INTRODUCTION — Puberty refers to the physical transitions that occur during adolescence. Adolescents also experience cognitive maturation and psychosocial maturation.
The most visible changes during puberty are growth in stature and development of secondary sex characteristics. Equally profound are changes in body composition; achievement of fertility; and changes in most body systems such as bone (with increased growth and mineralization), brain (with ongoing development), and the cardiovascular system (with greater aerobic power reserve, electrocardiographic changes, and blood pressure changes).
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 "Approach to the patient with delayed puberty".)
●Pubertal physiology – Puberty is the general term for the transition from sexual immaturity to sexual maturity. There are two main physiological events in puberty:
•Gonadarche is the activation of the gonads by the pituitary hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
•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 components 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 menstrual bleed. This first menstrual bleed is often 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 caused by the interplay of estradiol and progesterone produced by the ovaries. (See "Normal menstrual cycle".)
•Spermarche is the time of the first sperm production (heralded by nocturnal sperm emissions and appearance of sperm in the urine), which is due to the combined effects of FSH, which acts directly on the seminiferous tubules, and LH, which acts indirectly by stimulating high intratesticular concentrations of testosterone .
•Pubarche is the appearance of pubic hair, which is primarily due to the effects of androgens from the adrenal gland. The term is also applied to the first appearance of axillary hair, apocrine body odor, and acne.
●Pubertal timing – There is a broad range for age at pubertal onset among children; pubertal timing outside of this range is considered precocious or delayed:
•Precocious puberty (more accurately, precocious gonadarche) is defined as pubertal onset at an age 2 to 3 standard deviations (SD) below the mean age of onset of puberty, ie, before an age at which 97 to 99 percent of individuals of the same sex and ethnic background initiate sexual maturation. In the United States, this has led to a traditional definition of precocious puberty as the appearance of breast development before the age of eight years in girls and testicular enlargement before the age of nine years in boys. This statistical definition of puberty is necessary because of limited knowledge about the biologic mechanisms that control the timing of puberty, and the specific SD or age threshold used to define precocious puberty is somewhat arbitrary. Of note, statistical definitions do not distinguish between pathologic causes and normal physiologic variation.
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 2 to 3 SD above the mean age of onset of puberty, ie, by an age at which 97 to 99 percent of children of that sex and culture have initiated sexual maturation. In the United States, this corresponds to an upper limit of 12 to 13 years for girls (for breast development) [2-5] and of 13 to 14 years for boys (for testicular enlargement) [2,6-8]. The age threshold for undertaking a clinical evaluation for delayed puberty, like that for precocious puberty, is somewhat arbitrary. (See "Approach to the patient with delayed puberty".)
PHYSIOLOGY AND ENDOCRINOLOGY OF PUBERTY — Gonadarche is driven by an increase in the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus . GnRH stimulates the gonadotroph cells of the anterior pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH), with increases in frequency and amplitude of both FSH and LH pulses (but more so the latter), which in turn stimulate sex steroidogenesis and eventually gametogenesis in the gonads. (See "Physiology of gonadotropin-releasing hormone".)
In girls, 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 boys, 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, the high local concentration of which further stimulates the growth of the seminiferous tubules (figure 1B). Testosterone also induces growth of the penis, deepening of the voice, growth of hair, and increases in muscularity. Some testosterone is converted to estradiol, which has the same effects on growth and skeletal maturation as in girls (and can also lead to some breast development in males, as it does in females). (See 'Gynecomastia' below.)
Adrenarche begins when the zona reticularis of the adrenal gland begins to synthesize the adrenal androgens dehydroepiandrosterone (DHEA), androstenedione, and 11-ketotestosterone . 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".)
Sexual maturity rating (Tanner stages) — Puberty consists of a series of events that usually proceed in a predictable pattern with some variation in timing of onset, sequence, and tempo (figure 2A-B).
The staging system utilized most frequently is that of sexual maturity ratings. These are also known as "Tanner stages" because they were initially published by Marshall and Tanner [11,12]. These consist of systematized descriptions of the development of secondary sex characteristics, consisting of breast changes in females, genital changes in males, and pubic hair changes in both females and males. Sexual maturity ratings for pubic hair, breast, and genitalia each consist of five stages, with stage 1 representing prepuberty and stage 5 representing full development (table 1). The stages are illustrated by the figure in girls (picture 1A-B) and boys (picture 2).
As is discussed below, the timing of pubertal maturation has an important influence on self-esteem, behavior, growth, and weight. As an example, early maturation is associated with slightly shorter adult stature [13,14] and with greater adult ponderosity and adiposity [14,15]. Details of the physiologic changes expected during puberty are discussed below. (See 'Sequence of pubertal maturation' below.)
Growth spurt — Approximately 20 percent of adult height accrues during puberty . The increase in height affects both axial (trunk) and appendicular (limb) components . 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 . The growth spurt typically lasts for approximately two years in both sexes. Modest seasonal variations in growth have been reported even in well-nourished populations, with greater growth typically occurring in the spring .
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) . 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 , and the Bone Mineral Density in Childhood Study, which used data collected from 2002 to 2009 . 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 for the pubertal growth spurt in early-maturing versus late-maturing children.
The overall average difference in adult height between women and men results from differences in the timing and magnitude of the growth spurt in girls and boys. The timing of the growth spurt (peak height velocity) varies by sex, with peak height velocity occurring approximately two years earlier on average in girls than in boys (figure 3A-B). As a result, boys have an additional two years of prepubertal growth (at a rate of 3 to 8 cm per year) by the time the growth spurt starts. Furthermore, boys experience a greater peak height velocity than do girls (average 10.3 versus 9.0 cm/year). In girls, peak height velocity occurs, on average, 0.5 years prior to menarche .
Extremely early onset of puberty (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 also may adversely influence adult stature. In one study in girls, early menarche was associated with greater peak height velocity but shorter adult stature, while early thelarche had no effect on adult stature . In a study in boys, those who mature relatively early but within the normal range had a modest reduction in adult height . The diminished adult height was attributable to shorter leg length; sitting height was not reduced. Body weight appears to influence these results: In the same study, boys who were underweight during childhood tended to have longer leg length and no change in adult height. It is probably not appropriate to extrapolate these results to girls, because obesity is sometimes associated with earlier onset of puberty in girls, and obesity may have the opposite effect in boys. (See "Overview of the health consequences of obesity in children and adolescents", section on 'Growth and puberty'.)
Bone 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 then bone density . The rate of bone mineral accrual peaks around the age of menarche in girls, which occurs after peak height velocity is reached [25,26]. The disparity in the timing of bone growth and mineralization may place the growing adolescent at increased risk for fracture. (See 'Musculoskeletal injuries' below.)
Approximately one-half of total body calcium is laid down during puberty in females and one-half to two-thirds in males [24,27]. By the end of puberty, males have nearly 50 percent more total body calcium than do females. The increase in bone density during puberty is greater in African American individuals than in White individuals .
The risk for osteoporosis during adulthood may be related to both specific "insults" and the timing of factors impacting bone deposition during puberty . These data suggest that the window of opportunity to maximize peak bone mass may be limited . Possible effects of certain hormonal contraceptives on peak bone mass are discussed separately. (See "Contraception: Issues specific to adolescents", section on 'Depot medroxyprogesterone acetate'.)
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 girls compared with boys. Growth curves for body mass index (BMI) describe 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 annual increase in BMI is driven primarily by changes in lean body mass. Later, the increase in BMI tends to be driven by increases in fat mass . This general pattern diverges between the sexes:
●Boys tend to have a decrease in body fat in early puberty and then proceed to a substantial increase in lean body mass.
●Girls tend to have a higher proportion of fat mass than boys at each phase, and after 16 years of age, the annual increase in BMI is largely because of increases in fat mass [29,30].
These general patterns are altered by the individual's nutritional status; either boys or girls who gain excessive weight during puberty may experience an ongoing increase in body fat, regardless of sex or pubertal stage. Obesity tracks from adolescence to adulthood, and earlier onset of obesity is associated with increased cardiovascular morbidity and mortality [31-34]. (See "Overview of the health consequences of obesity in children and adolescents", section on 'Cardiovascular'.)
SEQUENCE OF PUBERTAL MATURATION — Most adolescents follow a predictable path through pubertal maturation, although some variability occurs between individuals with regard to the timing, sequence, and tempo.
Girls — The earliest detectable secondary sex characteristic on physical examination in most girls is breast/areolar development (thelarche) (picture 1A) . Ovarian enlargement and growth acceleration typically precede breast development but are not apparent on a single physical examination. Approximately 15 percent of girls have pubic hair as the initial manifestation (pubarche) (picture 1B) . The likelihood of pubarche as the initial manifestation of puberty increases threefold with maternal preeclampsia; the likelihood is directly related to the severity of preeclampsia [36,37].
Estrogen stimulation of the vaginal mucosa causes a physiologic leukorrhea, which is 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 puberty (figure 2A) [11,21,38]. (See "The pediatric physical examination: The perineum", section on 'Preadolescent and adolescent females'.)
The initial manifestation of puberty predicts body morphology and composition throughout pubertal maturation into early adulthood. As an example, girls with breast development as the initial manifestation of puberty have both an earlier age of menarche and greater body mass index (BMI) throughout puberty and adulthood as compared with girls who exhibit pubarche first . Earlier menarche (before 12 years of age) is associated with higher BMI during adulthood as compared with later menarche [15,40-42]. Most of this effect may be attributable to the influence of childhood obesity on both menarcheal age and adult obesity .
Boys — The earliest stage of male maturation that is detectable on physical examination is an increase in testicular volume (figure 5). Almost all boys have an increase in testicular size (volume ≥4 mL and length ≥2.5 cm) approximately six months prior to the appearance of penile growth and pubic hair (picture 2) [35,44]. The appearance of sperm in the urine and the onset of nocturnal sperm emissions occur shortly after the attainment of peak height velocity; many consider these events the male equivalent of menarche (figure 2B).
Testicular volume is typically estimated using the Prader orchidometer, a series of three-dimensional ellipsoids with a volume from 1 to 25 mL or more (picture 3).
Penile length is measured using a straight edge on the dorsal surface in the non-erect state from the pubic ramus to the tip of the glans while compressing the suprapubic fat pad and applying gentle traction. Mean stretched penile length is approximately 3.75 cm (±0.54 cm) at one year of age, gradually increases to 4.84 cm by late childhood, and increases sharply to approximately 9.5 cm (±1.12 cm) by late puberty (according to measurements from a predominantly White population) . This measurement is rarely used for monitoring of pubertal progress because penile growth is not an early event in puberty, accurate measurement is difficult and may be awkward for the adolescent boy, and there is not as clear of a "pubertal threshold" for penile stretched length as there is for testicular volume.
There is a steady increase in testicular volume across pubertal stages (figure 5) . 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 small testicular volumes in a fully virilized adolescent boy may be a sign of Klinefelter syndrome or inappropriate use of exogenous androgens.
TIMING OF PUBERTAL EVENTS
Typical pubertal timing — The timing of pubertal onset varies widely among individuals of a given sex. It is partly predicted by family history, body weight, and race or ethnic background. (See 'Definitions' above.)
●Girls – Longitudinal studies in a large multiethnic cohort of American girls reported the following pubertal milestones [4,46]:
•Breast stage 2 – The first sign of puberty in girls is typically breast development, or sexual maturity rating breast stage 2 (picture 1A). In this American cohort, breast development started at a mean age of 8.8 years in Black girls, 9.2 years in Hispanic girls, 9.6 years in White non-Hispanic girls, and 9.9 in Asian girls . Body mass index (BMI) accounted for approximately 14 percent of the variance, while race/ethnicity accounted for 4 percent . For White girls, this age was three months earlier than the mean age reported in an earlier cross-sectional study . (See 'Trends in pubertal timing' below.)
•Menarche – Median age for menarche was 12.2 years and varied by race and ethnicity: 11.8 years in Black girls, 11.6 years in Hispanic girls, 12.0 years in Asian girls, and 12.5 years in White non-Hispanic girls . BMI accounted for 11 percent of the variance, while race/ethnicity accounted for 6 percent.
●Boys – A large cross-sectional study of American boys reported the following pubertal milestones :
•Testicular volume ≥4 mL – The first sign of puberty in boys is testicular enlargement; this occurred at a mean age of 11.8 years in Black boys, 11.3 years in Hispanic boys, and 11.5 years in White non-Hispanic boys.
•Pubic hair stage 2 – Mean age for pubic hair stage 2 (picture 2) was 10.2 years in Black boys, 11.4 years in Hispanic boys, and 11.5 years in White non-Hispanic boys.
Trends in pubertal timing — Demographic studies over the past 30 years have indicated a trend towards earlier pubertal timing in girls and probably also in boys. 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 and menarche. While several factors are known to influence pubertal timing, the precise physiologic determinants of pubertal timing remain obscure.
Pubertal onset in girls has been trending earlier in the United States and other developed countries. A meta-analysis examined the trend in onset of breast development and noted a decrease of 0.24 years per decade across the globe over the past 36 years . 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 one-year advancement in age at thelarche across an approximately 15-year time span, but the advancement in age at menarche was only four months . Furthermore, although age of menarche is generally earlier in African American compared with White girls, the difference between the groups decreased between the 1970s and the 1990s .
Pubertal onset in boys also appears to be occurring earlier in the United States. In a study including more than 4000 healthy American boys cited above, the mean age for entering puberty was 1.5 to 2 years earlier than historical norms . Similar trends have been reported from several European and Scandinavian countries and China [50-55]. (See "Endocrine-disrupting chemicals", section on 'Children'.)
The earlier onset of puberty has had important implications for the diagnosis of precocious puberty. Precocious puberty usually has been defined as breast development prior to eight years of age in girls and testicular enlargement before the age of nine years in boys. Because of the earlier onset of puberty in the United States, it has been suggested that a threshold of seven years in White girls and six years in African American girls be used for evaluation for precocious puberty . However, following these suggestions may lead to under-diagnosis of endocrine disorders, and the appropriate threshold for evaluation remains controversial and probably varies among populations; the need for evaluation depends not only on age but also on the degree and rate of maturation, as well as family history . (See "Definition, etiology, and evaluation of precocious puberty".)
Physiology of pubertal onset — Pulsatile secretion of GnRH from the hypothalamus is a critical hormonal event in puberty. What triggers the increase in GnRH secretion is uncertain, 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 and neurokinin B, which are produced by KNDy neurons in hypothalamus that produce kisspeptin, neurokinin B, and dynorphin:
•Kisspeptin appears to have an important role in the initiation of puberty in humans [57,58]. Kisspeptin potently stimulates hypothalamic GnRH secretion. In humans, loss-of-function mutations in the KISS1 gene, which encodes the kisspeptin preprohormone, or in the KISS1R gene (formerly GPR54), which encodes the kisspeptin receptor, cause lack of pubertal development due to idiopathic hypogonadotropic hypogonadism [59,60]. Expressions of hypothalamic KISS1 messenger RNA and kisspeptin peptide appear to increase across the pubertal transition in animal models, suggesting that kisspeptin may be a key instructive signal in the initiation of puberty , but this raises a new question: "What triggers the increased expression of KISS1 at puberty?" (See "Definition, etiology, and evaluation of precocious puberty", section on 'Genetics'.)
•Neurokinin B signaling also appears to be an important stimulus for pubertal onset . In humans, mutations in the TAC3 gene, which encodes the neurokinin B preprohormone, and in the TACR3 gene, which encodes the primary neurokinin B receptor, also cause idiopathic hypogonadotropic hypogonadism . A unique feature of patients with mutations in TAC3 or TACR3 is that they have a propensity for "reversal" of their hypogonadotropic hypogonadism, that is, recovery of reproductive endocrine function in adulthood . Furthermore, mutations in TAC3 and TACR3 have been found in patients with delayed puberty , and common genetic variants near TACR3 have been found to influence the timing of normal puberty [64,65]. 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.
Although glutamate has long been known to stimulate GnRH neuronal activity in animal models, whether it is directly involved in determining pubertal timing remains unclear . Similarly, while the hormone leptin is required for normal pubertal onset in humans, it seems unlikely to play a role in determining pubertal timing, as discussed above. (See 'Body fat and leptin' below.)
●Inhibitors of GnRH secretion – Patients with precocious puberty provide insight into potential inhibitors of GnRH secretion. It has long been recognized that lesions of the central nervous system can cause precocious puberty (see "Definition, etiology, and evaluation of precocious puberty"). This implies that pathways within the central nervous system suppress GnRH neuronal activity during childhood, such that disruption of these pathways results in precocious puberty, though the precise identity of these pathways remains obscure.
Mediators for an inhibitory influence on GnRH secretion include:
•Gamma-aminobutyric acid (GABA) is a neurotransmitter that appears to play an important role in these inhibitory pathways. In rhesus monkeys, secretion of GABA in the hypothalamus decreases across the pubertal transition , and pharmacologic disruption of signaling through the GABAA receptor induces early puberty .
•Loss-of-function mutations in the MKRN3 gene have been found to be a genetic cause of central (GnRH-dependent) precocious puberty . MKRN3 is maternally imprinted (ie, only the paternal allele is expressed); mutations in MKRN3 therefore cause precocious puberty only if inherited from the father. MKRN3 encodes makorin ring finger protein 3, a protein that may have a role in ubiquitination (addition of the protein ubiquitin to target proteins, which have yet to be identified). In mice, Mkrn3 expression decreases around the time of sexual maturation, suggesting that this gene has a role in suppressing reproductive endocrine function prior to puberty. In humans, mutations in MKRN3 have been found in approximately one-third of familial cases of precocious puberty and approximately 3 percent of sporadic cases [69,70].
•Mutations in the DLK1 gene have also been suggested to be a cause of precocious puberty. In one family, a deletion disrupting DLK1 was found in five family members with precocious puberty . DLK1 is located in the chromosomal region deleted in Temple syndrome, of which precocious puberty is one feature. (See "Definition, etiology, and evaluation of precocious puberty", section on 'Genetics'.)
Determinants of pubertal timing — Genetics accounts for the majority of the variability in the timing of pubertal onset in developed countries. The timing of puberty and menarche in a girl is best predicted by the timing of menarche in her mother. (See 'Physiology of pubertal onset' above.)
Other factors that influence pubertal onset include overall health (with poor health associated with delayed pubertal onset) and social environment (such as family stress or the presence of an adult, nonbiologically related male in the household, which are associated with earlier pubertal onset) [49,72-75]. Studies have suggested an interaction between genetics and the environment. The influence of environmental factors, including endocrine disruptors, on timing of pubertal maturation is a subject of active research . (See 'Trends in pubertal timing' above and "Endocrine-disrupting chemicals", section on 'Children'.)
Body fat and leptin — For girls, overweight or obesity is associated with earlier pubertal onset and/or pubertal progression [4,77-79]. For boys, the relationship between pubertal onset and obesity is not clear, with some studies suggesting that increased BMI and fat mass is associated with earlier puberty, similar to findings in girls [50,78-81], while others suggest the opposite association [82,83]. A possible explanation for these disparate findings comes from a study that found a nonlinear relationship between body weight and pubertal onset in boys, with earlier onset of puberty in boys with increasing BMI, except for the most obese boys, who instead exhibited later pubertal timing .
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  or percent body fat  is the primary determinant [40,85-87]. However, body weight or composition alone probably is not a sufficient explanation. The overall earlier onset of puberty among the general population has been attributed to the increasing prevalence of obesity, but again, it is unclear whether it is sufficient to explain this trend. (See 'Trends in pubertal timing' above.)
Leptin, a hormone that is produced primarily in adipocytes, is one of several factors that influence the activity of the gonadotropin-releasing hormone (GnRH) pulse generator, probably as a signal of the availability of metabolic fuel . In one study in girls, 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 reproductive endocrine function and puberty, rather than the instructive signal that initiates the onset of puberty. A preponderance of studies in boys have suggested that changes in serum leptin at puberty are a result of changes in body composition with puberty rather than a trigger of pubertal onset [89-91]. 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 [92,93].
The pathways activated by leptin in the brain are being actively investigated. For appetite, metabolic rate, and weight homeostasis, one of the primary mediators of the effects of leptin is signaling through melanocortin receptors, primarily the melanocortin 4 receptor but also the melanocortin 3 receptor  (see "Obesity: Genetic contribution and pathophysiology"). For the reproductive endocrine system, the melanocortin 3 receptor may play a larger role as variants in MC3R (the gene encoding the melanocortin 3 receptor) that result in decreased receptor signaling have been found to be associated with delayed pubertal onset [95,96].
Genetics — Overall, genetic factors have been estimated to account for 50 to 75 percent of the variation in normal pubertal timing [97-100]. Several genetic loci have now been identified that are associated with age of pubertal onset [64,95,97-100]. A large genome-wide study including more than 370,000 women identified common variants or single-nucleotide polymorphisms at 389 genetic loci that were associated with age at menarche . A comparable genome-wide association study of timing of male pubertal hallmarks in over 205,000 men identified 76 genetic loci associated with male pubertal timing . Most but not all of these loci affect pubertal timing in both females and males [64,100,102].
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 (see 'Physiology of pubertal onset' above). Furthermore, some of the genetic variants associated with age at menarche have also been associated with variation in adult height [97-99]. 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 were also associated with earlier age at menarche [97,98] (see "Obesity: Genetic contribution and pathophysiology", section on 'Common (multifactorial) obesity'). However, how most of the loci may regulate menarcheal timing remains unclear. As an example, one of the strongest associations in both females and males is with LIN28B (Caenorhabditis elegans, homolog of B), which is a regulator of microRNA processing involved in developmental timing in C. elegans but whose role in human reproduction is unclear [64,98-100].
Despite these significant advances in understanding the genetics of pubertal timing, most of the genetic basis remains unexplained since the variants described in the study on age at menarche account for only 7.4 percent of the variation in pubertal timing . Collectively, these findings provide glimpses into the physiologic mechanisms that determine pubertal timing, but an integrated model for the onset of puberty remains elusive.
PUBERTY-RELATED HEALTH CONCERNS — Puberty is associated with a number of undesirable changes that present challenges to the patient and family. These include anemia, gynecomastia, acne, psychological correlates of puberty, certain types of sports-related injuries, myopia, scoliosis, and abnormal uterine bleeding.
Anemia — Anemia and iron deficiency are more common among adolescent girls than adolescent boys or school-aged children (figure 6). Hemoglobin and serum ferritin concentrations increase with advancing pubertal stage in males but not in females [103,104]. Males are less prone to anemia because testosterone increases erythropoiesis, while females are more prone to anemia because of menstrual bleeding and, for many, insufficient iron intake . (See "Iron requirements and iron deficiency in adolescents".)
Gynecomastia — Pubertal gynecomastia (in contrast with neonatal or senescent gynecomastia) occurs in approximately one-third of teenage boys at an average age of 13 years, and it persists for 6 to 18 months . Although the underlying diagnosis usually is "idiopathic pubertal gynecomastia," other etiologies must be considered. The underlying mechanisms presumably reflect an imbalance in the effective estrogenic-to-androgenic stimulation because of 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 . (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. With pubertal maturation in both boys and girls, the number of acne lesions increases, with a greater number of comedones than inflammatory lesions at all stages . In girls, the severity of acne in later puberty is associated with higher serum levels of dehydroepiandrosterone sulfate (DHEAS) and a greater number of acne lesions in early puberty . Although acne is common during puberty, moderate or severe acne in early puberty, usually with 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 in adolescents", section on 'Acne'.)
Psychological changes — Pubertal maturation has an impact on psychological and social issues . Puberty does not affect cognitive development , although the timing of pubertal maturation may affect psychosocial functioning.
Prior to adolescence, no sex/gender differences in depression occur; during adolescence, however, the prevalence of depression is twice as great in girls than boys . As puberty progresses, boys develop a more positive self-image and mood. By contrast, girls tend to become less satisfied with their physical appearance, and some girls exhibit diminished self-worth as they pass from early to mid-adolescence . 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. For example, the early-maturing girl may experience a greater decrease in self-esteem and body satisfaction when compared with on-time or late-maturing girls . In a large cross-sectional study, girls who were early-maturing and boys who were late-maturing were more likely to have psychopathology. 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 boys who were late-maturing 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 . Girls with early maturation are more likely to have older friends  and to be more vulnerable to peer pressures .
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) . 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 . 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 girls 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 provide a neurodevelopmental predilection for risk-taking .
Musculoskeletal injuries — Pubertal changes may help to explain the risk and type of musculoskeletal injuries related to sports participation in adolescents . 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 . Similarly, the age of peak incidence of distal radius fractures matches the age of peak height velocity in both boys and girls  (see 'Bone growth' above). 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 'Growth spurt' above.)
A common injury 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 consequences — Once a girl reaches menarche, rapid maturation of the reproductive axis ensues. By one year after menarche, 65 percent of girls have regular menstrual cycles, with 10 or more periods per year . Girls with later onset of menarche 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 .
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 estrogen stimulates the endometrium, leading to a sustained proliferative phase rather than maturing to a secretory endometrium. Estrogen levels ultimately cannot sustain the hyperplastic endometrial lining, leading to irregular, sometimes heavy, menstrual bleeding. (See "Abnormal uterine bleeding in adolescents: Evaluation and approach to diagnosis", section on 'Terminology' and "Abnormal 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 . (See "Refractive errors in children", section on 'Refractive errors'.)
Scoliosis — Accelerated progression of the degree of scoliosis occurs during puberty due to growth in the axial skeleton. (See "Adolescent idiopathic scoliosis: Management and prognosis", section on 'Risk for progression'.)
Sexually transmitted infections — Sexually active adolescents are at increased risk for sexually transmitted infections . Both behavioral and biologic factors are important. (See "Sexual development and sexuality in children and adolescents" and "Sexually transmitted infections: Issues specific to adolescents".)
PUBERTAL TIMING AND ADULT MORBIDITIES — Pubertal timing affects risks for a number of adult conditions . There is a negative linear correlation between pubertal timing and adult body mass index (BMI) . Multiple studies have reported the association of earlier age at menarche with breast cancer, with a decreased risk of 7 percent per year that menarche is delayed for premenopausal breast cancer and 3 percent per year that menarche is delayed for postmenopausal breast cancer [128,129].
Earlier puberty is also associated with increased risk for other reproductive cancers: endometrial and ovarian cancer in women and prostate cancer in men . The relationship of pubertal timing and cardiovascular disease is more complex; in women, both earlier and later age at menarche are associated with increased risk of coronary heart and cerebrovascular diseases . Additionally, earlier age at menarche is associated with increased risk for type 2 diabetes and impaired glucose tolerance; part of this association is mediated by increased adiposity and part is independent of adiposity . 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 [132,133]. Other associations described for later pubertal onset include lower bone mineral density, increased fracture risk, and, in men, 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 longer pubertal growth period .
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 5th to 6th 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 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
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●Pubertal sequence and timing
•Puberty consists of a series of predictable events that usually proceed in a predictable pattern, with considerable variation in timing of onset, sequence, and tempo (figure 2A-B). (See 'Pubertal changes' above.)
•In girls 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 median age of menarche is 12 years and varies by weight status and race/ethnic group. (See 'Timing of pubertal events' above.)
•In boys, the mean age of pubertal onset (marked by testicular enlargement) is approximately 10 years. (See 'Timing of pubertal events' above.)
•Precocious puberty is defined as pubertal onset at an age 2 to 3 standard deviations (SD) below the mean age of onset of puberty. Similarly, delayed puberty is defined as lack of pubertal onset by an age 2 to 3 SD above the mean age of onset of puberty. 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 "Approach to the patient with delayed puberty".)
●Pubertal stages – 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 by the figure in boys (picture 2) and in girls (picture 1A-B). (See 'Sexual maturity rating (Tanner stages)' above.)
•In most girls, the earliest secondary sex characteristic is breast/areolar development (thelarche) (picture 1A), although approximately 15 percent have pubic hair as the initial manifestation (picture 1B). Menarche occurs, on average, 2.6 years after the onset of puberty and 0.5 years after peak height velocity (figure 2A). (See 'Girls' above.)
•In boys, 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). The appearance of sperm in the urine and the onset of nocturnal sperm emissions occur shortly after the attainment of peak height velocity; many consider these events the male equivalent of menarche (figure 2B). (See 'Boys' above.)
●Growth and body composition
•The growth spurt occurs approximately two years earlier in girls than in boys (figure 2A-B). Extremely early onset of puberty (precocious puberty) is associated with reduced adult height due to early epiphyseal closure. Whether pubertal onset that is early but within the normal range is associated with reduced adult stature is less clear. (See 'Growth spurt' above.)
•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 girls as compared with boys.
•Commonly used cross-sectional growth curves describe the typical increases in height and body mass that occur during puberty (figure 4A-B) but do not reflect the differences between early-maturing and late-maturing children. (See 'Weight and body composition' above.)
●Physiology of pubertal onset – 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 of pubertal onset' above.)
●Associated health concerns – Puberty is associated with a variety of physiologic changes that may come to medical attention, including acne and scoliosis, gynecomastia in boys, and anemia and abnormal uterine bleeding in girls. Psychologic and emotional changes are common, with increased rates of depression and risk-taking behaviors. (See 'Puberty-related health concerns' above.)
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