Physiology 5th Ed.

SEXUAL DIFFERENTIATION

Sexual differentiation includes the development of the gonads, internal genital tract, and external genitalia. “Maleness” or “femaleness” can be characterized in three ways: (1) genetic sex, whether the sex chromosomes are XY or XX; (2) gonadal sex, whether the gonads are testes or ovaries; and (3) phenotypic or genital sex, whether the person looks like a male or a female (Fig. 10-1).

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Figure 10–1 Determination of genetic sex, gonadal sex, and phenotypic sex.

Genetic Sex

Genetic sex is determined by the sex chromosomes—XY in males and XX in females. During the first 5 weeks of gestational life, the gonads are indifferent or bipotential—they are neither male nor female. At gestational weeks 6 to 7 in genetic males, the testes begin to develop; at gestational week 9 in genetic females, the ovaries begin to develop. Therefore, genetic sex normally determines gonadal sex, and the gonads appear in males slightly before they appear in females.

Gonadal Sex

Gonadal sex is defined by the presence of either male gonads or female gonads, namely, the testes or the ovaries. The gonads comprise germ cells and steroid hormone–secreting cells.

The testes, the male gonads, consist of three cell types: germ cells, Sertoli cells, and Leydig cells. The germ cells produce spermatogonia, the Sertoli cells synthesize a glycoprotein hormone called antimüllerian hormone, and the Leydig cells synthesize testosterone.

The ovaries, the female gonads, also have three cell types: germ cells, granulosa cells, and theca cells. The germ cells produce oogonia. The meiotic oogonia are surrounded by granulosa cells and stroma, and in this configuration, they are called oocytes. They remain in the prophase of meiosis until ovulation occurs. The theca cells synthesize progesterone and, together with the granulosa cells, synthesize estradiol.

There are two key differences between the male and female gonads that influence phenotypic sex: (1) The testes synthesize antimüllerian hormone, and the ovaries do not; and (2) the testes synthesize testosterone, and the ovaries do not. Antimüllerian hormone and testosterone are decisive in determining that the fetus will be a phenotypic male. If there are no testes and, therefore, no antimüllerian hormone or testosterone, the fetus will become a phenotypic female by “default.”

Phenotypic Sex

Phenotypic sex is defined by the physical characteristics of the internal genital tract and the external genitalia. In males, the internal genital tract includes the prostate, seminal vesicles, vas deferens, and epididymis. The external genitalia in males are the scrotum and the penis. In females, the internal genitalia are the fallopian tubes, uterus, and upper one third of the vagina. The external genitalia in females are the clitoris, labia majora, labia minora, and lower two thirds of the vagina. As previously noted, phenotypic sex is determined by the hormonal output of the gonads as follows:

image Male phenotype. Gonadal males have testes that synthesize and secrete antimüllerian hormone and testosterone, both of which are required for the development of the male phenotype. Embryologically, the wolffian ducts give rise to the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts. Testosterone, which is present in gonadal males, stimulates the growth and differentiation of the wolffian ducts. Testosterone from each testis acts ipsilaterally (same side) on its own wolffian duct. In this action on the wolffian ducts, testosterone does not have to be converted to dihydrotestosterone (discussed later in chapter). At the same time, antimüllerian hormone produced by testicular Sertoli cells causes atrophy of a second set of ducts, the müllerian ducts. (The müllerian ducts would have become the female genital tract if they had not been suppressed by antimüllerian hormone.) The external male genitalia, the penis and scrotum, differentiate at gestational weeks 9 to 10. Growth and development of the external male genitalia depend on conversion of testosterone to dihydrotestosterone and the presence of androgen receptors on the target tissues (Box 10-1).

BOX 10–1 Clinical Physiology: Androgen Insensitivity Syndrome

DESCRIPTION OF CASE. A girl who is apparently normal begins to develop breasts at age 11, and at age 13, she is considered to have larger-than-average breasts among her peers. However, by age 16, she has not begun to menstruate and has scant pubic and axillary hair. Upon pelvic examination, a gynecologist notes the presence of testes and a short vagina, but no cervix, ovaries, or uterus. Chromosomal evaluation reveals that the girl has an XY genotype. Suspecting a form of androgen insensitivity syndrome (a testicular feminization), the physician orders androgen-binding studies in genital skin fibroblasts. The studies show no binding of testosterone or dihydrotestosterone, suggesting that androgen receptors in the tissue are absent or defective. She has mildly elevated levels of plasma testosterone and elevated levels of luteinizing hormone (LH). The young woman’s testes are removed, and she is treated with intermittent estrogen replacement therapy. She is advised, however, that she will never have menstrual cycles or be able to bear children.

EXPLANATION OF CASE. This girl has a female phenotype with female external genitalia (lower vagina, clitoris, and labia). At puberty, she develops breasts. However, she has a male genotype (XY) and male gonads (testes).

The basis for her disorder, a form of androgen insensitivity syndrome, is lack of androgen receptors in target tissues, which results in resistance to androgens. Her testes, which are normal, secreted both antimüllerian hormone and testosterone in utero. As in normal males, antimüllerian hormone suppressed development of the müllerian ducts in utero; therefore, the girl has no fallopian tubes, uterus, or upper vagina. The testes also secreted testosterone in utero, which should have stimulated growth and differentiation of the wolffian ducts into the male genital tract and development of the male external genitalia. The male genital tract and external genitalia did notdevelop, however, because the target tissues lack androgen receptors. Thus, although the testes secreted normal amounts of testosterone, testosterone could not act on the tissues of the male genital tract. (Lack of androgen receptors also explains the girl’s scant body hair at puberty.) The female phenotype (short vagina, labia, and clitoris) is present because, in the absence of testosterone receptors, the fetus became a phenotypic female by “default.”

The girl’s breasts developed at puberty because her testes are producing estradiol from testosterone, stimulated by the high circulating levels of LH. The estradiol then promotes breast development.

TREATMENT. In androgen insensitivity syndrome, because the testes can develop a neoplasm, they are removed. Following removal of the testes (and, therefore, removal of the testicular source of estradiol), the girl is treated with estrogen therapy to maintain her breasts. She will not be able to bear children, however, because she lacks ovaries and a uterus.

image Female phenotype. Gonadal females have ovaries that secrete estrogen, but they do not secrete antimüllerian hormone or testosterone. Thus, in females, no testosterone is available to stimulate growth and differentiation of the wolffian ducts into the internal male genital tract, and no antimüllerian hormone is available to suppress differentiation of the müllerian ducts. Consequently, the müllerian ducts develop into the internal female tract (fallopian tubes, uterus, and upper one third of the vagina). Like the internal genital tract, the development of the external female genitalia (clitoris, labia majora, labia minora, and lower two thirds of the vagina) does not require any hormones, although growth of these structures to normal size depends on the presence of estrogen.

  If a gonadal female is exposed to high levels of androgens in utero (e.g., from excessive production by the adrenal cortex) when the external genitalia are differentiating, then a male phenotype results. If such exposure occurs after differentiation of the external genitalia, the female phenotype is retained, but perhaps with enlargement of the clitoris (Box 10-2).

BOX 10–2 Clinical Physiology: Congenital Adrenal Hyperplasia

DESCRIPTION OF CASE. At birth, a baby is found to have ambiguous external genitalia. There is no penis, and a clitoris is significantly enlarged. Chromosomal evaluation reveals that the baby has an XX genotype. She is found to have ovaries but no testes. Tests confirm that the baby has a form of adrenal hyperplasia in which there is congenital lack of the adrenal cortical enzyme 21β-hydroxylase. Treatment involves surgical reconstruction of the external genitalia to conform to the female phenotype and the administration of glucocorticoids and mineralocorticoids. The child will be raised as a female.

EXPLANATION OF CASE. The baby has a congenital absence of 21β-hydroxylase, the adrenal enzyme that normally converts steroid precursors to mineralocorticoids and cortisol (see Chapter 9Fig. 9-23). As a result of this defect, steroid precursors accumulate behind the enzyme block and are directed toward the production of the adrenal androgens, dehydroepiandrosterone and androstenedione. The high levels of androgens caused masculinization of the external genitalia (enlargement of the clitoris) in utero. The genotype is XX (female), and the internal organs are female including ovaries, fallopian tubes, uterus, and upper vagina. The fallopian tubes, uterus, and upper vagina developed because, without testes, there was no source of antimüllerian hormone to suppress differentiation of müllerian ducts into the female genital tract. There is hyperplasia of the adrenal cortex because the absence of cortisol increases secretion of adrenocorticotropic hormone (ACTH), which then has a trophic effect on the adrenal cortex.

TREATMENT. Surgical correction of the ambiguous external genitalia involves reconstruction to conform to a phenotypic female. Because the baby has normal ovaries, fallopian tubes, and uterus, she should begin normal menstrual cycles at puberty and have a normal reproductive capacity. Hormone replacement therapy has two goals: (1) to replace the missing adrenal glucocorticoids and mineralocorticoids and (2) to suppress ACTH secretion (by the negative feedback of glucocorticoids on the anterior pituitary) to reduce the adrenal output of androgens and prevent further masculinization.