Normal puberty

INTRODUCTION — 

Puberty refers to the physical changes that occur during adolescence. There is also significant cognitive and psychosocial maturation during this time. The physical changes that occur during puberty include growth in stature, changes in body composition, development of secondary sex characteristics, achievement of fertility, and changes in most organ systems.

The normal sequence of pubertal events and associated physical and psychosocial health concerns are reviewed here. Precocious and delayed puberty are discussed separately. (See "Definition, etiology, and evaluation of precocious puberty" and "Delayed puberty: Approach to evaluation and management".)

DEFINITIONS

●Pubertal physiology – There are two main physiological events in puberty:

•Gonadarche is the increase in activity of the hypothalamic-pituitary-gonadal axis.

•Adrenarche is the increase in production of androgens by the adrenal cortex.

While puberty encompasses changes due to both gonadarche and adrenarche, the term "puberty" is often used to refer specifically to gonadarche and associated changes, particularly in the phrases "precocious puberty" and "delayed puberty." Adrenarche is discussed in detail separately. (See "Physiology and clinical manifestations of normal adrenarche" and "Premature adrenarche".)

●Pubertal events – A number of other terms describe specific clinical signs of puberty:

•Thelarche is the appearance of breast tissue, which is primarily due to the action of estradiol from the ovaries.

•Menarche is the first episode of menstrual bleeding. This is usually not associated with ovulation; it is typically caused solely by the effects of estradiol on the endometrial lining. Menstrual bleeding with regular ovulatory cycles is initiated by the interaction of estradiol and progesterone produced by the ovaries. (See "Normal menstrual cycle".)

•Spermarche is the first sperm production (heralded by nocturnal sperm emissions and appearance of sperm in the urine), which is due to the combined effects of follicle-stimulating hormone, which acts directly on the seminiferous tubules, and luteinizing hormone, which acts indirectly by stimulating high intratesticular concentrations of testosterone [1].

•Pubarche is the appearance of pubic hair, which is primarily due to an increase in production of androgens from the adrenal gland (adrenarche). The term is also applied to the first appearance of axillary hair, apocrine body odor, and acne.

●Pubertal timing – There is a broad age range for typical pubertal onset; pubertal onset outside of this range is considered precocious or delayed:

•Precocious puberty (more accurately, precocious gonadarche) is defined as pubertal onset at an age two or more standard deviations (SD) below the mean age of onset of puberty for sex assigned at birth, race, and ethnic background.

Considerations for the age threshold for undertaking a clinical evaluation for precocious puberty, given population trends toward earlier pubertal onset, are discussed separately. (See "Definition, etiology, and evaluation of precocious puberty".)

•Delayed puberty is defined as the absence of signs of puberty by an age two or more SD above the mean age of onset of puberty. The age threshold for undertaking a clinical evaluation for delayed puberty is discussed separately. (See "Delayed puberty: Approach to evaluation and management".)

PHYSIOLOGY AND ENDOCRINOLOGY OF PUBERTY

●Gonadarche – Gonadarche is driven by an increase in the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus [2]. GnRH, in turn, stimulates the gonadotrope cells of the anterior pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Increases in the frequency and amplitude of FSH and LH pulses stimulate sex steroidogenesis and eventually gametogenesis in the gonads. (See "Physiology of gonadotropin-releasing hormone".)

•In children assigned female at birth – FSH stimulates the growth of ovarian follicles and, in conjunction with LH, stimulates production of estradiol by the ovaries (figure 1A). Early in puberty, estradiol stimulates breast development and growth of the skeleton, leading to pubertal growth acceleration. Later in puberty, the interplay between pituitary secretion of FSH and LH and the secretion of estradiol by ovarian follicles leads to ovulation and menstrual cycles (see "Normal menstrual cycle"). Estradiol also induces maturation of the skeleton, eventually resulting in fusion of the growth plates and cessation of linear growth.

•In children assigned male at birth – FSH stimulates the Sertoli cells of the testes to support growth of seminiferous tubules and, as a result, increases in testicular volume. LH stimulates the Leydig cells of the testes to produce testosterone, and the high local concentration of testosterone further stimulates the growth of the seminiferous tubules (figure 1B). Testosterone also induces growth of the penis, deepening of the voice, growth of facial and body hair, and increases in muscularity and erythropoiesis. Some testosterone is converted to estradiol, which has the same effects on growth and skeletal maturation as in children assigned female at birth (and can also lead to some breast development). (See 'Gynecomastia' below.)

●Adrenarche – Adrenarche begins when the zona reticularis of the adrenal gland begins to synthesize the adrenal androgens dehydroepiandrosterone sulfate, androstenedione, and 11-ketotestosterone [3]. These induce androgenic changes including growth of pubic and axillary hair, maturation of the apocrine sweat glands (leading to adult-type body odor), and development of acne. (See "Physiology and clinical manifestations of normal adrenarche".)

●Pubertal onset – Increase in pulsatile secretion of GnRH from the hypothalamus is a critical hormonal event in the initiation of puberty. It is not clear what triggers the increase in GnRH frequency and amplitude, but it likely involves the emergence of activators of GnRH secretion and suppression of inhibitors of GnRH secretion.

•Activators of GnRH secretion – Potential activators of GnRH secretion at puberty include:

-Kisspeptin – Kisspeptin appears to have an important role in the initiation of puberty in humans [4]. Kisspeptin potently stimulates hypothalamic GnRH secretion. In humans, loss-of-function variants in the genes encoding kisspeptin (KISS1) or the kisspeptin receptor (KISS1R, formerly GPR54) result in decreased secretion of LH and FSH (ie, idiopathic hypogonadotropic hypogonadism) [5,6]. Expression of hypothalamic KISS1 messenger ribonucleic acid RNA (mRNA) and kisspeptin peptide increase across the pubertal transition in animal models, suggesting that kisspeptin may be a key instructive signal in the initiation of puberty [7]. (See "Definition, etiology, and evaluation of precocious puberty".)

-Neurokinin B – Neurokinin B signaling also appears to be an important stimulus for pubertal onset [4]. In humans, pathogenic variants in the genes encoding neurokinin B (TAC3) and the neurokinin B receptor (TACR3) also cause idiopathic hypogonadotropic hypogonadism [8]. A unique feature of patients with pathogenic variants in TAC3 or TACR3 is that they have a propensity for spontaneous "reversal" of their hypogonadotropic hypogonadism, with emergence of reproductive endocrine function in adulthood [9]. Furthermore, variants in TAC3 and TACR3 have been found in patients with delayed puberty [10], and common genetic variants near TACR3 have been found to influence the timing of puberty in the general population [11-13]. Collectively, these findings suggest that signaling by neurokinin B may have a specific role in activation of the reproductive endocrine system at the time of puberty but may have a less important role in maintaining reproductive endocrine function in adulthood.

•Inhibitors of GnRH secretion – Potential mediators for an inhibitory influence on GnRH secretion include:

-Gamma-aminobutyric acid (GABA) – GABA is a neurotransmitter that appears to play an important role in these inhibitory pathways; however, research has not been conducted in humans. In rhesus monkeys, secretion of GABA in the hypothalamus decreases across the pubertal transition [14], and pharmacologic disruption of signaling through the GABA_A receptor subtype induces early puberty [15].

-Genetic variants – Loss-of-function variants in the MKRN3 gene are a genetic cause of central (GnRH-dependent) precocious puberty [16]; thus, the inferred function of MKRN3 is to delay pubertal onset. Only the paternal allele of MKRN3 is expressed; pathogenic variants in MKRN3 therefore cause precocious puberty only if inherited from the father. MKRN3 encodes makorin ring finger protein 3, a protein that may add the protein ubiquitin to target proteins. In humans, pathogenic variants in MKRN3 have been found in approximately one-third of familial cases of precocious puberty and approximately 3 percent of sporadic cases [16,17].

Pathogenic variants in the DLK1 gene, which is also expressed only from the paternal allele, are another cause of precocious puberty [18,19]. (See "Definition, etiology, and evaluation of precocious puberty".)

•Body weight – For children assigned female at birth, obesity or being overweight is associated with earlier pubertal onset and/or pubertal progression [20-23]. However, for those assigned male at birth, the relationship between pubertal onset and obesity is not clear. Some studies in children assigned male at birth suggest that increased body mass index and fat mass are associated with earlier puberty [22-26], while others suggest the opposite association [27,28].

The mechanism for how body weight (or percent body fat) contributes to the timing and tempo of pubertal events is uncertain. It had been proposed that a critical body weight [29] or percent body fat [30] is the primary determinant of pubertal onset [29-32]. However, this hypothesis was not upheld by subsequent studies. Similarly, the overall earlier onset of puberty among the general population has been attributed to the increasing prevalence of obesity, but it is unclear whether this mechanism is sufficient to explain this trend. (See 'Trends in pubertal timing' below.)

•Leptin – Leptin is a hormone that is produced primarily in adipocytes and is one of several factors that influence the activity of the GnRH pulse generator [33]. In one study, a 1 ng/mL increase in serum leptin predicted earlier menarche by one month; a 1 kg increase in body fat was associated with earlier menarche by 13 days. On the basis of such studies, it was proposed that leptin could be the trigger for pubertal onset; however, leptin appears to be a permissive signal that is required for normal puberty and reproductive endocrine function, rather than the instructive signal that initiates the onset of puberty.

Studies in children assigned male at birth suggest that changes in serum leptin starting at pubertal onset are a result of changes in body composition rather than a trigger of pubertal onset [34-36]. Moreover, mice or humans deficient in leptin fail to undergo pubertal development, and administration of leptin results in pubertal onset, but only at a normal age, indicating that the leptin signal is necessary but not sufficient for pubertal onset [37,38].

FACTORS INFLUENCING PUBERTAL TIMING — 

The timing of pubertal onset is influenced by genetics (family history), body weight, and race/ethnicity.

Genetic factors account for an estimated 50 to 75 percent of the variation in normal pubertal timing [39-42]. Several genetic loci have now been identified that are associated with age of pubertal onset [11,13]. A large genome-wide study including more than 370,000 adult females identified common variants or single-nucleotide polymorphisms at 389 genetic loci that were associated with age at menarche [13]. A comparable genome-wide association study of timing of male pubertal hallmarks in over 205,000 adult males identified 76 genetic loci associated with male pubertal timing [43]. Most, but not all, of these loci affect both female and male pubertal timing [43].

Some of the genes near these loci have known roles in reproduction, such as ESR1 (which encodes the estrogen receptor alpha), TACR3, MKRN3, and DLK1 (described above). Furthermore, some of the genetic variants associated with age at menarche have also been associated with variation in adult height [39-41]. These observations suggest a genetic basis for previously observed associations between age at menarche and height; in some cases, this association might be mediated by earlier epiphyseal closure caused by earlier exposure to estrogens. Similarly, several genes that are associated with childhood obesity are also associated with earlier age at menarche [39,40]. (See "Obesity: Genetic contribution and pathophysiology", section on 'Common (multifactorial) obesity'.)

Despite these significant advances in understanding the genetics of pubertal timing, most of the genetic basis remains unexplained; the variants described in the above genome-wide association study on age at menarche account for only 7.4 percent of the variation in pubertal timing [13]. Collectively, these findings provide glimpses into the physiologic mechanisms that determine pubertal timing, but an integrated model for the onset of puberty remains elusive.

Other factors that influence pubertal onset in children assigned female at birth include overall health (with poor health associated with delayed pubertal onset), social environment (such as family stress or the presence of a nonbiologically related adult male in the household, which are associated with earlier pubertal onset), and high altitude (associated with later pubertal onset) [44-48]. (See 'Trends in pubertal timing' below.)

PUBERTAL CHANGES — 

Most adolescents follow a predictable path through pubertal maturation, although variability occurs among individuals regarding the timing, sequence, and tempo.

Secondary sex characteristics (Tanner stages) — The development of secondary sex characteristics consists of a series of events that usually proceed in a predictable order, with some variation in timing of onset, sequence, and tempo (figure 2A-B).

Sexual maturity ratings are the staging system used most frequently. These are also known as "Tanner stages" because they were popularized by Marshall and Tanner [49,50].

Tanner stages describe the development of secondary sex characteristics, consisting of breast changes in children with a predominantly estradiol-driven puberty, genital changes in children with a predominantly testosterone-driven puberty, and pubic hair changes in both.

Sexual maturity ratings for pubic hair, breasts, and male genitalia each consist of five stages, with stage 1 representing prepuberty and stage 5 representing full adult development (table 1). The various stages are illustrated in the pictures (picture 1A-B and picture 2).

The timing of pubertal maturation can have an important influence on self-esteem, behavior, growth, and weight (see 'Psychological changes' below and 'Physiology and endocrinology of puberty' above). As an example, early maturation is associated with slightly shorter adult stature [51,52] and with greater adult ponderosity and adiposity [52,53]. Details of the physiologic changes expected during puberty are discussed above. (See 'Physiology and endocrinology of puberty' above.)

Linear growth spurt — Approximately 20 percent of adult height is accrued during puberty [54]. The increase in height occurs in both axial (trunk) and appendicular (limb) components [55]. The limbs accelerate before the trunk, with the distal portions of the limbs accelerating before the proximal portions; thus, the adolescent in early puberty is "all hands and feet." In later puberty, however, the growth spurt is primarily truncal [55]. The linear growth spurt typically lasts for approximately two years. Modest seasonal variations in growth have been reported even in well-nourished populations, with greater growth typically occurring in the spring [56].

●Height velocity can be plotted and compared with norms using height velocity charts.

The most commonly used charts are those published by Tanner and Davies (figure 3A-B) [57]. These charts are useful for longitudinal tracking and acknowledge the variation between early, average, and late maturers; however, their accuracy is limited because they were generated using data from the 1970s and earlier.

Other growth charts were generated from longitudinal data, such as the series of charts published by the Harvard Six-Cities study, which used data collected from 1974 to 1989 [58], and the Bone Mineral Density in Childhood Study, which used data collected from 2002 to 2009 [59].

By contrast, the cross-sectional height-for-age charts that are commonly used for growth monitoring (eg, those prepared by the Centers for Disease Control and Prevention) do not reflect the differences in timing of the pubertal growth spurt in early- versus late-maturing children.

●The overall average difference in adult height between those assigned female at birth and those assigned male at birth results from differences in the timing and magnitude of the growth spurt. The timing of the growth spurt (peak height velocity) varies by sex, with peak height velocity occurring approximately two years later in assigned males than in assigned females (figure 3A-B). As a result, assigned males have an additional two years of prepubertal growth by the time the growth spurt starts. Furthermore, they experience a greater peak height velocity than assigned females (average 10.3 versus 9.0 cm per year), whose peak height velocity occurs, on average, 0.5 years prior to menarche [60].

Precocious puberty results in earlier peak height velocity, which often leads to a transient period of tall stature but is associated with reduced adult height due to early epiphyseal closure, leading to cessation of growth. (See "Treatment of precocious puberty", section on 'Decision to treat'.)

Earlier pubertal onset within the normal range may also influence adult stature. In one study, early menarche was associated with greater peak height velocity but shorter adult stature, while early thelarche had no effect on adult stature [61]. In a study in assigned males, those who matured relatively early but within the normal age range had a modest reduction in adult height [62]. The diminished adult height was attributable to shorter leg length; sitting height was not reduced. Body weight also appeared to influence these results.

Bone mineralization and growth — Bone growth accelerates during puberty in concert with height velocity, but bone mineralization initially lags behind. Bone growth occurs first in length, followed by width, then mineral content, and finally bone density [63,64]. The disparity in the timing of bone growth and mineralization may place the growing adolescent at increased risk for fractures. (See 'Musculoskeletal injuries' below.)

The risk for osteoporosis during adulthood is associated with the timing of puberty [55]. This suggests that there may be a narrow age window of opportunity for pubertal changes to exert maximal effects on peak bone mass [63]. Possible effects of certain hormonal contraceptives on peak bone mass are discussed separately. (See "Contraception: Overview of issues specific to adolescents", section on 'Other progestin-only methods'.)

Weight and body composition — Puberty is associated with significant changes in body weight and alterations in body composition, especially in lean body mass and the proportion of body fat (adiposity), with different patterns in assigned females compared with assigned males. Growth curves for body mass index (BMI) reflect the typical increase in body mass that occurs during puberty (figure 4A-B) but do not reflect the differences between early-maturing and late-maturing children, nor do they distinguish between changes in lean body mass versus adipose tissue.

In early puberty, the increase in BMI is driven primarily by changes in lean body mass. Later in puberty, the increase in BMI tends to be driven by increases in fat mass [65], with fat mass contributing more to BMI increases in assigned females than assigned males.

These general patterns are altered by the individual's nutritional status; adolescents who gain excessive weight during puberty may experience an ongoing increase in body fat, regardless of sex assigned at birth and pubertal stage. Obesity tracks from adolescence to adulthood, and earlier onset of obesity is associated with increased cardiovascular morbidity and mortality [66-69]. (See "Overview of the health consequences of obesity in children and adolescents", section on 'Cardiovascular'.)

Changes in children assigned female at birth — The earliest detectable secondary sex characteristic in most assigned females is breast/areolar development (thelarche) that occurs on average at age 9.3 years (picture 1A) [20,70]. However, 15 to 30 percent develop pubic hair first (pubarche) (picture 1B) [70]. Growth acceleration typically precedes thelarche slightly, but unless height is closely monitored, growth acceleration will not be detected prior to the appearance of breast tissue. Ovarian enlargement also typically precedes breast development, but it is not apparent on physical examination.

Longitudinal studies from 2000 through 2010 in a large multiethnic cohort of American adolescents reported that the mean age at thelarche varied by race and ethnicity: 8.8 years in Black children, 9.2 years in Hispanic children, 9.6 years in White non-Hispanic children, and 9.9 in Asian children [20,71]. Variation in prepubertal BMI accounted for approximately 14 percent of the variance, while differences in race/ethnicity accounted for 4 percent [20].

Height velocity begins to increase shortly before thelarche and peaks, on average, 6 to 12 months before menarche during Tanner stage 3. Following menarche, linear growth nears completion; most adolescents grow approximately two additional inches over the subsequent two years. However, some adolescents may grow more, particularly those with earlier pubertal onset.

Physiologic leukorrhea, a thin, white, non-foul-smelling vaginal discharge, also typically begins 6 to 12 months before menarche and is caused by estrogen stimulation of the vaginal mucosa. (See "The pediatric physical examination: The perineum", section on 'Preadolescent and adolescent females'.)

Menarche occurs, on average, 2.6 years after thelarche (figure 2A) [49,60,72]. In a longitudinal cohort study, the mean age for menarche was 12.2 years and varied by race and ethnicity: 11.8 years in Black children, 11.6 years in Hispanic children, 12.0 years in Asian children, and 12.5 years in White non-Hispanic children [71]. Variation in BMI accounted for 11 percent of the variance, and race/ethnicity accounted for 6 percent.

The initial manifestation of puberty predicts body morphology and composition throughout pubertal maturation into early adulthood. As an example, assigned females with breast development as the initial manifestation of puberty have both an earlier age of menarche and greater BMI throughout puberty and adulthood as compared with those who exhibit pubarche first [73]. Earlier menarche (before 12 years of age) is associated with higher BMI during adulthood as compared with later menarche [32,53,74,75]. Most of this association may be attributable to the influence of childhood obesity on both menarcheal age and adult obesity [76].

Changes in children assigned male at birth — The earliest detectable secondary sex characteristic on physical examination in assigned males is an increase in testicular volume, which typically occurs between approximately 9 and 13 years and precedes penile growth and appearance of pubic hair by approximately six months (figure 5). Testicular volume is typically estimated using the Prader orchidometer, a series of three-dimensional ellipsoids with volumes from 1 to 25 mL or more (picture 3). Before puberty, testicular volumes are typically 2 mL (or lower, in younger children). While a testicular volume of 3 mL generally indicates that puberty has started, some prepubertal children may have testicular volumes approaching 3 mL [77], and testicular volumes are often overestimated by Prader orchidometry. Therefore, testicular volume of 4 mL is considered an unequivocal signal that puberty has started (with rare exceptions [eg, a prepubertal individual with only one testicle, which may have a slightly higher size of 3 to 4 mL]).

Penile length increases during Tanner stages 2 and 3; width begins to increase during Tanner stage 3 and continues through the remainder of puberty.

Penile length is measured using a straight edge on the dorsal surface in the nonerect state from the pubic ramus to the tip of the glans while compressing the suprapubic fat pad and applying gentle traction to the penis. This measurement is rarely used to monitor pubertal progress because penile growth is not an early event in puberty and accurate measurement is difficult and may be awkward for the adolescent.

Although there is some temporal variation in the appearance and progression of testicular volume, penile growth, and pubic hair development, a clear discrepancy between these physical findings may indicate a pathologic condition. For example, a finding of low testicular volumes in a fully virilized adolescent may be a sign of Klinefelter syndrome or inappropriate use of exogenous androgens.

Height velocity begins to increase shortly before testicular enlargement and peaks, on average, two to three years later.

Trends in pubertal timing — Since the mid-1800s, there has been a clear decrease in age at menarche in industrialized countries; this trend has been attributed to improvements in health and nutrition and was thought to have plateaued in the mid-1900s. However, demographic studies over the last several decades have indicated a continued (albeit slower) trend towards earlier pubertal onset, with larger changes in assigned females than in assigned males. This trend has captured the attention of the lay press, which often exaggerates the findings and/or conflates events that occur in early versus late puberty, such as thelarche versus menarche. While several factors are known to influence pubertal timing, the precise physiologic determinants of pubertal timing and the reason for these trends remain unclear. Factors that may contribute to these trends include endocrine-disrupting chemicals, nutrient intake, and obesity.

●A meta-analysis that examined the trend in age at thelarche in assigned females reported an average decrease of 0.86 years between 1977 and 2013 [78].

There has also been a trend toward earlier menarche, though the change has been more modest than the change in timing of thelarche. As an example, the Copenhagen puberty study showed a decrease of one year in average age at thelarche over a 15-year period, but the decrease in average age at menarche was only four months [79]. A cohort study from the United States reported a decrease in the mean age of menarche from 12.5 years of age in those born between 1950 and 1969 to 11.9 years in those born between 2000 and 2005 [80].

●Pubertal onset in assigned males also appears to be occurring earlier in the United States. In a 2012 study including more than 4000 healthy American adolescents, the mean age for entering puberty was 1.5 to 2 years earlier than historical norms [81]. Similar trends have been reported from several European countries and China [24,82-86]. (See "Endocrine-disrupting chemicals", section on 'Children'.)

Identifying precocious and delayed puberty

●Precocious puberty – Precocious puberty is usually defined as breast development prior to eight years of age in assigned females and testicular enlargement before the age of nine years in assigned males.

The trend toward earlier onset of puberty in assigned females has important implications for the diagnosis of precocious puberty. In the United States, it has been suggested that a threshold of seven years for thelarche in White children and six years in Black children be used for initiating an evaluation for precocious puberty [51]. However, concerns have been raised that following these suggestions may lead to underdiagnosis of pathological disorders.

The appropriate threshold for evaluation remains controversial and probably varies among populations. Determining the need for an evaluation depends not only on age but also on the degree and rate of maturation, as well as family history [87]. (See "Definition, etiology, and evaluation of precocious puberty".)

●Delayed puberty – Delayed puberty is usually defined as lack of breast development by 12 to 13 years of age in assigned females and lack of testicular enlargement by 13 to 14 years of age in assigned males.

As with precocious puberty, the appropriate threshold for evaluation of delayed puberty depends not only on age but also on other factors, particularly family history. (See "Delayed puberty: Approach to evaluation and management".)

PUBERTY-RELATED HEALTH CONCERNS — 

Puberty may be associated with several undesirable changes that present challenges to the patient and family. These include anemia, gynecomastia, acne, disruption of psychosocial functioning, certain types of sports-related injuries, abnormal uterine bleeding, myopia, and scoliosis.

Anemia — Anemia and iron deficiency are more common among adolescents assigned female at birth than those assigned male at birth and prepubertal children (figure 6). Testosterone increases erythropoiesis, which increases hemoglobin and serum ferritin concentrations with advancing pubertal stage in assigned males [88,89]. On the other hand, menstrual bleeding and insufficient iron intake make menstruating adolescents more prone to anemia. (See "Iron requirements and iron deficiency in adolescents".)

Gynecomastia — Pubertal gynecomastia is common (in contrast with neonatal or senescent gynecomastia) and occurs in approximately one-third of assigned males at an average age of 13 years. It typically persists for 6 to 18 months [90]. Although the underlying diagnosis usually is "idiopathic pubertal gynecomastia," other etiologies must be considered, particularly if the gynecomastia is marked or persistent. The underlying mechanisms presumably reflect an imbalance in the effects of estrogens (which promote breast development) and androgens (which inhibit breast development). This may be caused by an increase in the production or action of estrogens or estrogen-like compounds, a decrease in the production or action of androgens, or enhanced breast tissue sensitivity to estrogens or estrogen-like compounds [91]. (See "Gynecomastia in children and adolescents".)

Acne — Acne, a disorder of the pilosebaceous unit, is characterized by follicular occlusion and inflammation caused by androgenic stimulation associated with both adrenarche and gonadarche. With pubertal maturation, the number of acne lesions increases, with a greater number of comedones than inflammatory lesions at all stages [92]. In assigned females, more severe acne in later puberty is associated with higher serum levels of dehydroepiandrosterone sulfate, reflecting the contribution of adrenal androgens, and a greater number of acne lesions in early puberty [93]. Although acne is common during puberty, moderate or severe acne in early puberty, particularly when accompanied by other signs of androgen excess, should alert the clinician to the possibility of an endocrinologic disorder such as nonclassic congenital adrenal hyperplasia or polycystic ovary syndrome. (See "Pathogenesis, clinical manifestations, and diagnosis of acne vulgaris" and "Definition, clinical features, and differential diagnosis of polycystic ovary syndrome (PCOS) in adolescents", section on 'Acne'.)

Psychological changes — Although pubertal maturation does not affect cognitive development [94], timing relative to peers may affect psychosocial functioning [95].

Prior to adolescence, there are no sex/gender differences in depression; during adolescence, however, the prevalence of depression is twice as high in assigned females compared with assigned males [96,97]. As puberty progresses, assigned males develop a more positive self-image and mood. By contrast, assigned females tend to become less satisfied with their physical appearance, and some exhibit diminished self-worth as they pass from early to mid-adolescence [98]. The epidemiology and clinical assessment of depression in adolescents are discussed in a separate topic review. (See "Pediatric unipolar depression: Epidemiology, clinical features, assessment, and diagnosis".)

Pubertal development may have an especially negative psychological impact when there is a mismatch between the timing of pubertal development and chronologic age. In a large cross-sectional study, early-maturing girls and late-maturing boys were more likely to have psychopathology [99]. Girls who matured early were more likely to have a lifetime history of disruptive behavior (attention deficit, hyperactivity, oppositional, or conduct disorders) and suicide attempts, whereas late-maturing boys were more likely to have internalizing behaviors and emotional reliance on others. In a separate study, higher rates of depression and antisocial behaviors among early-maturing girls persisted into early adulthood [100]. These adolescents are more likely to have older friends [101] and to be more vulnerable to peer pressure [102].

Decision-making — Certain cognitive characteristics have long been observed in adolescents, in which they make very different decisions when under the influence of strong emotions ("hot" cognition) as compared with decisions made under conditions of low emotional arousal ("cool" cognition) [103]. Adolescents may display these cognitive characteristics because the dorsolateral prefrontal cortex, an area of the brain involved in impulse control, matures later than the remainder of the brain [104]. Thus, in times of stress, the brain of the adolescent may be less able to modulate the affective component as compared with adults. Multiple studies have documented an association between early pubertal maturation in assigned females and increased engagement in risk-taking behaviors. This association could be mediated by peer associations, mismatch of chronologic age and physical appearance, or other factors. In addition, studies using functional magnetic resonance imaging have suggested that brain development is impacted by both pubertal stage and timing of puberty and may lead to a neurodevelopmental predilection for risk-taking [105].

Musculoskeletal injuries — Pubertal changes may help to explain the risk and type of musculoskeletal injuries related to sports participation in adolescents [106]. The greatest risk of damage to epiphyseal growth plates occurs during periods of peak height velocity, which also is the time of greatest change in bone mineral content [107]. Similarly, the age of peak incidence of distal radius fractures matches the age of peak height velocity in adolescents [108]. The asynchronous growth of body parts may result in a limited range of motion of some joints; when combined with the increase in muscle mass that occurs shortly after peak height velocity, the limited range of motion may lead to sprains or strains. (See 'Linear growth spurt' above.)

A common issue that can arise in teens is Osgood-Schlatter disease, which is an inflammation of the tibial tubercle apophysis; the risk is associated with periods of rapid skeletal growth and participation in sports that involve running and jumping. (See "Osgood-Schlatter disease (tibial tuberosity avulsion)".)

Gynecologic concerns — When an adolescent reaches menarche, rapid maturation of the reproductive axis ensues. By one year after menarche, 65 percent have regular menstrual cycles, with 10 or more periods per year [109]. Adolescents with later onset of menarche tend to progress more slowly to regular ovulatory cycles; when menarche occurs after the age of 13, only one-half will ovulate regularly within 4.5 years [110].

Abnormal uterine bleeding refers to excessive, prolonged, and/or irregular endometrial bleeding. In adolescents, anovulation accounts for approximately 80 percent of cases of abnormal uterine bleeding. With anovulatory cycles, unopposed estradiol stimulates the endometrium, leading to a sustained proliferative phase rather than maturing to a secretory endometrium. Estradiol alone, however, cannot sustain the hyperplastic endometrium, so prolonged exposure can lead to irregular, sometimes heavy, endometrial bleeding. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Abnormal uterine bleeding' and "Anovulatory uterine bleeding in adolescents: Management".)

Myopia — The greatest incidence of myopia occurs during puberty and is caused by growth in the axial diameter of the eye [111]. (See "Refractive errors in children", section on 'Refractive errors'.)

Scoliosis — Accelerated progression of the degree of scoliosis occurs during puberty due to rapid growth in the axial skeleton. (See "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Risk for progression'.)

PUBERTAL TIMING AND ADULT MORBIDITIES — 

Pubertal timing affects risks for a number of adult conditions [112]. There is a negative linear correlation between pubertal timing and adult body mass index [21]. Multiple studies have reported an association between earlier age at menarche and breast cancer [113,114]. The risk of premenopausal breast cancer was decreased by 7 percent per year that menarche was delayed, and the risk of postmenopausal breast cancer was decreased by 3 percent per year that menarche was delayed.

Earlier puberty is also associated with increased risk for other reproductive cancers: endometrial and ovarian cancer in adults assigned female at birth and prostate cancer in people assigned male at birth [13]. The relationship of pubertal timing and cardiovascular disease is more complex; in assigned females, both earlier and later age at menarche are associated with increased risk of coronary heart and cerebrovascular diseases [115]. Additionally, earlier age at menarche is associated with increased risk for impaired glucose tolerance and type 2 diabetes; part of this association is mediated by increased adiposity and part is independent of adiposity [116].

Other associations described for earlier puberty include increased risk for angina, osteoarthritis, and depression; higher blood pressure; earlier age at first sexual intercourse; and lower educational attainment [117,118]. Associations described for later pubertal onset include lower bone mineral density, increased fracture risk, and, in assigned males, increased risk for depression and anxiety. The mechanistic bases for these associations are not known. However, the association of earlier menarche and pubertal growth with breast cancer risk may be explained through higher insulin-like growth factor 1 (IGF-1) concentrations, greater lifelong estrogen exposure, and a longer pubertal growth period [119].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Normal puberty and puberty-related disorders".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)

●Basics topics (see "Patient education: Normal puberty (The Basics)" and "Patient education: Early puberty (The Basics)" and "Patient education: Late puberty (The Basics)")

SUMMARY

●Physiology of puberty – While the hormonal changes that drive pubertal development are well described (figure 1A-B), the physiologic mechanisms that determine pubertal timing remain poorly understood. (See 'Physiology and endocrinology of puberty' above.)

●Pubertal changes – Pubertal changes include the development of secondary sex characteristics, the linear growth spurt, bone mineralization and growth, and changes in weight and body composition.

Sexual maturity ratings (Tanner stages) for pubic hair, breast, and male genitalia consist of five categories, with stage 1 representing prepuberty and stage 5 representing adult development (table 1). These stages are illustrated in the pictures for children assigned male at birth (picture 2) and female at birth (picture 1A-B). (See 'Secondary sex characteristics (Tanner stages)' above.)

The peak growth spurt occurs approximately two years earlier in children assigned female at birth than those assigned male at birth (figure 2A-B). (See 'Linear growth spurt' above.)

Puberty is associated with substantial changes in body weight and alterations in body composition, especially in lean body mass and the proportion of body fat (adiposity), with different patterns in children assigned female at birth compared with those assigned male.

●Sequence and timing of pubertal changes

•Puberty consists of a series of events that usually proceed in a predictable pattern, but with considerable variation in timing of onset, sequence, and tempo (figure 2A-B). (See 'Pubertal changes' above.)

•In most children assigned female at birth, the earliest secondary sex characteristic is breast/areolar development (thelarche) (picture 1A), although approximately 15 to 30 percent have pubic hair as the initial manifestation (picture 1B). Menarche occurs, on average, 2.6 years after thelarche and 6 to 12 months after peak height velocity (figure 2A). (See 'Changes in children assigned female at birth' above.)

In the United States, the mean age for the first signs of puberty (growth acceleration, breast-budding) varies from 8.8 to 9.9 years depending on race and ethnicity. The mean age of menarche is 12.2 years and varies by weight status and race/ethnic group. (See 'Changes in children assigned female at birth' above.)

•In children assigned male at birth, the earliest stage of maturation is almost always an increase in testicular volume, followed by penile growth and the appearance of pubic hair (picture 2). (figure 2B). (See 'Changes in children assigned male at birth' above.)

The range for pubertal onset (marked by testicular enlargement) is between 9 and 13 years. (See 'Changes in children assigned male at birth' above.)

•Precocious puberty is defined as pubertal onset at an age two or more standard deviations (SD) below the mean age of onset. Similarly, delayed puberty is defined as lack of pubertal onset by an age two or more SD above the mean age of onset. Considerations for the age threshold for undertaking a clinical evaluation for precocious or delayed puberty are discussed separately. (See 'Definitions' above and "Definition, etiology, and evaluation of precocious puberty" and "Delayed puberty: Approach to evaluation and management".)

●Puberty-related health concerns – Puberty is associated with a variety of physiologic changes that may come to medical attention, including acne and scoliosis, gynecomastia in children assigned male at birth, and anemia and abnormal uterine bleeding in children assigned female at birth. Psychological and emotional changes are common, with increased rates of depression and risk-taking behaviors. (See 'Puberty-related health concerns' above.)