Chapter 540. Normal Pubertal Development

Changes in hypothalamic-pituitary-gonadal endocrine function lead to the striking changes associated with secondary sexual development. Endocrine changes of puberty are divided into (1) gonadarche, or the awakening of gonadal action during which increased pituitary gonadotropins cause the secretion of gonadal steroids, and (2) adrenarche, or the awakening of adrenal androgen secretion caused by still undefined factors.

Stages of pubertal development are described using a sexual maturity rating scale popularized by Tanner. Staging provides an objective, consistent description of physical development (Fig. 540-1). Breast development (caused by ovarian estrogens) and pubic hair development (caused by adrenal androgens) are usually, but not always, coordinated in girls (eg, premature adrenarche or premature thelarche) so that each should be documented. Similarly, in boys, testicular/penile development and pubic hair development may not be synchronous because the adrenal gland can produce its own androgens out of sequence with testicular androgen secretion, due to either adrenal disease or adrenarche.

Male Puberty

Changes used for Tanner staging among boys are shown in Figure 540-1A. The onset of normal male puberty is heralded by an increase in the longest diameter of the testes to more than 2.5 cm, excluding the epididymis. Volume measurements of the testes are accomplished by means of comparison with the standard ellipsoids of a Prader orchidometer. The onset of puberty corresponds to an increase in testicular volume greater than 4 mL. If other signs of pubertal development occur without an increase in testicular volume, an adrenal or exogenous source of androgen production is the cause. Stage 2a is proposed as a stage when testicular volume reaches 3 mL because 82% of boys progress through puberty within 5 months after this milestone. The brow, nose, and chin develop more among boys, and the larynx changes shape and vocal cords lengthen to cause the change in voice of puberty and the development of the “Adam’s apple.”

Female Puberty

Changes used for Tanner staging among girls are shown in Figure 540-1B. Breast development among girls can start unilaterally, and such asymmetric breast development is not abnormal in early puberty. Other physical changes occur during puberty that are not described with Tanner staging. Axillary hair appears and thickens as axillary odor appears as signs of adrenarche. The prepubertal reddish color of the vaginal lining becomes pink and dull because of cornification of the vaginal mucosa and secretion of a clear or whitish (this is not referring to pus) discharge stimulated by estrogen in girls. The labia minora and majora thicken under estrogen stimulation, and fat develops in the area of the mons pubis. Percentage of body fat increases during puberty among girls, and subcutaneous fat deposition accounts for much of the change in body shape.

The pubertal growth spurt is the most rapid period of growth after the fetal and neonatal periods. The mean 5-inch (12.5 cm) difference in adult height between men and women is partially related to the fact that, on average, the male pubertal growth spurt occurs 2 years later than the pubertal growth spurt of girls and partially due to the greater height gained during the growth spurt in boys. The pubertal growth spurt is thus an early pubertal event for girls and occurs before menarche; a postmenarcheal girl has little growth left. For boys, the pubertal growth spurt is a late pubertal event; a boy in early puberty likely has substantial growth left.

Serum concentrations of IGF-1 are low at birth but increase throughout childhood until puberty, when serum concentration of IGF-1 increases severalfold, followed by a decrease to the adult range. The pubertal increase in serum concentrations of IGF-1 is partly due to stimulation of growth hormone (GH) by estradiol. Serum estradiol is secreted by the ovaries in girls and is produced by aromatization of testosterone in boys. Increased sex steroids also increase the production of IGF-1 locally in the cartilage, independent of changes in secretion of GH.1 Children with delayed puberty will have serum concentrations of IGF-1 appropriate for their delayed bone age but not their chronologic age (see Chapter 541).

Growth in stature is accompanied by advancement of skeletal development, reflected in measured bone-age. Menarche onset occurs at a bone age of roughly 13 years in girls, with 2 to 7 cm of growth following menarche. The farther bone age is from the age of epiphyseal fusion (a bone age of 15 years for girls and 17 years for boys), the more growth remains. Bone age is advanced in sexual precocity and accounts for the paradox of a child with early puberty having tall childhood stature but ultimately having short adult stature. Epiphyseal fusion occurs due to estradiol in both boys and girls. In persons with estrogen receptor defects who cannot respond to estradiol and others with aromatase deficiency who cannot produce estradiol, the epiphyses can remain open well after 20 years, allowing continued growth into the third decade of life, resulting in tall adult stature.

Bone density increases during puberty, which is a period of maximal accretion of bone mineral. The peak of calcium deposition is 2 years later for boys than for girls, but both sexes achieve maximal bone density after the pubertal growth spurt. Untreated hypogonadism leading to delayed or absent puberty, decreases ultimate bone mass and can lead to osteoporosis later in life. The teenage years are crucial for the achievement of appropriate bone density to help maintain healthy bones for the remainder of life.

Age at onset of menarche (as a reflection of the age of puberty) has decreased 2 to 3 months per decade in the developed world over the last 2 centuries This trend has slowed, but apparently not ceased, in the United States over the last few decades.2 The population average age at menarche in US girls is 12.54 years.3 African American girls are more likely to reach menarche before white girls of the same age and relative weight, but menarche occurs before age 9 years in only 0.4% of all girls.4

A cross-sectional survey of more than 17,000 girls in the United States showed that 2.4% of African American girls had breast development by 5 years, 3.4% had pubic hair by 5 years, 15.4% had breast development at 7 years, and 17.7% had pubic hair by 7 years. Among white girls, 1.5% had breast development by 5 years, 0.4% had pubic hair by 5 years, 5% had breast development by 7 years, and 2.8% had pubic hair by 7 years. Thus, African American girls who enter puberty after their sixth birthday and white girls who enter puberty after their seventh birthday in the absence of any predisposing disease are now considered to be normal by many authorities, rather than precocious. However, there is a dissenting view that still considers 8 years of age as the lower limits of onset of female puberty: for maximum safety it appears best to use the 8-year guideline for girls being evaluated by providers in general practice, and pediatric endocrinologists can best determine which of those require in-depth evaluation and perhaps treatment.5 Boys normally enter puberty after 9 years of age.

If a boy does not enter puberty by 14 years of age, puberty is considered delayed. If a girl does not enter puberty by 13 years, puberty is delayed, and if there is absence of menarche by age 15, further evaluation is indicated. Any state of chronic disease or malnutrition can delay the onset of menses and puberty, and these are the most common causes of delayed puberty worldwide. Obesity tends to advance skeletal maturation, increase growth rate, and decrease age at menarche.4,6 The obesity epidemic appears to be causing a tendency toward a lower age of pubertal development.

Hypothalamic-Pituitary-Gonadal Hormones

The hormones that cause pubertal development and reproduction emanate from the hypothalamic-pituitary-gonadal axis and the adrenal glands. Hypothalamic gonadotropin-releasing hormone (GnRH) is secreted from the median eminence into the hypophyseal portal vascular system in a pulsatile manner to reach the pituitary gland. Aminobutyric acid exerts a suppressive effect on GnRH secretion and can be an important factor in the relative quiescence of gonadotropin secretion that characterizes the “juvenile pause” that occurs after infancy and ends before the endocrine activity of puberty resumes. Sex steroids, mainly testosterone, estrogen, and progesterone, inhibit GnRH pulse frequency by negative feedback. In midpuberty, estrogen can have a positive feedback effect on GnRH, making ovulation possible. Gonadotropin-releasing hormone in turn stimulates the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the gonadotrophs in a pulsatile manner. If gonadotrophs are exposed to continuous rather than episodic GnRH, the GnRH receptors are downregulated with decreased responsiveness. This phenomenon is utilized in a pharmacologic manner when GnRH agonists, which mimic a continuous infusion of GnRH, are employed to treat central precocious puberty.

In boys, circulating LH activates membrane-bound receptors on testicular Leydig cells to stimulate testosterone secretion. Follicle-stimulating hormone supports spermatogenesis by attaching to the FSH receptor on the cellular membrane of the seminiferous tubules. The main component responsible for growth of the testes is enlargement of the seminiferous tubules, not Leydig cell development. Thus, patients with excess human chorionic gonadotropin (hCG which has LH activity only) have only minimal enlargement of the testes but secrete exceptional amounts of testosterone from the Leydig cells, as seen, for example, in patients with hCG-secreting tumors. Androgens exert other effects in the body: testosterone stimulates muscle development, enzymatic activity in the liver, and hemoglobin synthesis and decreases the level of high-density lipoprotein cholesterol. Androgens susceptible to aromatization stimulate bone maturation at the epiphyseal plate only after conversion to estradiol.

In girls, FSH binds to cell-surface receptors on ovarian follicular cells to stimulate secretion of estrogen. Luteinizing hormone becomes important later in pubertal development in completing the menstrual cycle of girls when it exerts its effects on the theca cell after the onset of ovulation. Estradiol produced at puberty in girls affects the breast and uterus and the distribution of adipose tissue and bone mineralization, but estradiol has no role in normal female fetal development.

Other Hormonal Changes at Puberty

The serum concentration of prolactin increases in normal female puberty but is not affected by male puberty. Inhibin, produced by testicular Sertoli cells, ovarian granulosa cells, and the placenta, suppresses FSH secretion. With gonadal failure, serum concentration of FSH is markedly elevated, compared to LH concentration, due to the lack of FSH inhibition by inhibin. Activin is the homodimers of the beta subunit of inhibin and has the opposite effect of inhibin; activin stimulates secretion of FSH. Leptin is a polypeptide hormone secreted by adipose cells that acts on the hypothalamus to suppress appetite. Leptin is necessary but not sufficient for pubertal development, as leptin administration will not cause a prepubertal individual to enter puberty.7 The absence of leptin or its receptors is associated with absent gonadotropin secretion; leptin replacement in a patient with congenital leptin deficiency and hypogonadotropic hypogonadism lead to the onset of gonadotropin secretion and the progression of pubertal development.

The control of puberty resides in the central nervous system (CNS).8 Gonadotropin secretion from the fetal pituitary gland increases through midgestation under the stimulation of hypothalamic gonadotropin-releasing hormone (GnRH) once the hypophyseal portal system develops allowing GnRH to reach the pituitary gland. The fetal testes secrete testosterone under stimulation by first placental hCG, and later, by both luteinizing hormone (LH) and human chorionic gonadotropin (hCG). Inhibition of GnRH secretion by the CNS increases toward term, and negative feedback from placental estrogens decreases LH and follicle-stimulating hormone (FSH) secretion in all fetuses and also decreases testosterone secretion in males. At birth, serum LH and FSH rise due to the release of inhibition by placental estrogen. This peaks in the first 1 to 3 months of life. Infant boys at 1 to 3 months of age usually have transient rises in serum testosterone concentrations equal to those found in the midpubertal period. Gonadotropin secretion is followed by peaks of estrogen up to the fourth year of postnatal age in girls and peaks of testosterone up to the second year in boys.

After infancy, concentrations of serum gonadotropins and sex steroids decline for a period of time labeled the juvenile pause. In the normal situation, the juvenile pause continues until the time of pubertal development, being caused by central suppression of hypothalamic function. Endocrine activity of the hypothalamic-pituitary-gonadal axis begins increasing in the peripubertal period, before the physical changes of secondary sexual development become apparent. Increased GnRH secretion causes gonadotropin levels to increase, first during the night, causing a pattern of diurnal variation, and later during the entire day and night with an absence of diurnal variation. In the past, a GnRH or GnRH agonist stimulation test was necessary to determine whether the pubertal increase in endogenous gonadotropin secretion had occurred, but new ultrasensitive gonadotropin assays (third-generation assays) now allow evaluation of gonadarche with a single measurement of LH. The serum concentration of estradiol in girls is extremely variable throughout the day; in boys, the serum testosterone concentration is relatively stable.

Menarche requires the advent of positive feedback of estrogen on GnRH secretion.9 As discussed above, the onset of menarche varies between age 9 years and 15 years. Most menstrual cycles for adolescents are between approximately 20 and 45 days.10 Evaluation is necessary if the onset of menarche or length of menstrual cycle is outside these ranges (see Chapter 541) and if different evaluation is necessary. As the pattern of gonadotropin secretion changes from diurnal variation to a more constant pattern, a progression of changes brings about this mature state. Secretion of FSH always is greater in girls than in boys, and FSH stimulates follicle formation in the early pubertal ovary. The follicle produces estrogen, which increases GnRH secretion, increases pituitary sensitivity to GnRH, and increases gonadotropin secretion. Each subsequent pulse of GnRH primes the gonadotropes to increase gonadotropin secretion further.

The ovarian follicle must be of adequate size to produce sufficient estrogen to exert the positive feedback effect, the pituitary gland must have sufficient readily releasable LH to effect a surge of LH release, and the hypothalamus must be able to secrete adequate GnRH to cause stimulation of the pituitary gland to cause a pulse of LH to be released.9 Then there is a large release of estrogen that stimulates release of LH by positive feedback loop. The LH peak stimulates prostaglandin, which causes an inflammatory response in the follicle that leads to ovulation. This same peak of estrogen suppresses FSH to allow the follicular cells to luteinize, ultimately increasing progesterone production, which increases LH secretion.

These conditions do not develop until well into puberty, and ovulation is a middle to late pubertal event. The first 2 years of menses are anovulatory in 55% to 90% of cycles, but by 5 years after menarche only 20% of periods are anovulatory. Nonetheless, girls may be fertile before physical sexual maturity, and pregnancy has preceded the first documented menstrual period in many cases.

The increased estrogenic activity of the midcycle ovary stimulates growth of the endometrium, but the decrease in endocrine activity toward the end of the cycle leaves the hyperplastic endometrium with no endocrine support. This and the local action of prostaglandins and constriction of arterioles lead to necrosis of the endometrium, and the menstrual flow begins.

An increase in level of adrenal androgens occurs several years before the onset of increasing gonadotropin secretion.11 This elevation in the level of the androgen precursor dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) occurs at a mean age of 6 to 7 years in girls and 7 to 8 years in boys, but it takes about 2 more years for pubic hair to appear. Serum concentrations of DHEAS continue to increase through midpuberty and reach maximal values in the mid-20s (eFig. 540.1). Factors controlling adrenarche are unknown but are separate from the mechanisms of gonadotropin stimulation. Adrenocorticotropic hormone is necessary but not sufficient for adrenarche to occur. Premature adrenarche occurs when the increase in DHEAS level occurs at a younger than average age, and early growth of pubic hair soon follows.