10th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology
Puberty : Physiology
Jean-Michel Dubuis
Division d'Endocrinologie et Diabétologie Pédiatriques Hôpital des Enfants H.U.G. Genève
PUBERTY
From a biological perspective, puberty is the stage of physical maturation in which an individual becomes physiologically capable of sexual reproduction. The biological changes that occur during puberty include several neurosecretory factors and/or hormones, all of which modulate somatic growth, the development of the sex glands, and their endocrine as well as exocrine secretions.
The resultant increase in sex steroid production will ensure the appearance and maintenance of sexual characteristics and the capacity for reproduction. The entire endocrine system is altered during adolescence. However, it is essentially the activation of the hypothalamic-pituitary-gonadal axis that induces and enhances the progressive ovarian and testicular sex hormone secretion that are responsible for the profound biological, morphological, and psychological changes to which the adolescent is subjected.
Puberty proceeds through five stages from childhood to full maturity (P1 to P5) as described by Marshall and Tanner. In both sexes, these stages reflect the progressive modifications of the external genitalia and of sexual hair. Secondary sex characteristics appear at a mean age of 10.5 years in girls and 11.5 to 12 years in boys.
Puberty is considered precocious if these changes are noted prior to 8 years of age in girls and 9 years of age in boys and is considered delayed when such changes do not occur prior to 13 years of age in girls and 14 years of age in boys.
Secondary sexual development in girls involves the enlargement of the ovaries, uterus, vagina, labia, and breasts and growth of pubic hair. A discrete budding of the breast appears at first and usually follows a short-lived prepubertal slowing in growth kinetics. Between 11 and 14.5 years of age, the typical adolescent growth spurt takes place, and acne is frequent.
Initially, a small breast subareolar nodule is observed, followed within approximately 6 months by the appearance of pubic hair and, shortly thereafter, axillary hair. A progressive increase in breast size, sexual hair, and genital development with the vaginal mucosa becoming more humid, of a darker pink colour, and taking on a secretory appearance will follow. The uterus increases in size up to stage P4 when the first menstruation occurs, and the maximal growth rate is reached.
Most girls reach menarche around 12.5 to 13 years of age; however, its occurrence may be as early as 10 or as late as 15 years of age in otherwise-normal girls.
First ovulatory cycles usually occur at a median age of 9 to 10 months after menarche. However, the time sequence in the appearance of sex characteristics may vary. If breast development, pubic and/or axillary hair, and menses occur earlier than normal variations from the mean, the terms premature thelarche, pubarche and/or adrenarche, and menarche are used. Puberty is completed usually within 3 to 4 years of its onset, and the final height resulting from complete fusion of the epiphyses occurs within approximately 2 years after menarche.
Growth kinetics are enhanced from early puberty, however maximal velocity is attained only around 14 to 15 years of age. Progressively, the testis increases in size, mainly at the expense of the seminiferous tubules. The interstitial (Leydig) cells develop and ensure synthesis and secretion of testosterone. A testicular volume of 4 ml or a longitudinal diameter greater than or equal to 2.5 cm and a slight progressive increase in scrotal folds and pigmentation constitute the first signs of puberty. Then the progression of pubertal development including penile size follows in close relation to the secretion of testosterone (stage P3), followed by the growth of pubic hair several months later. Axillary hair appears around 13 years of age with characteristic body odour and lowering of the voice pitch, and acne is frequent. Finally, although prostatic development is initiated earlier, spermarche occurs at a mean age of 14 years.
In prepubertal children, no significant luteinizing hormone (LH) or follicle-stimulating hormone (FSH) response to intravenous or subcutaneous administration of GnRH is observed. During adolescence, the LH response to GnRH increases progressively in both sexes. The increase of FSH is much less marked than that of LH. The primary triggering mechanism that initiates the activation of the hypothalamic-pituitary-gonadal axis at puberty is still hypothetical. One of the important neuroendocrine mechanisms that control the onset of puberty is probably an increase in the frequency of GnRH pulse stimulation of the pituitary. Whatever the mechanism, the process is not abrupt but develops over several years, as evidenced by slowly rising plasma concentrations of the gonadotropins and testosterone or estrogens.
The first demonstrable biological change of puberty is the appearance of pulsatile LH release during sleep. As puberty progresses, the frequency and amplitude of LH secretory peaks increase, although peaks are also found during the wake period. At the end of puberty, the difference between sleep and wake LH secretory patterns disappears. In girls, circulating FSH levels increase progressively from 10 to 11 years of age (stage P2), approximately 1 year prior to those of LH. Thereafter, gonadotropins continue to increase throughout puberty, but important fluctuations are observed in relation to the menstrual cycle. In boys, a significant increase in both plasma FSH and LH is also found from the onset of puberty (stage P2), closely linked to the rapid increase in testicular size characteristic of this pubertal stage. A further significant increase in circulating gonadotropins is also observed at late puberty (stages P4 and P5).
Serum prolactin concentrations increase modestly during female puberty but remain stable in boys. The physiological role of prolactin in the course of puberty, if any, is unknown.
Adrenal androgens vary from infancy through adolescence. This phenomenon is called adrenarche. In girls, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) increase as early as 6 to 7 years of age, followed within 1 to 2 years by a concomitant increase in androstenedione.
In boys, DHEA and DHEAS increase as early as 8 to 9 years of age, followed by androstenedione 1 to 2 years later. Adrenarche begins before the rise in gonadotropin secretion. The adrenal androgens are responsible for the appearance of axillary hair and, in part, for the appearance of pubic hair in the adolescent; however they do not appear to play a decisive role in determining the initiation of puberty.
The rising levels of plasma gonadotropins stimulate the ovary to produce increasing amounts of estradiol. Estradiol is responsible for the development of secondary sexual characteristics, that is, growth and development of the breasts and reproductive organs, fat redistribution (hips, breasts), and bone maturation. The maturation of the ovary at adolescence correlates well with estradiol secretion and the stages of puberty.
In prepuberty, the ovarian size volume extends from 0.5 cm3 (0.3 to 0.9 cm3) to 1.0 cm3 or more, indicating that puberty has begun. During puberty, the ovarian size increases rapidly to a mean postpubertal volume of 4.0 cm3 (1.8 to 5.3 cm3).
The prepubertal uterus is tear-drop shaped, with the neck and isthmus accounting for up to two-thirds of the uterine volume; then, with the production of estrogens, it becomes pear shaped, with the uterine body increasing in length and thickness proportionately more than the cervix.
During puberty, plasma estradiol levels fluctuate widely, probably reflecting successive waves of follicular development that fail to reach the ovulatory stage. The uterine endometrium is affected by these changes and undergoes cycles of proliferation and regression, until a point is reached when substantial growth occurs so that withdrawal of estrogen results in the first menstruation (menarche). Plasma testosterone levels also increase at puberty although not as markedly as in males. Plasma progesterone remains at low levels even if secondary sexual characteristics have appeared. A rise in progesterone after menarche is, in general, indicative that ovulation has occured. The first ovulation does not take place until 6-9 months after menarche because the positive feedback mechanism of estrogen is not developed.
The increase in testicular size observed during prepuberty and puberty results essentially from the development of the seminiferous tubules under the stimulating effect of FSH. The testicular volume increases throughout puberty up to Tanner stage P4 when a longitudinal diameter of 5.0 + 0.5 cm or a volume of 17.6 + 4.0 ml is reached.
Long-standing pulsatile LH secretion induces the differentiation of interstitial cells into testosterone-secreting Leydig cells, which, in turn, exert a negative feedback control on LH secretion. As puberty progresses, spermatogenesis is initiated and then sustained by FSH and by testosterone produced by the Leydig cells under LH control. A significant increase of plasma testosterone is found only between Tanner pubertal stages P3 and P4. Dihydrotestosterone shows a pattern similar to that of testosterone, and the proportion of dihydrotestosterone to testosterone decreases gradually until adulthood, when dihydrotestosterone levels are approximately 10% of those of testosterone.
There is accumulating evidence that GH plays a role in pubertal development.
In experimental animals, GH seems to stimulate FSH-induced differentiation of granulosa cells directly, increase ovarian levels of IGF-I, and amplify the ovarian response to gonadotropins. IGF-I, in turn, enhances the gonadotropin effect on the granulosa cell, and GH seems to act synergistically with a still-developing pattern of gonadotropin secretion to facilitate ovarian maturation postmenarche. It also appears that the local production or accumulation of GH and IGF-I exerts an intraovarian paracrine control on steroidogenesis.
Puberty of patients with isolated GH deficiency is frequently delayed, Leydig cell function is diminished, and the response to chorionic gonadotropins is decreased. GH administration can restore testicular responsiveness to LH and Leydig cell steroidogenesis.
Growth hormone-releasing factor (GRF) levels and GH secretion increase considerably during puberty, mainly at night. The amplitude of GH peaks increases early in puberty. IGF-I is an important modulator of growth during childhood and adolescence. Adrenal androgens seem to have no physiological role in normal growth. The characteristic pubertal growth spurt results mainly from the synergetic effect of gonadal sex steroids, growth hormone, and IGF-I production, with all showing a significant increase at the time of pubertal growth acceleration.
Insulin is also important for normal growth. Plasma insulin levels increase throughout childhood, but the rise is particularly pronounced during puberty with a strong positive correlation with IGF-I.