, the age at menarche has declined in the Yunnan Province in China (107). This decline has been attributed to the improvement in socioeconomic conditions. Currently, the dialogue continues as to whether the trend towards earlier puberty is persisting and, if so, what are the factors driving this process.

Data regarding pubertal milestones in American girls were obtained through the cross-sectional Third National Health and Nutrition Examination Survey (NHANES III) between 1988 and 1994. Among these American girls, mean ages in years for breast development, pubic hair development, and menarche were 9.5, 9.5, and 12.1 for non-Hispanic black girls; 9.8, 10.3, and 12.2 for Mexican-American girls; and 10.3, 10.5, and 12.7 years for non-Hispanic white girls, respectively (108). In 1997, the Pediatric Research in Office Settings (PROS) study reported earlier onset of thelarche with the caveat that breast palpation was not performed (109). The Copenhagen Puberty Study reported that mean age at breast development was lower in the 2006 cohort compared to the 1991 cohort whereas mean age at menarche was similar in both cohorts. Independent of BMI, gonadotropin concentrations were comparable between these cohorts while estradiol concentrations were lower in the 2006 cohort (110).

Beginning in 2004, the Breast Cancer and Environment Research Program (BCERP) prospectively recruited three cohorts of girls aged 6-8 years. This program recruited non-Hispanic white, Hispanic, non-Hispanic black girls, and Asian girls living in New York, Ohio, and California. The overall median age at menarche was 12.25 years with ethnic background median ages as follows: Hispanic girls 11.6 years, black girls at 11.8 years, white girls at 12.5 years, and Asian girls at 12.0 years (111). This cohort differed from the NHANES III study because Hispanic girls experienced menarche earlier than the black girls. These studies, all performed in the United States, report race and ethnicity-related differences in onset of pubertal milestones. Detailed assessment of the potential impact of socio-economic factors was not performed. Notably, differences noted in pubertal timing are smaller than the overall variation among individuals in the population. Most importantly, clinical decision-making should reflect an individual patient's characteristics and family history with less dependence on racial or ethnic backgrounds.

Comparable studies from Spain and Greece have also reported earlier onset of breast development and slower pubertal tempo (112, 113). Thus, available data including a systemic review of international studies largely confirm the ongoing trend for earlier breast development with minimal decline in age at menarche (114).

Several questions regarding this earlier onset of puberty, predominantly earlier thelarche, need to be considered. Does this earlier breast development reflect earlier resumption of GnRH pulse generator activity, extragonadal estrogen production, or environmental exposures? What, if any, is the relationship of BMI to puberty? Another consideration is that race/ethnicity are socio-political constructs and are not fully representative of biology. While genetic ancestry likely influences the onset of puberty, nutritional factors and environmental exposures play important roles. Hence, should cut-off points based primarily on race/ethnicity continue to be utilized?

Based on single unstimulated gonadotropin concentrations, data from the Copenhagen puberty in girls study suggest that gonadotropin concentrations are not obviously increased in girls with early thelarche. Thus, the phenomenon of early thelarche appears to be independent of gonadotropin secretion and may not signify early resumption of GnRH pulse generator activity (115).

The possibility that exposure to endocrine-disrupting chemicals (EDCs) can induce early thelarche has been questioned. EDCs are defined as exogenous chemicals that interfere with hormone action. EDCs include phthalates, phenols, phytoestrogens, organochlorine pesticides, polybrominated flame retardants, diphenyl ethers, heavy metals, and perfluorochemicals. In addition to pesticides, these chemicals can be found in common household products such as hair products, soaps, toothpaste, perfumes, plastics, essential oils, and cleaning products (116). Valid assessment of the consequences of EDCs on puberty is problematic because exposure may occur in utero and generally involves a mixture of assorted EDCs with differing half-lives and activities. Differences in the duration and route of the exposure(s), methodology to detect EDCs, and potential sample contamination further confound analyses. One potential example regarding EDCs involved transient past exposure to organochlorine pesticides among internationally adopted girls in Belgium who subsequently developed precocious puberty (117). Animal models suggest that EDCs can affect puberty through epigenetic mechanisms (118). Nevertheless, most data available regarding the consequences of EDCs on human puberty are inconclusive (119).

VARIATIONS IN PUBERTAL DEVELOPMENT

Timing of the onset of puberty reflects complex interactions between hormonal and neuronal signals with genetic, metabolic, and environmental factors. These interactions presumably begin early in development and ultimately lead to the re-activation of the HPG axis concomitant with the onset of puberty. Multiple factors, both known and unknown, influence the reactivation of the GnRH pulse generator modulating pubertal onset. As noted above, familial patterns of pubertal development and twin studies highlight the role of genetic factors. Studies of families with either delayed or precocious puberty led to discovery of genes relevant to pubertal onset. In addition, genetic factors including single nucleotide polymorphisms (SNPs) have been associated with pubertal timing in both sexes and across ethnic groups. Epigenetic mechanisms have been suggested to affect the development and function of the GnRH neuronal network ultimately influencing HPG axis function. How confounders such as socioeconomic, environmental, and nutritional status influence pubertal development is unclear. These factors can influence puberty timing, HPG axis function, and fertility.

Precocious puberty is defined as the development of puberty prior to age 8 in girls, and age 9 in boys (134, 135). In girls, delayed puberty is defined as the absence of breast development by age 13 years, absence of menarche by age 15 or lack of menses after 3 years since breast development. In boys, delayed puberty is defined as absence of pubertal development by age 14 (136). Evaluation of a child with abnormal timing of puberty entails thorough knowledge of normal pubertal development, typical variations of normal pubertal development, and causes of abnormal pubertal development. The next section focuses on the evaluation of a patient presenting with a variation in pubertal development.

PRECOCIOUS PUBERTY

Traditionally, the diagnosis of precocious puberty is considered when signs of puberty develop prior to 8 years of age in girls and 9 years in boys (137). These ages are based on Tanner’s original observations on English children regarding typical ages at specific pubertal stages. However, these age criteria should be used as guidelines to complement the evaluation of individual patients. Precocious puberty can be categorized as central or gonadotropin-dependent precocious puberty (CPP) or non-gonadotropin-dependent or peripheral precocious puberty (PPP). Additionally precocious puberty can be further classified as familial or sporadic and syndromic or non-syndromic. The specific etiologies and management differ between the two broad categories of CPP or PPP. Potential consequences of early puberty and menarche in girls include increased risks for breast cancer and diabetes as adults (138, 139).

CENTRAL PRECOCIOUS PUBERTY OR GONADOTROPHIN DEPENDENT PRECOCIOUS PUBERTY

Central precocious puberty (CPP) is associated with early maturation of the HPG with premature reactivation of the GnRH pulse generator and sequential maturation of breasts and pubic hair in females. In males, sequential maturation of testicular volume, penile enlargement, and pubic hair is observed. Typically, the pubertal characteristics are appropriate for the child's sex (isosexual). Despite the earlier onset of puberty, the sequence of pubertal events is usually normal. CPP is due to organic lesions in approximately 40-100 percent of boys whereas idiopathic precocious puberty is the most common diagnosis in girls (69-98%) (140). These children have accelerated linear growth for age, advanced bone age, and pubertal levels of LH and FSH. A Spanish observational report described an annual incidence of CPP ranging between 0.02 and 1.07 new cases per 100,000 (141) while a Korean study reported an incidence of 15.3 per 100,000 girls, and 0.6 per 100,000 boys (142). Distinguishing among CPP, isolated premature thelarche, and premature adrenarche is important because the pathophysiology and therapeutic interventions differ.

CNS LESIONS/INSULTS

CPP can be associated with central nervous system lesions. Hamartomas of the tuber cinereum are congenital benign lesions comprised of heterotopic gray matter, neurons, and glial cells. The prevalence is approximately 1 in 200,000 children (143). Hamartomas are the most commonly recognized CNS lesions associated with CPP in very young children. Hamartomas can be categorized as para-hypothalamic, attached or suspended from the floor of the third ventricle, or as intrahypothalamic, in which the mass is enveloped by the hypothalamus and distorts the third ventricle. The lesions do not grow over time, do not metastasize, and do not produce β-human chorionic gonadotropin-(β-hCG). In some instances, hamartomas are associated with gelastic (laughing or crying) seizures. Yet, most patients with hypothalamic hamartomas do not display neurological symptoms (144, 145). Most hypothalamic hamartomas are sporadic and appear to be idiopathic. Hypothalamic hamartomas can also occur in Pallister-Hall Syndrome (PHS) and oral-facial-digital syndrome (OFD) types I and VI (146). Genetic variants in the sonic hedgehog pathway have been associated with hypothalamic hamartoma (147, 148). The mechanism(s) through which hypothalamic hamartomas lead to CPP is unknown. Hamartoma located close to the infundibulum or tuber cinereum are often associated with CPP whereas those functionally connected to the mammillary bodies and limbic circuit are typically associated with epilepsy without CPP (149, 150). As discussed below, medical treatment is usually indicated for hypothalamic hamartomas associated with CPP. Surgical treatment should be limited to large hamartomas complicated by severe refractory drug-resistant epilepsy (151).

CNS tumors such as astrocytomas, ependymomas, and pinealomas have rarely been associated with CPP. Among girls, factors associated with CNS lesions include: (1) age younger than 6 years; (2) absence of pubic hair; and (3) estradiol concentrations greater than 30 pg/ml (110 pmol/L) (152, 153). As noted above, suspicion for CNS lesions is higher for boys than for girls.

Neurofibromatosis type 1 (NF1) is an autosomal dominant multi-system neurocutaneous disorder due to loss-of-function variants in the neurofibromin-1 (NF1) gene located at chromosome 17q11.2. NF1 is often associated with CPP typically due to optic glioma. The glioma is usually a benign pilocytic astrocytoma that can occur anywhere along the optic tract; the most common locations are within the optic nerve or chiasm. CPP has also been described in NF1 in the absence of optic glioma (154). Children with meningomyelocele and spina bifida also have an increased incidence of CPP. Although the precise mechanism responsible for CPP in these children is unclear, associated factors may include increased perinatal intracranial pressure and brainstem malformations such as Chiari II malformations (155). The mechanistic link between CPP and Rathke cleft cysts, Chiari malformation, and pineal and arachnoid cysts is unclear.

Septo-optic dysplasia (SOD) is a heterogeneous congenital condition characterized by presence of at least two features of the classic triad which include optic nerve hypoplasia, anterior pituitary hormone deficiencies, and midline brain anomalies. SOD is associated with genetic variants in HESX1, SOX2, SOX3, and OTX2 genes. Although SOD is typically associated with delayed puberty, CPP can occur (156, 157).

CNS tumors may be treated with CNS irradiation (158). In some instances, CNS irradiation is associated with acquired CPP (159). In this situation, concurrent growth hormone (GH) deficiency may be present. The linear growth spurt of CPP may mask the decreased linear growth velocity due to GH deficiency. Hence, in this setting, consideration should be given to evaluating the GH axis by provocative GH testing. If testing shows GH deficiency, the patient may benefit from treatment with GH combined with GnRH agonist therapy. Rarely, CPP occurs following head trauma and can develop many years after the injury(160, 161).

SECONDARY CPP

Some children exposed to elevated circulating high sex steroid concentrations occurring in other disorders such as McCune-Albright syndrome, congenital adrenal hyperplasia, and virilizing adrenocortical tumors may develop a secondary CPP (163). These individuals typically have accelerated bone age maturation. The precise mechanism responsible for development of the secondary CPP is unclear. The secondary CPP may represent a priming effect of sex steroids on the hypothalamus or potentially as the consequence of the acute decrease in sex steroid concentrations with treatment of the underlying etiology (164) (165).

NON-SYNDROMIC CPP

Specific genetic variants have been associated with non-syndromic CPP (See Table 1) (166). Loss of function MKRN3 variants are the most reported genetic cause of familial CPP. Paternally inherited loss-of-function MKRN3 variants have been reported in up to 33-46 percent of familial cases of CPP and nearly 0-20% percent of sporadic cases (167) . To date, at least 70 deleterious MKRN3 variants have been identified in patients with CPP. These variants lead to diminished inhibition of puberty results in early onset of puberty. Differing ubiquitination patterns suggests that MKRN3 has multiple molecular mechanisms associated with CPP (168). Curiously, a GWAS study investigating parental effects on pubertal development reported that the paternal allele of a specific SNP (rs12148769, G>A) in MKRN3 was associated with age at menarche in healthy girls suggesting that variants in this region affect pubertal timing within the normal range (132). Although circulating MKRN3 concentrations decrease with onset of puberty, peripheral blood MKRN3 concentrations are not adequately sensitive to distinguish CPP (169).

TABLE 1.

Genes Associated with Central Precocious Puberty (175)

Evaluation of another family with CPP led to identification of a loss of function variant in the delta-like 1 homologue (DLK1) gene. DLK1, also known as preadipocyte factor 1, plays a role in the Notch signaling pathway. DLK1 is a paternally expressed gene located at chromosome 14q32.2. Two differentially methylated regions influence the DLK1 imprinting pattern. DLK is located within the genetic locus associated with Temple syndrome. Temple syndrome is characterized by prenatal growth retardation, hypotonia in infancy, motor delay, small hands, CPP, and short stature. In addition to DLK1 loss, two other genes from the paternally inherited chromosome, RTL1 and DIO3, results in Temple Syndrome. Genetic findings associated with Temple syndrome include maternal uniparental disomy, paternal deletion, or loss of differential methylation at the DLK1/MEG3 region on chromosome 14 (170). Women with DLK1 variants also have a metabolic phenotype characterized by overweight/obesity and insulin resistance (171).

Gain-of-function variants in the kisspeptin 1 gene (KISS1) and its cognate receptor, KISS1R, gene have been identified in children with CPP. A heterozygous variant in the KISS1 gene, p.Pro74Ser, was identified in a boy who developed CPP at one year of age; in vitro studies suggested that this variant was more stable than the normal protein leading to a prolonged duration of action (172). A girl with precocious puberty was found to have a variant in the KISS1R gene; in vitro studies of this p.Arg386Pro variant showed prolonged activation of the intracellular signaling pathways following kisspeptin stimulation (173, 174).

Among a series of 586 children with familial CPP, both maternal and paternal inheritance patterns were found. Variants in MKRN3 were the most common cause in paternally inherited CPP. Among the maternally inherited cases, genetic analysis detected rare variants of unknown significance (175).

SYNDROMIC CPP

In addition to genetic and idiopathic CPP, CPP can occur as a feature in specific syndromes. Pallister-Hall and Temple Syndrome are described above. Other syndromes associated with CPP include Cowden and Cowden-like cancer predisposition syndromes associated with PTEN, SDHB-D and KLLN gene variants. These disorders are characterized by multiple multisystemic hamartomas which may be associated with CPP when the skull base, infundibulum, or hypothalamus are affected. Although Prader-Willi syndrome is typically associated with delayed puberty, CPP has also been reported (176). Other genetic syndromes associated with CPP include tuberous sclerosis and Williams-Beuren (See Table 2). Williams-Beuren is associated with genetic variant at chromosome 7q11.23 (177). Rare cases of precocious puberty have also been reported in Russell Silver syndrome (178).

Table 2.

Syndromic Causes of Central Precocious Puberty Without CNS Lesions (CPP)

NONPROGRESSIVE PRECOCIOUS GONADARCHE

Some children experience a nonprogressive (or slowly progressing) CPP (179). Typically, basal gonadotropin concentrations are prepubertal. In general, children with nonprogressive CPP show no or minimal pubertal responsiveness to GnRH stimulation. Height potential is generally unaffected. Typically, these individuals do not usually benefit from GnRH-Ra therapy. Physical findings alone cannot distinguish between progressive and nonprogressive CPP. Presumably this early pubertal development reflects a transient premature activation of the GnRH pulse generator. Longitudinal follow-up to assure that puberty is not progressive is the most appropriate management.

GONADOTROPH ADENOMA

The anterior pituitary gland consists of highly differentiated ectoderm-derived cells expressing specific hormones such as LH, FSH, GH, prolactin, and ACTH. LH and FSH are secreted by gonadotrophs which are derived from the steroidogenesis factor 1(SF-1) lineage. Gonadotroph adenomas, a type of pituitary adenoma, account for approximately 40% of pituitary adenomas (180, 181) in adults. In children, gonadotroph adenomas can very rarely cause central precocious puberty (182). Though, most gonadotroph adenomas are nonfunctional and benign, rare cases of functional adenomas have been reported. Hormone profiles of functioning adenomas most commonly show elevated FSH concentrations with or without increase in LH concentrations. Elevated TSH secretion resulting in hyperthyroidism may occur concurrently (180, 181).

GUT MICROBIOME AND PUBERTY

Microbiota interact with a variety of metabolic and endocrine pathways of the host through genetic expression of more than 100 times the human genome. The gut microbiome variety, composition and impact on health depend on a vast number of variables, both internal, such as age, genetic factors, gender, and endocrine and immune systems, as well as external factors, such as diet, environment, drugs, and pathogens. The relationship between sex hormones and gut microbiome is complex. Sex steroids may directly or indirectly influence the sex-specific gut microbiome that develops during puberty (183). One study reported several gut microbiome alterations in girls with CPP including Ruminococcus bromii, Ruminococcus callidus, Roseburia inulinivorans, Coprococcus eutactus, Clostridium sporosphaeroides, Clostridium lactatifermentans, Alistipes, Klebsiella and Sutterella (176). Although the evidence of the interaction between microbiota and sex hormones remains limited, evidence of diversity of the gut microbiota at different pubertal stages and that alterations may occur in girls with CPP represents an area for potential future development in the prediction and prevention of precocious puberty (184).

Treatment of central precocious puberty

GONADOTROPIN-RELEASING HORMONE ANALOGS

Long-acting Gonadotropin-releasing hormone analogs (GnRHa) have been the standard treatment of CPP since the mid-1980s (185, 186). The GnRHa are super-agonists that bind to the pituitary GnRH receptor downregulating the endogenous pituitary GnRH receptor resulting in decreased gonadotropin and sex steroid secretion. These medications are modified preparations of the native GnRH decapeptide engineered to increase potency and duration of action by substituting a D-isomer amino acid for the naturally occurring L-glycine at position 6. In some analogs, the tenth amino acid is deleted with modification of the naturally occurring L-proline at position 9 (14).

Several distinct GnRHa preparations are available differing in route of administration and duration of action (See Table 3) (28). The choice of a specific GnRHa depends on patient, caregiver, and physician preference and on insurance coverage/payment/authorization. Treatment with GnRHa leads to regression or stabilization of pubertal symptoms, deceleration of linear growth velocity, and slowing of skeletal maturation. Some girls experience estrogen withdrawal bleeding about 2-3 weeks following the first injection. Parents and the patient should be counseled to expect this episode of vaginal bleeding (187).

Table 3.

Currently Available GnRHa Therapeutic Options

Adverse Effects

In general, GnRHas are safe and effective. Adverse events include injection site reactions and sterile abscesses at the site of the injection or implant (188, 189, 190) which may result in loss of efficacy. Minor reported side effects include headaches, hot flashes, vaginal withdrawal bleeding, and mood swings (191). Extremely rare side effects include hypersensitivity reactions, seizures, slipped capital femoral epiphysis, idiopathic intracranial hypertension, and anaphylaxis. One concern regarding the histrelin implant is possible device fracture during extraction; ultrasound-guided removal of the remaining fragments may be necessary (192).

GnRHas, specifically only leuprolide and degarelix, have been associated with prolonged QT interval. A prolonged QT interval increases the risk of developing torsades de pointes (TdP) which is a ventricular arrhythmia associated with sudden cardiac death. Low serum potassium or magnesium may exacerbate the risk for prolonged QT interval. Individuals also taking anti-psychotics (typical and atypical), anxiolytics, and anti-depressants may have an increased risk for prolonged QT intervals when taking leuprolide. Hence, providers should inquire regarding other medications, history of congenital heart disease, and family history of Long QT Syndrome or sudden death. If positive, the provider should obtain screening and follow-up EKGs.

Studies conflict regarding how GnRHa treatment impacts weight gain and BMI. Some studies have reported weight gain during treatment (193, 194, 195, 196) whereas others have not found any significant change in weight or BMI (197, 198). As with all patients, counseling patients regarding the pre-treatment weight trajectory and healthy lifestyle is beneficial. Women with a history of CPP have been reported to have similar adult weight to the general population (199).

Bone mineral density is typically elevated at diagnosis with deceleration in bone mineral accrual during treatment. However, follow-up several years after treatment shows normal bone mineral density compared to population norms (200). Available outcome data suggest that fertility is not compromised for women or men with histories of CPP (192, 201, 202, 203, 204).

Despite suggestions that CPP is associated with subsequent development of PCOS, available data are inconsistent. Prospective longitudinal studies are needed to adequately address this concern (205, 206).

Who to Treat?

For patients less than 7 years of age with a confirmed diagnosis of CPP, the benefit of GnRHa treatment is generally unequivocal. However, the value of GnRHa treatment may be unclear for the peripubertal child (typically a girl) with onset of puberty between 7-9 years of age especially when treatment is unlikely to improve the predicted adult height (PAH) (207). Some girls and their families are comfortable with early pubertal onset and early menarche. In contrast, some girls and their families are distraught when even contemplating early puberty and premature menarche. Consistent evidence-based data regarding negative psychosocial consequences in children with CPP are lacking (208). Further, it may be challenging to justify the medical benefits of GnRHa therapy for early puberty due to the accompanying burdens of increased physician office visits and financial impact. Shared decision-making involving the patient, parents, and medical staff is indispensable to address the benefits and risks of GnRHa in the individual patient (209) .

Goals of Treatment

Goals of GnRHa treatment include prevention of pubertal progression and height preservation (210). Growth velocity can significantly decline in some children during GnRHa treatment particularly in those with a markedly advanced bone age (211). The use of other height augmenting medications including recombinant human growth hormone (GH) (212, 213, 214, 215), stanozolol (216, 217), and oxandrolone (218) have been explored but none are recommended for sole use or as an adjunct to GnRHa therapy (219, 220).

Increasing adult height must be judged considering the financial and psychological burdens of this intensive treatment regimen (221). Several recent studies have recommended treatment beyond a bone age of 12 years, however more rigorous studies are needed before such treatment is endorsed (222, 223).

Another goal of CPP treatment is to mitigate psychosocial distress and prevent adverse mental health outcomes. One epidemiological study of over 7000 women showed that adolescents with early age of menarche had higher rates of depression and antisocial behavior, which persisted into adulthood (224). Adverse psychosocial experiences reported in girls with early age at menarche include increased likelihood of teenage pregnancy and childbearing, sexual and physical assault, and reduced likelihood of high school graduation (225). However, studies thus far do not show that GnRHa therapy can mitigate these effects. One small study of 36 girls with CPP treated with GnRHas evaluated behavioral health diagnosis and health-related quality of life and found no abnormalities in psychological functioning (226). In a small study of 15 girls with CPP treated with GnRHa and 15 age-matched controls, comprehensive test batteries revealed similar scores in cognitive performance, behavioral, and psychosocial problems (227). A review of 15 studies evaluating the psychosocial impact of CPP showed an increased psychosocial and health-related quality of life burdens with CPP compared with controls (228). The same study showed qualitative data demonstrating emotional lability in patients with CPP and that physical differences associated with sexual precocity could increase feelings of shame and embarrassment which further increase isolation and social withdrawal (228). Again, larger studies are needed to better establish if and how GnRHas influences the psychosocial issues associated with CPP.

Monitoring of Treatment

Treatment efficacy can be monitored by repeat clinical exams assessing pubertal progression, ultrasensitive LH, FSH and sex hormone concentrations (estradiol in girls, testosterone in boys), rate of progression of bone maturation, estimates of PAH and change in PAH, and patient satisfaction. No uniform consensus exists regarding the optimal strategy for monitoring treatment efficacy in children with CPP. Progression of breast or testicular development may indicate poor adherence, treatment failure, or incorrect diagnosis (188).

Random basal LH concentrations to confirm treatment efficacy may be unhelpful because random LH levels often fail to revert to a prepubertal range even when the HPG axis is fully suppressed (229, 230). Therefore, random LH concentrations cannot be used to indicate treatment failure. To confirm gonadotropin suppression, a GnRH stimulation test with short-acting GnRH or, alternatively, a single LH sample 30–120 min after long-acting GnRH analog administration may be performed (231, 232) and different protocols exist regarding the specific timing and number of LH and FSH measurements (233). Some clinicians prefer to utilize clinical indices particularly in areas where hormone determinations are costly.

During treatment, breast tissue usually becomes softer with variable changes in size. The rate of bone maturation typically slows with adequate treatment resulting in a decline in BA/CA or a change in BA divided by time. Recent data show that the decline in BA/CA is non-linear and that larger declines are seen in the first 18 months of treatment (222). Thereafter, a slower rate of decrease suggests maintenance of suppression rather than treatment failure.

Height velocity is typically rapid prior to treatment and decreases on treatment. The height deceleration is most apparent during the first 18 months of treatment, similar to the deceleration in skeletal maturation. Subsequently, a prepubertal growth rate is often evident (222). Ideally, the rate of bone maturation decelerates resulting in a net gain in height potential. Therefore, calculating PAH during treatment helps assess efficacy. It is also important to understand that mid-parental height (MPH) influences height outcome. GnRHa treatment for CPP may restore genetic potential but rarely causes PAH to surpass genetic potential. Therefore, treatment efficacy by PAH assessment is always in comparison to MPH.

Discontinuation of Therapy

The decision to discontinue GnRHa treatment needs to be tailored to meet the patient’s specific needs. Factors influencing the decision-making process include synchronizing pubertal progression with peers, patient readiness for resumption of puberty, recent linear growth velocity, bone age X-ray results, and adult height prediction (234). Specific considerations for the developmentally delayed child may be reviewed with the caregivers (137, 234, 235). Pubertal manifestations generally reappear within months of discontinuation of GnRHa treatment; the mean time to menarche is approximately 16 months (217, 218). Several studies have reported that ovulatory function and menstrual cycles are normal once they resume (137, 236).

PREMATURE THELARCHE

Premature thelarche is the premature development of glandular breast development. The breast development may be unilateral or bilateral. Typically, premature thelarche develops in otherwise healthy girls between 12-24 months of age and is self-limited. No other pubertal changes are evident; linear growth velocity is normal and pubic/axillary hair are absent. On physical examination, the areolae and vaginal mucosa are prepubertal. The diagnosis can usually be made on a clinical basis without bloodwork or bone age X-rays (311). Pelvic ultrasound showed increased prevalence of ovarian microcysts in girls with premature thelarche compared to age-matched controls; no correlation between ovarian cysts, gonadotropin concentrations, and estradiol concentrations has been found (312). Longitudinal follow-up is appropriate to confirm the diagnosis and assess for the unlikely possibility of progression to CPP.

PREMATURE ADRENARCHE

Pubarche refers to the appearance of pubic/axillary hair, increased apocrine odor, and acne due to the onset of adrenarche. Adrenarche refers to the pubertal maturation of the adrenal zona reticularis. Adrenarche which normally occurs in children between 6-8 years of age and is characterized by increased secretion of the adrenal androgen precursors DHEA, DHEAS, and androstenedione.

Premature adrenarche is characterized by premature pubarche, which is defined as the development of pubic or axillary hair before 8 years in girls or 9 years in boys. There is no breast development in females and no testicular enlargement in males. Bone age is usually not advanced. Premature adrenarche is a diagnosis of exclusion. Thus, exclusion of other disorders such as CAH, androgen-secreting tumors, exogenous androgen exposures, and other rare genetic disorders such as apparent cortisone reductase and PAPS synthase 2 (PAPSS2) deficiencies is essential (313).

Children with premature adrenarche and early androgen excess may be at a higher risk to develop the metabolic syndrome. Waist circumference (WC), waist/hip ratio, and total and truncal fat mass increase are detected in premature adrenarche. Increases in systolic and diastolic blood pressure (BP), total cholesterol (TC), very low-density lipoprotein (VLDL), TC/high density lipoprotein (HDL), low density lipoprotein (LDL)/HDL ratio, and atherogenic index (AI) have been reported. Increased insulin concentrations starting from prepubertal ages may occur suggesting that premature adrenarche may be one of the first symptom of insulin resistance (IR) in childhood (314, 315). T2DM may occur in a subset of these cases. Ovarian hyperandrogenism, hirsutism, ovulatory dysfunction, and polycystic ovaries may be more frequent in girls with premature adrenarche during post pubertal ages than normal population. Although, early retrospective data in a homogenous population suggests an association between premature adrenarche and adolescent hyperandrogenism (316), more recent longitudinal data suggests that premature adrenarche was not associated with adolescent ovarian dysfunction and was only associated with lower SHBG concentrations (317).

EXPOSURE TO EXOGENOUS SEX STERIODS

Feminization, including gynecomastia in males, has been attributed to excess estrogen exposure from creams, ointments, and sprays. Other possible sources of estrogen exposure include contamination of food with hormones, phytoestrogens (e.g., in soy), and over-the-counter remedies such as lavender oil and tea tree oil (318, 319, 320, 321). Similarly, virilization of young children has been described following inadvertent exposure to androgen-containing creams/gels (322).

DELAYED PUBERTY

Gonadarche associated with the reactivation of the GnRH pulse generator, is signified by breast development in girls and testicular enlargement in boys. Delayed puberty is defined as absence or delayed onset of gonadarche at a chronologic age >2 standard deviations later than the population mean. In girls, delayed puberty is defined as absence of breast development by age 13 years or lack of menarche by age 15 years (331) or 3 years from onset of thelarche (332). In boys, delayed puberty is defined as the lack of testicular enlargement to a volume >= 4 ml by age 14 years (333). Delayed puberty is more common in boys than in girls.

Four main categories of delayed puberty have been described (See Table 4).

• transient hypogonadotropic hypogonadism associated with delayed maturation of the HPG axis also known as constitutional delay of growth and puberty (CDGP)
• hypergonadotropic hypogonadism characterized by primary gonadal dysfunction with consequent elevated LH and FSH concentrations.
• hypogonadotropic hypogonadism with low LH and FSH concentrations due to congenital (CHH) or acquired causes
• functional hypogonadotropic hypogonadism (FHH), as seen in chronic health disorders such as cystic fibrosis, renal failure, inflammatory bowel disease, restrictive eating disorders etc.

Table 4.

Etiologies of Delayed Puberty (458)

Hypogonadotropic Hypogonadism

Pubertal delay associated with hypogonadotropic hypogonadism is usually associated with disorders affecting the neurons that secrete GnRH or the pituitary gonadotrophs that secrete the FSH and LH. These conditions may be present at birth or acquired as described below.

CONGENITAL HYPOGONADOTROPIC HYPOGONADISM

The initiation and maintenance of reproductive capacity in humans depends on pulsatile GnRH secretion. Congenital hypogonadotropic hypogonadism (CHH) results from the absence of the normal pulsatile GnRH secretion or deficient pituitary gonadotropin secretion leading to delayed puberty and infertility. The number of genetic loci associated with CHH continues to expand (Table 4). CHH may be associated with variants in genes involved in the development or migration of GnRH neurons as well as genes involved in the secretion or action of GnRH (368). Autosomal recessive, autosomal dominant, X-linked, and oligogenic inheritance have been described (369, 370). Additional genetic influences include epigenetic factors (371). Clinical heterogeneity has been described between and within families (372).

Given the developmental origins of GnRH neurons in the olfactory placode, CHH can be associated with anosmia or hyposmia. The association of CHH and anosmia is known as Kallmann syndrome. Classic Kallmann syndrome is associated with variants in the ANOS1 gene which is mapped to the X chromosome. Other features of Kallmann syndrome due to ANOS1 variants include unilateral renal agenesis, sensorineural hearing loss, dental agenesis, synkinesia (alternating mirror movements), and cleft lip/palate (373).

In syndromic CHH, associated clinical features may help identify the possible gene(s). For example, clinical features associated with FGFR1 variants include anosmia/hyposmia, cleft lip/cleft palate, dental agenesis, and skeletal anomalies. CHH can also occur in the CHARGE syndrome, which is characterized by coloboma, congenital heart disease, choanal atresia, genital anomalies, ear anomalies, and development delay. CHH can occur with impaired pituitary development associated with PROP1, HESX1, or LHX variants. CHH is also associated with variants in the GnRH, GnRHR, LHB, and FSHB genes (See Table 5). Although some genetic loci are common to both CDGP and CHH, the genetic architectures of these two conditions are largely distinct (374).

Table 5.

Genes Associated with Delayed Puberty (338)

ACQUIRED HYPOGONADOTROPIC HYPOGONADISM

Several conditions are associated with primary gonadal insufficiency. These conditions include auto-immune disorders, trauma, neoplasia, vascular events, and infection. Autoimmune disorders can be associated with premature ovarian and testicular insufficiency. Biallelic mutations in the autoimmune regulator (AIRE) gene are associated with autoimmune polyendocrine syndrome type 1 which is also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Associated features include mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency (375). The detection of autoantibodies directed against tissue-specific antigens suggests an autoimmune diagnosis.

Antineoplastic chemotherapy with alkylating agents, as well as localized ionizing radiation, may permanently damage germ cells leading to infertility. In males, Sertoli cells are more susceptible to such toxicity than Leydig cells such that testosterone production may remain intact despite Sertoli and germ cell injury. Mumps orchitis should be considered, especially in unvaccinated males. Decreased blood flow to the gonads from surgical injury (e.g., orchiopexy in boys), torsion, or trauma can lead to ischemia and atrophy, with resultant primary testicular insufficiency.

The presence of otherwise normal male external genitalia associated with nonpalpable gonads indicates that the testes were present and functioning at least early in gestation. The “vanishing testes syndrome” also known as testicular regression is associated with atrophy or regression of testicular tissue initially formed during early embryonic development. Potential etiologies of the testicular regression include in utero vascular disruption or testicular torsion. Pathogenic variants of the DEAH-box RNA helicase DHX37 (DHX37) gene have been identified in boys with testicular regression and in association with gonadal dysgenesis (376).

In addition to autoimmune etiologies, premature ovarian insufficiency can be associated with ovarian/pelvic tumors, chemotherapy, especially alkylating agents, and radiation therapy. The location of the pelvic tumor and treatments influence the ovarian reserve and risk for premature ovarian insufficiency. Low or declining serum AMH levels provide an indirect measure of ovarian reserve. However, due to much variability and lack of diagnostic thresholds, measuring AMH values does not accurately predict ovarian insufficiency in cancer survivors (377).

Acquired hypogonadotropic hypogonadism (HH) can be due to central nervous system tumors such as craniopharyngiomas and germ cell tumors. Such tumors can disrupt the hypothalamic-pituitary stalk or can impact pituitary function producing decreased gonadotropin production. Hyperprolactinemia due to prolactin-secreting adenomas can cause acquired HH (378). Other central nervous system disorders associated with acquired HH include hypophysitis, histiocytosis, and hemochromatosis. Intracranial surgeries and/or cranial radiation therapy greater than 30 Gy are known risk factors for HH. Moderate to severe trauma to the brain is associated with injuries to the hypothalamus, stalk (infundibulum), or pituitary gland itself; the consequences of traumatic brain injury may not manifest for many years. Chronic steroid treatment can be associated with acquired HH in boys with Duchenne muscular dystrophy (379, 380). Inflammatory and infiltrative diseases of the pituitary gland are other rare causes of acquired HH.

FUNCTIONAL HYPOGONADOTROPIC HYPOGONADISM

Functional HH is the hypothalamic response to intense physical or emotional stress, caloric deficit, or chronic systemic illness (381). In this situation, the otherwise normal HPG axis fails to function due to the concomitant stress. Puberty can be delayed or stalled until the underlying condition has been adequately addressed. The finding of hypercortisolemia in women with functional HH associated with restrictive eating disorders highlights the relevance of HPA axis function in FHH (382). Importantly, functional HH can have long lasting adverse consequences on bone health (383).

The hypothalamus receives numerous inputs regarding body energy status and subsequently modulates reproductive status based on this information. Hence, nutritional status and energy output influence HPG axis activity in part via leptin signaling which regulates the sensitivity of the pituitary to GnRH (384). Energy deficits may occur due to weight loss, excessive energy expenditure (rigorous physical activity, renal disease, cystic fibrosis, congenital heart disease), decreased caloric intake or malabsorption (disordered eating behaviors, bowel disorders such as celiac, Crohn’s, and ulcerative colitis) are associated with delayed or stalled puberty and functional hypothalamic amenorrhea (385, 386, 387). Elevated circulating levels of cytokines (as seen in some acute or inflammatory conditions) may also inhibit the HPG axis. Elevated prolactin levels, due to prolactinoma or severe primary hypothyroidism may inhibit gonadotropin release.

Some boys with obesity have low gonadotropin and testosterone levels and manifest delayed puberty (388). It is important to recognize that certain medications such as antipsychotics (typical and atypical), certain antidepressants, and opioids can alter menses (364).

EVALUATION OF A CHILD WITH A VARIATION IN PUBERTAL DEVELOPMENT

The diagnostic tools are comparable for the evaluation of either precocious or delayed puberty. Detailed medical history and physical examination provide the preliminary information to guide the differential diagnosis for a child with a variation in pubertal development (165, 396) (see Figures 5-8). Laboratory, imaging, and genetic studies are subsequently utilized to ascertain the specific diagnosis. The tools for evaluation of a child with a variation in pubertal development are described below. The tools are comparable, but the interpretation of test results differs for precocious and delayed puberty.

Figure 5.

Algorithm to evaluate a girl presenting with precocious puberty. *follow clinical progression every 3-6 months. FSH: Follicle Stimulating Hormone; LH: Luteinizing Hormone; CAH: Congenital Adrenal Hyperplasia; ACTH: Adrenocorticotrophic Hormone; GnRH: Gonadotropin Releasing Hormone; DHEAS: Dehydroepiandrosterone Sulfate; 17OHP: 17-hydroxy progesterone; NF-1: Neurofibromatosis-1.

Figure 6.

Algorithm to evaluate a boy presenting with precocious puberty. FSH: Follicle Stimulating Hormone; LH: Luteinizing Hormone; MRI: Magnetic Resonance Imaging.

Figure 7.

Algorithm to evaluate a girl presenting with delayed puberty. FSH: Follicle Stimulating Hormone; LH: Luteinizing Hormone; CDGP: Constitutional Delay in Growth and Puberty; CHH: Congenital Hypogonadotropic Hypogonadism; MRI: Magnetic Resonance Imaging.

Figure 8.

Algorithm to evaluate a boy presenting with delayed puberty. FSH: Follicle Stimulating Hormone; LH: Luteinizing Hormone; CDGP: Constitutional Delay in Growth and Puberty; CHH: Congenital Hypogonadotropic Hypogonadism; MRI: Magnetic Resonance Imaging.

SUMMARY

Pubertal development and maturation of the neuroendocrine system involve the ontogeny, activity, and interactions of the GnRH neurons. Pubertal onset is accompanied by an increase in kisspeptin and neurokinin B secretion regulating the pulsatile GnRH secretion that stimulates pulsatile pituitary LH and FSH secretion. LH and FSH stimulate gonadal sex steroid secretion promoting development of secondary sex characteristics and influencing hypothalamic-pituitary function via negative feedback inhibition.

Alterations of gut microbiome at different pubertal stages may present an area for future development in the prediction and prevention of precocious puberty. Use of genetic testing including targeted next generation sequencing and whole exome sequencing may have increasing utility as diagnostic tools early on in the evaluation of pubertal disorders.

Discovery regarding the details of normal reproductive physiology followed by identification of the genetic basis for disorders of pubertal timing established our current knowledge base for the evaluation and management of children with disorders affecting the timing of puberty. Despite the vast expansion of our knowledge, much remains to be learned about the physiology and regulation of the HPG axis from the fetus to the young adult.

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