General Medical Information

Physical Events of Puberty

Sander S. Shapiro and Joel S. Krasnow

In utero, the fetus is exposed to high estrogen levels. Acute withdrawal of estrogen at birth can result in endometrial shedding, which manifests clinically as vaginal bleeding. In infant girls between 1 and 6 months of age, the uterus decreases in size, achieving an average length of 32 mm. The ratio of corpus to cervix in the prepubertal uterus is 1:2. When GnRH pulse frequency increases sufficiently to cause multiple follicular development and estradiol production, uterine growth begins. The first change is a lengthening of the corpus, followed by an increase in the width and thickness of both corpus and cervix. This process is initiated between 7 and 9 years of age. A uterine cross-sectional area of 4 × 2 cm usually is achieved by 12 years of age. Before initiation of puberty, the endometrium consists of a single layer of cuboidal cells. As estradiol levels increase, the endometrium begins to proliferate. A rapid increase in endometrial thickness immediately preceding menarche can be visualized by ultrasound evaluation.

Like the uterus, the vagina is an estrogen-responsive tissue. During puberty, newly elevated estrogen levels stimulate overall growth as well as epithelial proliferation. Under the influence of estrogen, the vaginal epithelium increases in thickness, with cornification of its superficial cell layers. This change has been quantified and the karyopyknotic index used as a sign of estrogenic status. Multiple metabolic alterations of the epithelium also result from estrogen exposure. These bring about a change in vaginal secretions and pH, providing greater resistance to local infection.

Both the labia minora and majora respond to estrogen by increasing in size and thickness. Concomitantly, the hymen thickens and its orifice enlarges to about 1 cm in diameter. At the same time, the vestibular glands begin active secretion and the clitoris undergoes general enlargement. The relative contribution of estrogen and androgens to this latter change remains ill defined.

Breast development is often the first visible change of puberty, although it may follow pubarche by many months. Before thelarche, male and female breast tissue is histologically indistinguishable. Breast development at puberty requires the presence of multiple hormones including prolactin, glucocorticoids, and insulin. However, it is gonadarche with its production of estrogens that induces thelarche. It is the direct estrogen stimulation of mammary epithelium that causes ductal proliferation and the site-specific adipose deposition that accounts for the majority of female breast development. Males fail to produce significant breast mass, primarily because they lack optimal levels of circulating estrogen. The extent to which testosterone inhibits breast development (during embryogenesis and/or puberty) remains uncertain. In complete testicular feminization, substantial breast tissue usually is present despite only minimal increases in estrogen compared to the testosterone-sensitive, normal male, suggesting the potential importance of androgens in limiting male breast development. Once thelarche begins, the duration of time at each Tanner stage is variable. Overall, breast development usually proceeds smoothly to maturity in about 3 years.

Temporally associated with the development of secondary sexual characteristics is a marked increase in growth referred to as the “adolescent growth spurt.” This growth spurt, which is measured by a change in skeletal growth rate, actually represents a more global process involving an increase in muscle mass and growth of almost all internal organs. These processes are dependent on both growth hormone and sex steroids, predominantly estrogen in both sexes. Adrenal, as well as gonadal hormones, are thought to contribute to this change in growth rate. In addition to their direct anabolic effects, sex steroids have been demonstrated to increase the secretion of growth hormone and consequently insulin-like growth factor. The rise in serum sex steroid levels initiates a change in growth velocity that often antedates pubarche and thelarche. A sudden increase in shoe size frequently is observed coincident with onset of the linear growth spurt. Peak growth velocity usually is attained midway in the course of pubertal maturation in females, which is 2 years earlier than in males. Prior to the adolescent growth spurt, growth velocity averages 3 to 6 cm per year. PHV in males averages 8.8 cm, with a standard deviation of 1.05 cm per year. In females, PHV is 8.13 cm, with a standard deviation of 0.78 cm per year. By the time PHV is reached, approximately 90% of the final adult height has been achieved. On completion of the adolescent growth spurt, very little additional height is gained. The average increase in height from the onset of the growth spurt to the cessation of growth is 25 cm in females and 28 cm in males. Thus, the greater final height achieved in males is a function of both the delay in onset of the growth spurt and a greater gain in height during the growth spurt. Children who progress through puberty earlier tend to attain a greater PHV but ultimately have a shorter final adult height than their peers.

There are several common variations in normal pubertal development. For example, one breast may begin to develop up to 6 months before the other. This may lead to an asymmetry that persists into adult life. Premature development of the breast bud is referred to as premature thelarche. When this occurs in early infancy, it may represent a delay in either establishment of negative estrogen feedback on the hypothalamus or inhibition of the intrinsic pulsatile activity of the hypothalamus by higher centers. In the older child, it may be an attenuated form of sexual precocity. In both instances, endocrinologic findings may reveal increased gonadotropins or increased gonadotropin response to GnRH. Total or free estradiol level may be elevated in plasma. Radiologic evaluation usually reveals some ovarian follicular activity. Follow-up is necessary to distinguish premature thelarche from true precocious puberty. In premature thelarche, breast development ceases and may even regress, bone age is not advanced, and there are no further signs of pubertal development. In contrast, during premature puberty, bone age will advance significantly and other signs of continued pubertal development, such as the appearance of pubic hair, will occur.

Premature development of sexual hair is referred to as premature pubarche. The majority of children with premature pubarche have early activation of adrenal androgen secretion. Adrenocorticotropic hormone stimulation of these individuals will reveal responses between those of adults and prepubertal children. Levels of DHEAS usually are elevated. Because puberty and adrenarche are independent events, there are no other signs of sexual precocity and bone age is not significantly advanced in these children.

In assessing children for suspected disorders of growth and development, charts displaying normative data provide valuable information. North American children grow faster and on average are taller than British children; therefore, appropriate standards for the population being studied should be used. The onset of gonadarche is associated with increased growth velocity. Because the time of initiation of gonadarche is quite variable, the range of heights in pubertal aged children will be greater than the range for prepubertal children. Therefore, the use of cross-sectional population curves to follow the growth of an individual child, once puberty has begun, is invalid. The use of the growth curves for North American children published by Tanner in 1985 take into account the variability in pubertal progression. For example, take two girls both destined for an adult height of 164 cm (50th percentile). At age 12 years, an “early maturer” (+2 SD) will have completed her growth spurt and measure 160 cm. The “late maturer” (–2 SD) will measure 144 cm. Because these curves are derived by averaging data from a large population, no single individual should be expected to follow the curve precisely. These graphs are particularly useful in evaluating girls with primary amenorrhea. When height and breast and pubic hair development are all progressing in accordance with the norms and an intact reproductive tract is present, the patient can be assured that menarche is imminent.

A distinction must be made between the late maturer who makes slow but steady progress and the individual exhibiting an arrest of pubertal development. Individuals who have initiated breast and pubic hair growth usually also will have noticed an increase in the size of their hands and feet. As indicated earlier, increasing shoe size is an indicator of normal pubertal development. Arrest of pubertal development is relatively rare, but when detected it may indicate hypothalamic, pituitary, gonadal, or systemic disease. Because the interval from thelarche to menarche is 2.3 ± 1.0 years, the absence of advancement in breast and pubic hair development and the absence of growth in the hands and feet over a 2- to 3-year period deserves further evaluation.

Girls who are late to initiate signs of pubertal development will usually also be late to experience menarche. It is not unusual for an individual initiating breast development at age 14 years to not experience first menses until age 17 or 18 years. As a general rule, one should expect healthy girls of 14 years to have begun to demonstrate the physical changes of puberty. Those that have not require special attention. When a young woman demonstrates substantial pubertal development yet has not experienced menarche by age 18 years, she too deserves thorough evaluation.

One of the more commonly seen variations from normal puberty is the failure to develop secondary sexual characteristics by age 14 years. These individuals usually are smaller than their peers due to the lack of initiation of a growth spurt. Commonly, their mothers also exhibited a delay in the onset of puberty. Bone age is useful in evaluating such patients, because it is more closely correlated with pubertal events than chronologic age. Clinical signs of pubertal development are present in approximately 95% of individuals when their bone age reaches 12.5 years. Constitutional delay in growth and pubertal development occurs as a result of a delay in maturation of the HPG axis. Most cases of delayed development are constitutional, but other causes of delayed puberty, as discussed in Chapter 13, need to be considered. In individuals with constitutional delay of pubertal development, endocrinologic findings should be consistent with the stage of development and may indicate impending onset of clinical signs.

In addition to changes in linear growth, the skeleton also undergoes a series of characteristic alterations in its osseous composition. These patterns define a bone age that, during adolescence, more closely correlates with the individual’s state of pubertal development than with their chronologic age. A radiographically defined bone age of 11 years usually is associated with the onset of either pubarche, thelarche, or both.

In conjunction with the physical changes described earlier, the appearance of acne, axillary hair growth, and phenotypical alterations in adipose distribution are part of the pubertal process. Each of these can be directly associated with the newly integrated hormonal changes that underpin puberty. On the other hand, there is little current evidence to support a direct relationship between adolescent patterns of social behavior and the chemical alterations that are an integral part of the pubertal process. This concept may change as a more thorough understanding of the effects that pubertal hormone changes have on neurobiochemical processes evolves.

Growth and development throughout childhood usually progresses in an orderly ashion. Any deviation from the perceived norm usually results in the child being brought to medical attention. Precocious, delayed, and aberrant development can cause alarm to parents, school officials, and medical personnel. Wide variation in the onset of developmental milestones evokes concern, as comparisons usually are made between children of similar chronologic age. The physician faced with such concerns must thoroughly evaluate the child’s current and past developmental status and utilize compilations of normative data including height, weight, skeletal age, and time of onset of individual pubertal events to determine the presence or absence of pathologic processes. For those children who deviate significantly from these established norms, a more thorough evaluation will be necessary.