Figure Permission was not granted to electronically reproduce figure 3—3 from In: Williams Textbook of Endocrinology, 9th ed. This figure is available in the more The versatile Sertoli cell also secretes inhibin, nurtures the germ cells, expresses stem cell factor, synthesizes an androgen binding protein, and prevents meiosis.
Leydig cells are first found at about 60 days of gestation. Leydig cells secrete testosterone, the regulator of male differentiation of the wolffian ducts, urogenital sinus, and external genitalia. After differentiation of the primitive testicular cords, they rapidly proliferate during the 3rd month and the first half of the 4th month. During this period the interstitial spaces between the seminiferous tubules are crowded with Leydig cells. The onset of testosterone biosynthesis occurs at about the 9th week Siiteri and Wilson, Human chorionic gonadotropin hCG -lutein izing hormone LH receptors are present in fetal Leydig cells by at least the 12th week of gestation, an observation that suggests that the initial secretion of testosterone at about 8 to 9 of weeks gestation is independent of hCG and fetal pituitary LH.
The concentration of testosterone in the plasma of the male fetus correlates with the biosynthetic activity of the fetal testis. Clinical as well as biochemical data indicate that the hCG secreted by the syncytiotrophoblast of the placenta stimulates testosterone secretion during the critical period of male sex differentiation. The number of Leydig cells decreases after week 18 of gestation, probably by dedifferentiation. Fetal pituitary gonadotropins are essential for the continued growth and function of the fetal testis after the early period of sex differentiation.
Fetal pituitary LH seems necessary in concert with hCG for the normal growth of the differentiated penis and scrotum during the latter half of gestation and for descent of the testes. Fetal Leydig cells differ from adult Leydig cells in their morphologies, their regulatory mechanisms, and their lack of desensitization to high doses of hCG and LH.
Figure 3—4 correlates the pattern of testosterone, hCG, and fetal pituitary LH and follicle-stimulating hormone FSH concentrations during gestation with the histological changes in the fetal testis.
Figure Permission was not granted to electronically reproduce figure 3—4 from In: In sum, organogenesis of the testis involves successive differentiation of the Sertoli cell and the seminiferous tubules with envelopment of the extragonadally derived germ cells by Sertoli cells, development of the tunica albicans, appearance of Leydig cells, and differentiation of the mesonephric tubules into ductule efferentes, which connect the seminiferous tubules and network with the epididymis to provide the pathway for sperm transport at the ejaculatory duct system Grumbach and Conte, Organogenesis of the Ovaries In the absence of testis-determining genes, the gonadal primordium has an inherent tendency to develop as an ovary, provided that germ cells are present and survive.
The indifferent stage persists in the female fetus weeks after testis organogenesis begins. There is, however, continued proliferation of the coelomic epithelium and primordial germ cells, which gradually enlarge and become oogonia.
Steroid biosynthesis by the fetal ovary is meager in early and midgestation and appears to arise from hilar interstitial cells in the ovarian primordium at about the 12th week of gestation. Both female and male human fetuses are bathed in estrogens of placental origin.
The fetal ovary does not contribute significantly to circulating estrogens, which in the fetus are almost exclusively of placental origin, nor does it secrete AMH. The ovary has no documented role in differentiation of the female genital tract Grumbach and Auchus, At about the 11th to 12th week of gestation, long after differentiation of the testis in the male fetus, germ cells in the ovary begin to enter the meiotic prophase, which characterizes the transition of oogonia to oocytes and marks the onset of ovarian differentiation.
The Wnt-4 gene, at least in the mouse, acts as a suppressor of the differentiation of steroidogenic cells in the fetal ovary. Differentiation of the Genital Ducts At the 7th week of intrauterine life, the fetus is equipped with both male and female genital ducts derived from the mesonephros. More than 50 years ago Alfred Jost, the French developmental endocrinologist, demonstrated that secretions from the fetal testis played a decisive role in determining the direction of genital duct development.
Female development is not contingent on the presence of an ovary because development of the uterus and tubes occurs if no gonad is present. Thus, testosterone leads to the development of the internal genitalia and dihydrotestosterone leads to the development of the external genitalia see Figures 3—1 , 3—2 , and 3—3.
In patients with ambiguous genitalia, male genital ducts are well differentiated only in those who have testes. Females with congenital adrenal hyperplasia do not display wolffian duct differentiation, even though their external genitalia may be highly virilized in utero. It is the critical role of the testes in male duct development to provide high local concentrations of testosterone.
Male duct development is therefore deficient, even though testes may be present, in patients with severe defects in steroid biosynthesis and in XY patients whose tissues are unresponsive to testosterone Grumbach and Conte, Differentiation of External Genital and Urogenital Sinus At the 8th fetal week the external genitalia of both sexes are identical and have the capacity to differentiate in either direction. They consist of the urogenital slit bounded by periurethral folds and more laterally by labioscrotal swellings.
The urogenital slit is surrounded by genital tubercles consisting of corpora cavernosa and glans. The mucosa-lined urethral folds may remain separate, in which case they are called labia minora, or they may fuse to form a corpus spongiosum enclosing a phallic urethra.
The fleshy labioscrotal swellings may remain separate to form labia major a, or they may fuse in the midline to form the scrotum and the ventral epidermal covering of the penis.
The distinction between the clitoris and penis is based primarily on size and whether or not the labia minora fuse to form a corpus spongiosum. By the mm crown-rump stage, male and female fetuses can be distinguished by inspection of the external genitalia; in the male, the urethral folds have fused completely in the midline to form the cavernous urethra and corpus spongiosa by the 12th to 14th weeks of gestation.
Penile length in the male increases linearly at about 0. A fold increase occurs from 0. The urogenital sinus separates from a common cloaca in early fetal life. In female development, proliferation of the vesicovaginal septum pushes the vaginal orifice posteriorally so that it acquires a separate external opening; thus, no urogenital sinus as such is preserved.
The prostate gland and the urethral glands of Cowper in the male are outgrowths of the urogenital sinus, in which male differentiation is mediated by dihydrotestosterone and requires the presence of androgen receptors Grumbach and Conte, Dihydrotestosterone binds to the androgen receptor and initiates the events that lead to androgen action.
As in the case of genital ducts, there is an inherent tendency for the external genitalia and urogenital sinus to feminize in the absence of fetal gonadal secretions. Complete differentiation of the external genitalia and urogenital sinus in males occurs only if the androgen stimulus is received during the critical period of development. Dihydrotestosterone stimulates growth of the urogenital tubercle and induces fusion of the urethral folds and labial fold swelling during this critical period; it also induces differentiation of the prostate and inhibits growth of the vesicle vaginal septum, thereby preventing the development of the vagina Griffin et al.
Androgen stimulation however, can cause clitoral hypertrophy at any time during the fetal life or after birth in the female. Table 3—2 provides some examples of variations in sexual differentiation. Selected Examples of Variations in Sexual Differentiation. PUBERTY Puberty is the transitional period between the juvenile state and adulthood during which the adolescent growth spurt occurs, secondary sexual characteristics appear resulting in the striking sexual dimorphism of mature individuals , fertility is achieved, and profound psychological changes take place.
Puberty tends to be regarded as a set of physical changes arising from reactivation of the hypothalamic-pituitary-gonadotropin-gonadal apparatus the feedback system integrating nervous and hormonal signals in the hypothalamus. These changes can be timed and measured. On the other hand, adolescence is a more general and gradual coming of age that transpires during most of the second decade of life.
Physiological and hormonal processes are involved in many aspects of this growth and development, with the onset of puberty a benchmark of the passage from childhood to adolescence. Puberty is not a de novo event but rather is a phase in the continuum of development of the hypothalamic-pituitary-gonadal function from fetal life through puberty to the attainment of full sexual maturation and fertility Grumbach and Styne, Endocrine events recognized as adolescent puberty actually begin early in fetal life.
The hypothalamic-pituitary-gonadotropin-gonadal system differentiates in function during fetal life and early infancy, is suppressed to a low level of activity during childhood the juvenile pause , and is reactivated at puberty Grumbach and Kaplan, ; Grumbach and Styne, As mentioned earlier, a significant sex difference in fetal pituitary gonadotropin levels and the high circulating testosterone levels in the male fetus through the 24th week of gestation are the most prominent features of the hypothalamicpituitary-gonadotropin-gonadal system.
There is no evidence that the concentrations of estradiol or other estrogens in serum differ in male and female fetuses. Within a few minutes after birth, the concentration of LH in serum increases abruptly about fold in the peripheral blood of the male newborn but not in that of the female newborn. This short-lived surge in LH release is followed by an increase in the serum testosterone level during the first 3 hours that persists for 12 hours or more.
In the female neonate, LH levels do not increase, and FSH levels in both males and females are low in the first few days of neonatal life. After the fall in circulating placental steroid levels, especially estrogens, during the first few days after birth, serum FSH and LH levels increase and exhibit a pulsatile pattern with wide perturbations for several months.
The FSH pulse amplitude is greater in female infants, and the FSH response to hypothalamic luteinizing hormone-releasing hormone LHRH or gonadotropin-releasing hormone is higher in females than males throughout childhood; LH pulses are higher in males.
A sex difference in plasma FSA and LH values is also present in anorchid boys and agonadal girls less than three years old. The high gonadotropin concentrations in infancy are associated with a transient second wave of differentiation of fetal-type Leydig cells and increased serum testosterone levels in male infants for the first 6 months or so and with elevated estradiol levels intermittently in the first 1 to 2 years of life in females. The mean FSH level is higher in females than males during the first few years of life.
By approximately 6 to 8 months of age in the male and 2 to 3 years of age in the female, plasma gonadotropin levels decrease to low values until the onset of puberty. Thus, the restraint of the hypothalamic LHRH pulse generator and the suppression of pulsatile LHRH secretion and thus FSH and LH release attain the prepubertal level of quiescence in late infancy or early childhood and earlier in boys than in girls for reviews see Grumbach and Styne  and Grumbach and Gluckman .
The juvenile pause that interval between early childhood and the peripuberty period when the LHRH pulse generator is at a low level of activity and circulating pituitary gonadotropin levels are low is not associated with complete suppression of pituitary gonadotropin-gonadal function. Some studies have used highly sensitive immunoassays to show that both prepubertal boys and prepubertal girls have a pulsatile pattern of serum LH and FSH concentrations, with higher concentrations during the night than during the day see Mitamura et al.
The pulses are of very low amplitude compared with the increase in the pulse amplitude that occurs with the approach of puberty. There is apparently no change or only a modest one in pulse frequency with the onset of puberty Mitamura et al. A striking sex difference has been detected in prepubertal children by a highly sensitive immunoassay for estradiol in serum.
Prepubertal girls have a mean estradiol concentration of 0. During prepuberty in both sexes, serum testosterone concentrations are detectable, but at a very low level.
The higher concentration of estradiol in prepubertal girls is associated with about a 20 percent advancement in bone age and may be a factor in the earlier onset of puberty in girls. For example, a bone age of about 11 years in girls is the equivalent of a bone age of 13 years in boys.
In addition, striking sex differences exist in the gonadally synthesized glycoprotein hormone inhibins throughout development in boys and girls Andersson et al. Inhibin B concentrations are strikingly elevated in males for the first 2 years of life and show a striking increase from childhood levels to adult levels at the onset of puberty, whereas levels of inhibin B are low or undetectable in prepubertal girls, followed by a sharp increase through midpuberty and then a decline.
Data on the normal variations in pubertal development in the United States are becoming more plentiful but are still incomplete. In recent years striking ethnic differences in the time of onset of puberty have been detected for girls but not for boys Biro et al.
In girls, two distinct phenomena occur in the development of secondary sex characteristics. The development of breasts is under the control of estrogen secreted by the ovaries; the growth of pubic and axillary hair is under the influence of androgen secreted by the adrenal cortex and the ovary. Most recent data suggest that the mean age of onset of breast development in Caucasian girls is The onset of breast development in African-American girls is about 1 year earlier than that in Caucasian girls, even though the average age of menarche in a large cross-sectional study was different by only 0.
A careful review of U. The age of menarche, a well-recognized landmark of pubertal development in girls, has not changed over the past four decades Eveleth and Tanner, In African-American girls the mean age of onset of breast development apparently is 1 year earlier; while ethnic differences in fat mass maybe a factor Kumanyika, , the nature of the discordance is uncertain.
In girls as will be discussed below the onset of puberty, in retrospect, is marked by an increase in the growth rate even before breast development. The beginning of pubertal onset in boys is marked by an increase in the size of the testes, which occurs in both white and African-American boys at a mean age of about 11 years Biro et al. It is well established that the changes in the levels of sex steroid and gonadotropin secretion may precede or anticipate for some years the onset of physical changes of puberty.
The actual dimorphic physical changes of puberty are primarily the consequence of testosterone secretion by the Leydig cells in boys and of estrogen secretion by the granulosa cells in girls Grumbach and Styne,