Chromosomes

The primary event in sexual differentiation is the establishment of either a 46 XX (female) or 46 XY (male) complement () of chromosomes at fertilization. The chromosome complement will normally determine the development of the fetal gonads by controlling differentiation of the genital ridges and of the primordial germ cells which migrate into them.

X chromosomes

In a normal female one X chromosome in most cells, other than oocytes, is largely inactivated. The inactive X chromosome is represented by a heterochromatic sex chromatin (Barr) body in the cell nucleus, which can be detected in cells from a buccal smear. The gene complement on the X chromosome includes genes controlling features unrelated to sexual differentiation, including colour blindness, some blood groups, and enzymes such as phosphoglycerate kinase and glucose-6-phosphate dehydrogenase.

Y chromosomes

These are smaller than X chromosomes and contain few genes other than those involved in male differentiation.

Monosomic (XO) and trisomic (XXX, XXY) situations arise through non-disjunction, i.e. failure of the chromosomes to separate in equal numbers into daughter cells; YO is incompatible with life. When there is more than one X chromosome all but one will be largely inactive. The cells of XXY men have one and those of XXX women have two sex chromatin bodies.

Differentiation of the fetal gonads

The urogenital ridges consisting of mesenchyme, covered by coelomic epithelium, develop in the mesonephric region and become elliptical in shape. Primordial germ cells migrate from the yolk sac to the genital ridges from 6 to 12 weeks post conception; during migration they multiply by mitosis. Female and male gonads appear similar during the early stages of development but differences become apparent soon after colonization by germ cells. There is earlier definitive development of the gonads and secondary sex characteristics in a male than in a female fetus ().

Male differentiation

In the testes Sertoli cells encompass germ cells close to the mesonephric tubules and the seminiferous tubules are then formed, at 6-7 weeks. The rete testis begins to form at 7 weeks. At 8 weeks Leydig cells appear between the tubules, which make contact with the rete testis. The germ cells continue to divide mitotically. Testosterone production by the Leydig cells commences at 8-10 weeks and reaches a peak at 12 weeks, possibly stimulated by placental hCG.

Female differentiation

In the ovary the germ cells initially divide mitotically many times. The resulting cells become enclosed by granulosa cells, which are thought to be homologous with Sertoli cells, forming rows of primordial follicles. Transformation of the germ cells into oocytes begins at about 3 months with the appearance of meiotic figures; meiosis is arrested in prophase. Approximately 7 million oocytes are present in the fetal ovaries in mid-pregnancy but the number is reduced by atresia to about 1 million by term and to 300000 by the age of 7 years (). No oocytes are formed after the neonatal period. Thecal cells differentiate from the stroma when the follices are still small and become organized around growing follicles.

Not many follicles are present in the neonatal ovary of an XO female and in most cases a streak gonad is formed, although in a few cases sufficient follicles are present to allow menarche and even pregnancy to occur, not only in those with mosaicism ().

Differentiation of internal and external genitalia

The differentiation of the reproductive and urinary tracts is closely linked and an abnormality in the development of one tract is often associated with an abnormality in the other.

Two ductal systems are present in the undifferentiated phase of development -the mesonephric (wolffian) ducts, and the paramesonephric (miillerian ducts). The miillerian ducts develop at about 5 weeks post conception and run parallel to the wolffian ducts.

In the male the epididymis and accessory glands are formed from the wolffian ducts, and the miillerian ducts regress after 8 weeks post conception.

In the female the upper part of the vagina, the uterus and the fallopian tubes develop from the miillerian ducts, and the mesonephric ducts persist only as remnants in the vagina (Gartner’s duct cysts) and broad ligaments. The miillerian ducts develop caudally and cranially from approximately 5 weeks post conception and the surrounding mesenchyme develops into the musculature of the genital tract. The lower end of the ducts reaches the urogenital sinus at about 6 weeks. The miillerian ducts fuse caudally and to a certain extent cranially and the septum between them normally degenerates by about 12 weeks to form the uterovaginal canal.

The external genitalia are initially undifferentiated and are represented by the genital tubercle (phallus), the urethral groove, which is limited laterally by two urethral folds, and two scrotolabial (genital) swellings. In the male they begin to differentiate at about 8 weeks. The genital tubercle forms the penis, the genital folds fuse to form the perineal raphe and the genital swellings form the scrotum.

In the female the genital tubercle forms the clitoris and the urethral groove remains open to form the vulva. The urethral folds form the labia minora and the genital swellings the labia majora. The vaginal plate is formed at 12-13 weeks by proliferation at the site of fusion of the caudal end of the miillerian ducts and the urogenital sinus; it becomes hollow and forms the vagina.

Control of differentiation

The female type of development of internal and external genitalia is the basic pattern and normal male development is imposed by two separate secretions from the testes. An androgen, probably testosterone or dihydrotestosterone, stabilizes the wolffian ducts and the rudiments of the external genitalia. Another secretion from the fetal testes (known as anti-mullerian hormone or miillerian inhibiting factor or substance) causes degeneration of the miillerian system after 8 weeks. It appears to be a protein with a molecular weight of approximately 200000 and is secreted by fetal Sertoli cells.

In the normal female fetus, and in an XY fetus with no gonadal development (XY gonadal dysgenesis), the wolffian ducts degenerate because of lack of androgen production, and the mullerian ducts develop because no mullerian inhibiting factor is produced. In an XY fetus with either a lack of testosterone receptor protein or of the enzyme 5a-reductase, which converts testosterone to dihydrotestosterone, wolffian and mullerian duct development fail to occur because the circulating androgens are ineffective and mullerian inhibiting factor produced by the testes suppresses development of the mullerian ducts (testicular feminization). Thus, although testes are present (usually intra-abdominal), the external genitalia are female in appearance and the internal genitalia are rudimentary.

Pseudohermaphroditism

Male pseudohermaphroditism implies that the fetus is XY but that the internal and/or external genitalia are ambiguous. Similarly the term female pseudohermaphroditism implies that the chromosomes are XX and that the genitalia are partially masculinized. True hermaphroditism is rare. Pseudohermaphroditism may be due to inherited abnormalities associated with enzyme defects, or defective responses to normal sex steroid levels or to exogenous intrauterine influences such as drugs. These conditions are discussed further in Chapter 6.

Other disorders of sexual differentiation

Mullerian duct abnormalities are common (). There may be incomplete fusion of the mullerian ducts, or incomplete canalization leading to disorders such as a double uterus or a longitudinal intrauterine or vaginal septum (American Fertility Society). Vaginal aplasia may be associated with uterine aplasia and failure of development of the mullerian ducts. A transverse vaginal septum may occur at the junction of the downgrowing mullerian ducts and the epithelium of the urogenital sinus and will prevent normal outflow of blood during a menstrual period and thus lead to cryptomenorrhoea (hidden menstruation). Mullerian abnormalities are often associated with abnormalities of the renal tract (). Diethylstilboestrol was administered to large numbers of pregnant women in the United States and to a smaller number of women in the United Kingdom in the 1950s; it has been shown to cause uterine malformations (particularly a T-shaped uterine cavity) and cervical and vaginal abnormalities in the daughters of the women to whom it was given ().

Differentiation of the hypothalamus and pituitary gland

The hypothalamus and pituitary differentiate at the same time as the gonads. The hypothalamus is identifiable by 22 days and the median eminence and pars tuberalis are evident at 16 weeks. The adenohypophysis of the pituitary gland is formed from Rathke’s pouch (an outgrowth of the roof of the mouth) at 4-5 weeks and the portal vessels begin to develop from 7 weeks but the portal system is not complete until 16 weeks. The neurohypophysis is an extension of the hypothalamus which together with the adenohypophysis becomes partially enclosed in the sella turcica by 12 weeks. Gonadotrophins are released from pituitaries cultured in vitro from 13 weeks onwards, and gonadotrophin release from the cultures is stimulated by the addition of luteinizing hormone releasing hormone (). Fetal plasma follicle stimulating hormone levels are higher in females than males in the second trimester and testosterone levels are higher in males than in females; testosterone production by the testes is probably stimulated by human chorionic gonadotrophin (). Prolactin is synthesized by the fetal pituitary from the end of the first trimester.

Anencephalic fetuses do not have a hypothalamus and their gonads are less well developed than those of normal fetuses; their gonadal development is probably due to stimulation with hCG.

Endocrinology of childhood and puberty

The hypothalamus, pituitary gland and gonads are highly active during fetal life but they are much less active during infancy and childhood. Elimination of human chorionic gonadotrophin occurs within a few days of birth. follicle stimulating hormone levels rise and remain elevated at a higher level in girls than in boys until about 4 years of age, when they decline. luteinizing hormone levels are higher in the first year than later in childhood and are higher in boys than in girls.

Gonadotrophin levels in girls rise again towards the age of 10 years. follicle stimulating hormone levels increase more than luteinizing hormone levels prior to puberty. As puberty approaches, gonadotrophins are released in an increasingly pronounced pulsatile and diurnal rhythm with increased release during sleep. Gonadotrophin levels rise markedly in late childhood in children with gonadal dysgenesis ().

In girls the increase in gonadotrophin and steroid levels leads to pubertal development and the menarche. In boys the testes enlarge under the influence of increased gonadotrophin levels. The Leydig cells produce increasing amounts of androgens which stimulate pubertal development ().

 

Selections from the book: “Introduction to Clinical Reproductive Endocrinology”. Edited by Gillian C. L. Lachelin, 1991.

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