Medical Physiology A Cellular and Molecular Approach, Updated 2nd Ed.


Ervin E. Jones

One of nature’s primary goals is perpetuation of the species. All living organisms must reproduce in some manner. Nature also favors those species that are able to produce diversification among members, an attribute critical to species survival as the nature of environmental (and other) stresses changes through time. One solution to this problem is sexual differentiation, that is, the evolution of two sexually dissimilar individuals belonging to the same species, one male and one female, and each equipped with its own specific attributes necessary for its particular contribution to the process of procreation. Each sex produces its own type of sex cell (gamete), and the union of male and female gametes generates species-specific progeny. In addition, mechanisms, some simple, some complex, have evolved to ensure the proximity and union of the sex cells (syngamy). Thus, within each species, the relevant sexual characteristics of each partner have adapted differently to achieve the most efficient union of these progenitor cells. These differences between the sexes of one species are called sexual dimorphism. For example, oviparous species such as frogs release their eggs into a liquid medium only when they are in relative proximity to sperm. As effective as this approach is, it also typifies the wastefulness of reproduction among higher species inasmuch as most gametes go unfertilized. (See Note: Definitions of Sex and Gender)

Even among species that normally reproduce sexually, sexual dimorphism is not universal. For example, monoecious (i.e., hermaphroditic) species, such as cestodes and nematodes, have the capacity to produce both sperm and eggs. By definition, the ability to produce just one kind of gamete depends on sexually dimorphic differentiation.

Throughout evolution, conservation and expression of genes involved in the perpetuation of a species have clearly followed a process of adaptation, which is an advantageous change in structure or function of an organ or tissue to meet the challenges of new conditions. Higher mammals normally have a single pair of sex chromosomes that are morphologically distinguishable from other chromosomes, the autosomes. Each of the sex chromosomes carries genetic information that determines the primary and secondary sexual characteristics of an individual, that is, whether the individual functions and appears as male or female. It has also become abundantly clear that genes determine gender, sexual expression, and as a result, mechanisms and patterns of reproduction.

The functional and spatial organization of all organ systems during development is genetically determined. Thus, the sex of the gonad is genetically programmed: Will a female gonad (ovary) or a male gonad (testis) develop? Although germ cells of the early embryonic gonad are totipotent, these cells develop into female gametes (ova) if the gonad becomes an ovary, but they develop into male gametes (sperm) if the gonad becomes a testis. These two anatomically and functionally distinct gonads determine either “maleness” or “femaleness” and dictate the development of both primary and secondary sexual characteristics. Endocrine and paracrine modulators that are specific for either the ovary or the testis are primarily responsible for female or male sexual differentiation and behavior and therefore the individual’s role in procreation.


Meiosis, which occurs only in germ cells, gives rise to male and female gametes

Mitosis is the only kind of cell division that occurs in somatic cells. Mitosis results in the formation of two identical daughter cells (Fig. 53-1A), each having the same number of chromosomes (i.e., 46 in humans) and same DNA content as the original cell. Mitosis is a continuum consisting of five phases: prophase, prometaphase, metaphase, anaphase, and telophase. One reason for the genetic identity of the two daughter cells is that no exchange of genetic material occurs between homologous chromosomes, so sister chromatids (i.e., the two copies of the same DNA on a chromosome) are identical. A second reason for the genetic identity is that the sister chromatids of each chromosome split, one going to each daughter cell during anaphase of the single mitotic division.


Figure 53-1 Mitosis and meiosis. A, In mitosis, the two daughter cells are genetically identical to the mother cell. B, In male meiosis, the four daughter cells are haploid. Cell division I produces both recombination (i.e., crossing over of genetic material between homologous chromosomes) and the reduction to the haploid number of chromosomes. Cell division II separates the chromatids of each chromosome, just as in mitosis. C, Female meiosis is similar to male meiosis. A major difference is that instead of producing four mature gametes, it produces only one mature gamete and two polar bodies. (See Note: Meiosis in Males versus Females)

Meiosis occurs only in germ cells. After having undergone several mitotic divisions, the germ cells (spermatogonia in males and oogonia in females)—still with a complement of 2N DNA (N = 23)—undergo two meiotic divisions in both males (Fig. 53-1B) and females (Fig. 53-1C) to reduce the number of chromosomes from the diploid number (2N = 46) to the haploid number (N = 23). Because of this halving of the diploid number of chromosomes, meiosis is often referred to as a reduction division. Meiosis is a continuum composed of two phases: the homologous chromosomes separate during meiosis I, and the chromatids separate during meiosis II. At the start of meiosis I, the chromosomes duplicate so that the cells have 23 pairs of duplicated chromosomes (i.e., each chromosome has two chromatids)—or 4N DNA. During prophase of the first meiotic division, homologous pairs of chromosomes—22 pairs of autosomal chromosomes (autosomes) in addition to a pair of sex chromosomes—exchange genetic material. This genetic exchange is the phenomenon of crossing over that is responsible for the recombination of genetic material between maternal and paternal chromosomes. At the completion of meiosis I, the daughter cells have a haploid number (23) of duplicated, crossed-over chromosomes—or 2N DNA. During meiosis II, no additional duplication of DNA takes place. The chromatids simply separate so that each daughter receives a haploid number of unduplicated chromosomes—1 N DNA. A major difference between male and female gametogenesis is that one spermatogonium yields four spermatids (Fig. 53-1B), whereas one oogonium yields one mature oocyte and two polar bodies (Fig. 53-1C). The details emerge for spermatogenesis in Chapters 54 and 55. When two haploid gametes fuse, a mature spermatozoon from the father and a mature oocyte from the mother, a new individual is formed, a diploid zygote—2 N DNA.

When an X- or Y-bearing sperm fertilizes an oocyte, it establishes the zygote’s genetic sex

The sex chromosomes that the parents contribute to the offspring determine the genotypic sex of that individual. The genotypic sex determines the gonadal sex, which, in turn, determines the phenotypic sex that becomes fully established at puberty. Thus, sex-determining mechanisms established at fertilization direct all later ontogenetic processes (processes that lead to the development of an organism) involved in male-female differentiation.

The process of fusion of a sperm and an ovum is referred to as fertilization, which is discussed in Chapter 55. Fusion of a sperm and egg—two haploid germ cells—results in a zygote, which is a diploid cell containing 46 chromosomes (Fig. 53-2), 22 pairs of somatic chromosomes (autosomes) and a single pair of sex chromosomes. In the female, these sex chromosomes are both X chromosomes, whereas males have one X and one Y chromosome.


Figure 53-2 Normal human karyotype. The normal human has 22 pairs of autosomal chromosomes (autosomes) as well as a pair of sex chromosomes. Females have two X chromosomes, whereas males have one X and one Y chromosome. (See Note: Karyotype)

When the karyotypes of normal females and males are compared, two differences are apparent. First, among the 23 pairs of chromosomes in the female, 8 pairs—including the 2 X chromosomes—are of similar size, whereas males have only 7½ such pairs. Second, instead of a second X chromosome, males have a Y chromosome that is small and acrocentric (i.e., the centromere is located at one end of the chromosome); this chromosome is the only such chromosome that is not present in the female.

In the offspring, 23 of the chromosomes—including 1 of the sex chromosomes—are from the mother, and 23—including the other sex chromosome—come from the father. Thus, the potential offspring has a unique complement of chromosomes differing from those of both the mother and father. The ovum provided by the mother (XX) always provides an X chromosome. Because the male is the heterogenetic (XY) sex, half the spermatozoa are X bearing, whereas the other half are Y bearing. Thus, the type of sperm that fertilizes the ovum determines the sex of the zygote. X-bearing sperm produce XX zygotes that develop into females with a 46, XX karyotype, whereas Y-bearing sperm produce XY zygotes that develop into males with a 46, XY karyotype. The genetic sex of an individual is therefore determined at the time of fertilization. The Y chromosome appears to be the fundamental determinant of sexual development. When a Y chromosome is present, the individual develops as a male; when the Y chromosome is absent, the individual develops as a female. In embryos with abnormal sex chromosome complexes, the number of X chromosomes is apparently of little significance.

Differentiation of the indifferent gonad into an ovary requires two intact X chromosomes

The primary sex organs of an individual are the gonads. Gene complexes on sex chromosomes determine whether the indifferent gonad differentiates into a testis or an ovary. As discussed later, the Y chromosome exerts a powerful testis-determining effect on the indifferent gonad. The primary sex cords differentiate into seminiferous tubules under the influence of the Y chromosome. In the absence of a Y chromosome, the indifferent gonad develops into an ovary. The differentiated gonads, in turn, determine the sexual differentiation of the genital ducts and external genitalia.

The indifferent gonad is composed of an outer cortex and an inner medulla. In embryos with an XX sex chromosome complement, the cortex develops into an ovary, and the medulla regresses. Conversely, in embryos with an XY chromosome complex, the medulla differentiates into a testis, and the cortex regresses. Loss of a sex chromosome causes abnormal gonadal differentiation or gonadal dysgenesis. Loss of one of the X chromosomes of the XX pair results in an individual with an XO sex chromosome constitution and ovarian dysgenesis (see the box titled Gonadal Dysgenesis). Thus, two X chromosomes are necessary for normal ovarian development. In an XO individual, the gonads appear only as streaks on the pelvic sidewall in the adult. Because these streak gonads of XO individuals may contain germ cells, germ cell migration apparently can occur during development. The absence of only some genetic material from one X chromosome in an XX individual—for example, as may occur as a result of breakage or deletion—may also cause abnormal sexual differentiation.

Gonadal Dysgenesis

The best known example of gonadal dysgenesis is a syndrome referred to as Turner syndrome, a disorder of the female sex characterized by short stature, primary amenorrhea, sexual infantilism, and certain other congenital abnormalities. The cells in these individuals have a total number of 45 chromosomes and a normal karyotype, except they lack a second sex chromosome. The karyotype is 45, XO. Examination of the gonads of individuals with Turner syndrome reveals so-called streak gonads, which are firm, flat, glistening streaks lying below the fallopian tubes. These glands generally do not show evidence of either germinal or secretory elements but, instead, are largely composed of connective tissue arranged in whorls suggestive of ovarian stroma. Individuals with Turner syndrome have normal female differentiation of both the internal and external genitalia, although these genitalia are usually small and immature for the patient’s age.

Partial deletion of the X chromosome may also result in the full Turner phenotype, particularly if the entire short arm of the X chromosome is missing.

The so-called ring chromosome is an example of an abnormality of the second sex chromosome. A ring chromosome is a small round or oval chromosome that often appears as a single black dot without a central hole. It forms as a result of a deletion and subsequent joining of the two free ends of the chromosome. Formation of a ring chromosome is, in effect, a deletion of the X chromosome and produces the same characteristics as gonadal dysgenesis.

The aforementioned defects result from disordered meiosis. A central genetic lesion is an abnormality of the second sex chromosome in some or all of the cells of the person. In at least half of affected individuals, this abnormality appears to be total absence of the second X chromosome. In others, the lesion is structural, as shown by the presence of ring chromosomes that have lost some genetic material. In at least a third of cases, these lesions appear as parts of a mosaicism; that is, some of the germ cells carry the aberrant or absent chromosome, whereas the rest are normal.

The testis-determining gene is located on the Y chromosome

Investigators have clearly established that a Y chromosome (Fig. 53-3A), with rare exception (see later), is necessary for normal testicular development. Thus, it stands to reason that the gene that determines organogenesis of the testis is normally located on the Y chromosome. This so-called testis-determining factor (TDF) has been mapped to the short arm of the Y chromosome and, indeed, turns out to be a single gene called SRY (for Sex-determining Region Y). The SRY gene encodes a transcription factor that belongs to the high-mobility group (HMG) superfamily of transcription factors. The family to which SRYbelongs is evolutionarily ancient. One portion of SRY, the 80–amino acid HMG box, which actually binds to the DNA—is highly conserved among members of the family.


Figure 53-3 The location of the testis-determining region of the Y chromosome and an example of translocation. A, The Y chromosome is much smaller than the X chromosome. Giemsa staining of the chromosome results in alternating light and dark bands, some of which are shown here. The short or p arm of the Y chromosome is located above the centromere, whereas the long or q arm is located below it. The numbers to the left of the chromosome indicate the position of bands. The TDF is the SRY gene. B, Crossing-over events between normal X and Y chromosomes of the father can generate an X chromatid that contains a substantial portion of the TDF region and a Y chromatid that lacks its TDF. The figure shows both an equal and an unequal recombination event. If a sperm cell bearing an X chromosome with a translocated TDF fertilizes an ovum, the result is a male with a 46, XX karyotype, because one of the X chromosomes contains the TDF. Conversely, if the sperm cell carries a Y chromosome lacking its TDF, the result can be a 46, XY individual that appears to be female.

Rarely, the TDF may also be found translocated on other chromosomes. One example is an XX male (Fig. 53-3B), an individual whose sex chromosome complement is XX but whose phenotype is male. During normal male meiosis, human X and Y chromosomes pair and recombine at the distal end of their short arms. It appears that most XX males arise as a result of an aberrant exchange of genetic material between X and Y chromosomes in the father; in such cases, the TDF is transferred from a Y chromatid to an X chromatid. If the sperm cell that fertilizes the ovum contains such an X chromosome with a TDF, the resultant individual will be an XX male.

Endocrine and paracrine messengers modulate phenotypic differentiation

Just as an individual’s genes determine whether the indifferent gonad develops into an ovary or a testis, so does the sex of the gonad dictate the gonad’s endocrine and paracrine functions. Normally, chemical messengers—both endocrine and paracrine—produced by the gonad determine the primary and secondary sexual phenotypes of the individual. However, if the gonads fail to produce the proper messengers, if other organs (e.g., the adrenal glands) produce abnormal levels of sex steroids, or if the mother is exposed to chemical agents (e.g., synthetic progestins, testosterone) during pregnancy, sexual development of the fetus may deviate from that programmed by the genotype. Therefore, genetic determination of sexual differentiation is not irrevocable; numerous internal and external influences during development may modify or completely reverse the phenotype of the individual, whatever the genotypic sex.

An abnormal chemical environment can affect sexual differentiation at the level of either the genital ducts or the development of secondary sex characteristics. Higher vertebrates, including humans, have evolved highly elaborate systems of glands and ducts for transporting gametes. This system of glands and conduits collectively comprises the accessory sex organs. Together with the gonads, these accessory sex organs constitute the primary sex characteristics. The gonads produce and secrete hormones that condition and develop these accessory sex organs and, to a large extent, influence phenotypic sexual differentiation; that is, they induce either “maleness” or “femaleness” and influence the psychobiological phenomena involved in sex behavior.

Secondary sex characteristics are external specializations that are not essential for the production and movement of gametes; instead, they are primarily concerned with sex behavior and with the birth and nutrition of offspring. Examples include the development of pubic hair and breasts. Not only do the sex steroids produced by the gonads affect the accessory sex organs, but they also modulate the physiological state of the secondary sex characteristics toward “maleness” in the case of the testes and “femaleness” in the case of the ovaries.


After migration of germ cells from the yolk sac, the primordial gonad develops into either a testis or an ovary

The primordial germ cells do not originate in the gonad; instead, they migrate to the gonad from the yolk sac along the mesentery of the hindgut at about the fifth week of embryo development (Fig. 53-4A, B). The primordial germ cells of humans are first found in the endodermal epithelium of the yolk sac in the vicinity of the allantoic stalk, and from there the germ cells migrate into the adjoining mesenchyme. They eventually take up their position embedded in the gonadal ridges. Gonadal development fails to progress normally in the absence of germ cells. Thus, any event that interferes with germ cell migration may cause abnormal gonadal differentiation.


Figure 53-4 The early gonad and germ cell migration. A, The primordial germ cells originate in the endodermal endothelium of the yolk sac. B, The primordial germ cells migrate along the mesentery of the hindgut and reach the region of the urogenital ridge called the gonadal ridge. C, The indifferent gonad consists of an outer cortex and an inner medulla. D, The testis develops from the medulla of the indifferent gonad; the cortex regresses. E, The ovary develops from the cortex of the indifferent gonad; the medulla regresses.

Discordance Between Genotype and Gonadal Phenotype

A group of individuals has been reported to have no recognizable Y chromosome but do have testes. Some of these individuals are 46, XX and are true hermaphrodites; that is, they possess both male and female sex organs. Other patients have mixed gonadal dysgenesis—a testis in addition to a streak ovary—and a 45, XO karyotype. Some are pseudohermaphrodites; that is, affected individuals have only one type of gonadal tissue, but morphological characteristics of both sexes. All these patterns can result from mosaicisms (e.g., 46, XY/46, XX) or from translocation of the SRY gene (Fig. 53-3B)—which normally resides on the Y chromosome—to either an X chromosome or an autosome. A “normal” testis in the absence of a Y chromosome has never been reported.

Another group of individuals with a sex chromosome complex of 46, XY has pure gonadal dysgenesis—streak gonads, but no somatic features of XO. In the past, investigators assumed that these individuals possessed an abnormal Y chromosome. Perhaps the SRY gene is absent, or its expression is somehow blocked.

The gonad forms from a portion of the coelomic epithelium, the underlying mesenchyme, and the primordial germ cells that migrate from the yolk sac. At 5 weeks’ development, a thickened area of coelomic epithelium develops on the medial aspect of the urogenital ridge as a result of proliferation of both the coelomic epithelium and cells of the underlying mesenchyme. This prominence, which forms on the medial aspect of the mesonephros, is known as the gonadal ridge (Fig. 53-4B, C).

Migration of the primordial germ cells to the gonadal ridge establishes the anlagen for the primordial gonad. The primordial gonad at this early stage of development consists of both a peripheral cortex and a central medulla (Fig. 53-4C) and has the capacity to develop into either an ovary or a testis. As discussed later, the cortex and medulla have different fates in the male and female. The germ cells themselves seem to direct the sexual development of the gonad. An embryo with an XY chromosome complement undergoes development of the medullary portion of the gonad to become a testis, and the cortex regresses. Conversely, XX germ cells appear to stimulate development of the cortex of the early gonad to become an ovary, and the medulla regresses.

Development of the Primitive Testis In male embryos, primordial germ cells migrate from the cortex of the gonad, in which they were originally embedded, into the primitive sex cords of the medulla (Fig. 53-4D). The primitive sex cords become hollowed out and develop into the seminiferous tubules. The primordial germ cells give rise to spermatogonia, the first cells in the pathway to mature sperm (see Chapter 54). The sex cords give rise to the Sertoli cells. The rete testis is a system of thin, interconnected tubules that develop in the dorsal part of the gonad; they drain the seminiferous tubules. The contents of the rete testis flow into the efferent ductules, which—as discussed later—develop from the adjoining tubules of the mesonephros. These tubular structures establish a pathway from the male gonad to the mesonephric duct, which—as also discussed later—evolves into the outlet for sperm. The cortex of the primordial gonad is a thin epithelial layer covering the coelomic surface of the testis.

Development of the Primitive Ovary In female embryos, the medulla of the gonad regresses, the primary sex cords are resorbed, and the interior of the gonad is filled with a loose mesenchyme that is highly permeated by blood vessels. However, the cortex greatly increases in thickness, and the primordial germ cells remain embedded within it (Fig. 53-4E). Masses of cortical cells are split up on the inner surface of the cortex into groups and strands of cells, or secondary sex cords, surrounding one or several primordial germ cells, or oogonia, during growth of the gonad. These germ cells become primary oocytes that enter the initial stages of oogenesis.

The embryonic gonad determines the development of the internal genitalia and the external sexual phenotype

As discussed in the next section of this chapter, several products of the developing male or female gonad have profound effects on differentiation of the internal sex ducts, as well as on development of the external genitalia. Thus, just as genetic sex determines the gonadal phenotype, so also products of the gonad primarily determine the sexual phenotype. Androgens produced by the developing testis cause development of the mesonephric or wolffian ducts. The paramesonephric or müllerian ducts degenerate in the male under the influence of antimüllerian hormone (AMH). In the female embryo, the müllerian ducts develop, whereas the wolffian ducts degenerate. In the absence of a functioning testis, the left and right müllerian ducts develop according to the female phenotype, that is, as the fallopian tubes (oviducts), the uterus, and the upper third of the vagina (see the next section).

Just as the absence of male hormones or androgens causes the internal genital ducts to follow a female pattern of differentiation, so also the absence of androgens causes the external genital development to be female. Conversely, testosterone and dihydrotestosterone (DHT) cause masculinization of the external genitalia (see the later section on differentiation of the external genitalia).


The genital ducts are an essential part of the genital organs and are the means by which the sex cells—ova and spermatozoa—are transported to a location where fertilization occurs. As discussed in the previous section, embryos of both sexes have a double set of genital ducts (Fig. 53-5A): the mesonephric or wolffian ducts, which in males develop into the vas deferens and other structures; and the paramesonephric or müllerian ducts, which in females become the oviducts, uterus, and upper third of the vagina.


Figure 53-5 Transformation of the genital ducts. A, At the time the gonad is still indifferent, it is closely associated with the mesonephros, as well as the excretory duct (mesonephric or wolffian duct) that leads from the mesonephros to the urogenital sinus. Parallel to the wolffian ducts are the paramesonephric or müllerian ducts, which merge caudally to form the uterovaginal primordium. B, In males, the mesonephros develops into the epididymis. The wolffian duct develops into the vas deferens, seminal vesicles, and ejaculatory duct. The müllerian ducts degenerate. C, In females, the mesonephros and the wolffian (mesonephric) ducts degenerate. The paramesonephric or müllerian ducts develop into the fallopian tubes, the uterus, the cervix, and the upper one third of the vagina.

During mammalian development, three sets of kidneys develop, two of which are transient. The pronephric kidney, which develops first, is so rudimentary that it never functions. However, the duct that connects the pronephric kidney to the urogenital sinus—the pronephric duct—eventually serves the same purpose for the second kidney, the mesonephric kidney or mesonephros, as it develops embryologically. Unlike the pronephric kidney, the mesonephros functions transiently as a kidney. It has glomeruli and renal tubules; these tubules empty into the mesonephric duct (Fig. 53-5A), which, in turn, carries fluid to the urogenital sinus. As discussed later, the mesonephros and its mesonephric duct will—depending on the sex of the developing embryo—either degenerate or develop into other reproductive structures. In addition to the mesonephric ducts, a second pair of genital ducts, the paramesonephric or müllerian ducts, will develop as invaginations of the coelomic epithelium on the lateral aspects of the mesonephros. These paramesonephric ducts run caudally and parallel to the mesonephric ducts. In the caudal region, they cross ventral to the mesonephric ducts and fuse to form a cylindrical structure, the uterovaginal canal. The third or metanephric kidney becomes the permanent mammalian kidney. Its excretory duct is the ureter.

In males, the mesonephros becomes the epididymis, and the mesonephric (wolffian) ducts become the vas deferens, seminal vesicles, and ejaculatory duct

During development, the mesonephros ceases to be an excretory organ in both sexes. The only part that remains functional is the portion—in males—that develops into the most proximal end of the epididymis, the efferent ductules. As the mesonephros degenerates, persisting mesonephric tubules develop into many parallel efferent ductules that connect the upstream rete testis to the head of the epididymis, which serves as a reservoir for sperm.

The mesonephric ducts develop into the channels through which the spermatozoa exit the testes (Fig. 53-5B). The most proximal portion of the mesonephric duct becomes the head, the body, and the tail of the epididymis. The tail of the epididymis connects to the vas deferens, which also arises from the wolffian duct. A lateral outgrowth from the distal end of the mesonephric duct forms the seminal vesicle. The portion of the mesonephric duct between the seminal vesicle and the point where the mesonephric duct joins the urethra becomes the ejaculatory duct. At about the level where the ejaculatory duct joins with the urethra, multiple outgrowths of the urethra grow into the underlying mesenchyme and form the prostate gland. The mesenchyme of the prostate gives rise to the stroma of the prostate, whereas the prostatic glands develop from endodermal cells of the prostatic urethra.

In females, the paramesonephric (müllerian) ducts become the fallopian tubes, the uterus, and the upper third of the vagina

In female embryos, both the mesonephros and the wolffian (mesonephric) ducts degenerate. The müllerian ducts establish three functional regions (Fig. 53-5C). The cranial portions of the müllerian ducts remain separate and give rise to the fallopian tubes. The upper end of the duct gains a fringe, which will become the fimbria, by adding a series of minor pits or müllerian tunnels. The midportions of the left and right müllerian ducts fuse and give rise to the fundus and corpus of the uterus. The most distal portions of the bilateral müllerian ducts had previously fused as the uterovaginal primordium. The cranial portion of this common tube gives rise to the cervix and remains the longest portion of the uterus until puberty. The caudal portion of this common tube becomes the upper third of the vagina.

In males, development of the wolffian ducts requires testosterone

As already noted, the developing embryo has two precursor duct systems (Fig. 53-6A). In a normal male embryo (Fig. 53-6B), the wolffian ducts develop, whereas the müllerian ducts regress. In a normal female embryo (Fig. 53-6C), the müllerian ducts develop, whereas the wolffian ducts regress. It appears that maturation of one of these systems and degeneration of the other depend on local factors produced by the developing gonad.


Figure 53-6 Jost experiments. A, Very early in development, both the wolffian (mesonephric) and the müllerian (paramesonephric) ducts are present in parallel. B, The wolffian duct develops into the vas deferens, the seminal vesicles, and the ejaculatory duct. The müllerian ducts degenerate. C, The paramesonephric or müllerian ducts develop into the fallopian tubes, the uterus, the cervix, and the upper one third of the vagina. The wolffian (mesonephric) ducts degenerate. D, Bilateral removal of the testes deprives the embryo of both AMH (also known as MIS) and testosterone, which are both testicular products. As a result of the absence of AMH, the müllerian ducts follow the female pattern of development. In the absence of testosterone, the wolffian ducts degenerate. Thus, the genetically male fetus develops female internal and external genitalia. E, After bilateral removal of the ovaries, müllerian development continues along normal female lines. Thus, the ovary is not required for female duct development. F, Unilateral removal of the testis results in female duct development on the same (ipsilateral) side as the castration. Duct development follows the male pattern on the side with the remaining testis. Virilization of the external genitalia proceeds normally. G, In the absence of both testes, administering testosterone preserves development of the wolffian ducts. However, because of the absence of AMH—which is a product of the testis—no müllerian regression occurs. H, In the presence of both ovaries, the testosterone promotes development of the wolffian ducts. Because there are no testes—and therefore no AMH—the müllerian ducts develop normally.

A classic series of experiments performed by Alfred Jost in 1953 revealed that masculine genital development requires factors produced by fetal testicular tissue. The experimental approach was to castrate rabbit fetuses at various stages of development and allow the pregnancies to continue. Castrating a male fetus before maturation of the wolffian ducts caused the müllerian ducts to persist (i.e., fail to regress) and induced the development of female internal and external genitalia (Fig. 53-6D). However, castrating female fetuses at a comparable stage in development had no appreciable effect, and müllerian development continued along normal female lines (Fig. 53-6E). Thus, although normal male development requires the testes, development of the fallopian tubes and uterus does not require the ovaries.

Unilateral removal of the testis resulted in female duct development on the same (ipsilateral) side as the castration, but virilization of the external genitalia proceeded normally (Fig. 53-6F). Removing both testes—and administering testosterone—resulted in essentially normal development of the wolffian ducts, but no müllerian regression was seen (Fig. 53-6G). Thus, although testosterone can support wolffian development, it is unable to cause müllerian regression. It became clear that a testicular product other than testosterone is necessary for regression of the müllerian ducts. Thus, one would predict that treating a normal female with testosterone would lead to preservation of the wolffian ducts, as well as the müllerian ducts. This pattern of dual ducts is indeed observed (Fig. 53-6H).

In males, antimüllerian hormone causes regression of the müllerian ducts

After Jost, other investigators performed experiments indicating that the Sertoli cells of the testis produce a nonsteroid macromolecule—AMH or müllerian-inhibiting substance (MIS)—that causes müllerian degeneration in the male fetus. AMH, a growth-inhibitory glycoprotein, is a member of the transforming growth factor β (TGF-β) superfamily of glycoproteins involved in the regulation of growth and differentiation (see Chapter 3). Besides TGF-β, this gene superfamily includes the inhibins and activins (see Chapter 55). The proteins produced by this gene family are all synthesized as dimeric precursors and undergo post-translational processing for activation. AMH is glycosylated and is secreted as a 140-kDa dimer consisting of two identical disulfide-linked subunits. The antimitogenic activity and müllerian duct bioactivity of AMH reside primarily in its C-terminal domain.

The human AMH gene is located on chromosome 19, and AMH is one of the earliest sexually dimorphic genes expressed during development. The transcription factor SRY, which represents the TDF, may be involved in initiating the transcription of AMH. The sequential timing of SRY and AMH expression is consistent with activation of AMH by SRY, a series of events that may control sexual dimorphism.

Although the exact mechanism of AMH action has not been completely clarified, it is thought to involve receptor-mediated dephosphorylation. AMH appears to act directly on mesenchymal cells of the müllerian duct and, indirectly through the mesenchyme, on müllerian duct epithelial cells. AMH binding has been localized to the mesenchymal cells surrounding the müllerian duct and to the developing oocytes in preantral follicles.

During embryogenesis in males, AMH—which is secreted by the Sertoli cells in the testis—causes involution of the müllerian ducts, whereas testosterone—which is secreted by the Leydig cells of the testis—stimulates differentiation of the wolffian ducts. In females, the müllerian ducts differentiate spontaneously in the absence of AMH, and the wolffian ducts involute spontaneously in the absence of testosterone.


The urogenital sinus develops into the urinary bladder, the urethra, and, in females, the vestibule of the vagina

Early in embryologic development, a tubular structure called the cloaca is the common termination of the urogenital and gastrointestinal systems (Fig. 53-7A). The cloacal membrane separates the cloaca from the amniotic fluid. Eventually, a wedge of mesenchymal tissue separates the cloaca into a dorsal and a ventral cavity (Fig. 53-7B). The dorsal cavity is the rectum. The ventral compartment is the urogenital sinus. Both the wolffian and the müllerian ducts empty into this urogenital sinus (Fig. 53-5A).


Figure 53-7 Differentiation of the urogenital sinus. A, The urorectal septum begins to separate the rectum (dorsal) from the urogenital sinus (ventral). The urogenital sinus is divided into a vesicle (i.e., urinary bladder) part, a pelvic part, and a phallic part. The common space into which the rectum and urogenital sinus empty—the cloaca—is closed by the cloacal membrane. B, At this stage, the rectum and the urogenital sinus are fully separated. The urogenital membrane separates the urogenital sinus from the outside of the embryo. C, The male has a common opening for the reproductive and urinary tracts. The prostatic utricle, which is the male homologue of the vagina, empties into the prostatic urethra. D, A solid core of tissue called the vaginal plate grows caudally from the posterior wall of the urogenital sinus. The lumen of the vagina forms as the center of this plate resorbs. Thus, the female has separate openings for the urinary and reproductive systems.

The urogenital sinus can be divided into three regions: the vesicle part, the pelvic part, and the phallic part. In the male (Fig. 53-7C), the vesicle part becomes the urinary bladder, the pelvic part becomes the prostatic part of the urethra, and the phallic part becomes the initial portion of the penile urethra.

In the female (Fig. 53-7D), the vesicle part of the urogenital sinus also develops into the urinary bladder. The pelvic part becomes the entire female urethra. The phallic portion of the urogenital sinus develops into the vestibule of the vagina; into this vestibule empty the urethra, the vagina, and the ducts of the greater vestibular glands of Bartholin.

As noted earlier, fusion of the caudal portion of the müllerian ducts produces the uterovaginal primordium. As this primordium contacts the dorsal wall of the urogenital sinus, it induces the development of paired sinovaginal bulbs, which grow into the urogenital sinus and then fuse to form a solid core of tissue called the vaginal plate. This plate grows caudally to the phallic portion of the urogenital sinus. Resorption of the center of the vaginal plate creates the vaginal lumen. The remaining cells of the vaginal plate appear to form the vaginal epithelium. During early fetal development, a thin membrane, the hymen, separates the lumen of the vagina from the cavity of the urogenital sinus. Usually, the hymen partially opens during the prenatal period. Occasionally, the hymenal membrane persists completely, does not allow escape of the menstrual effluvium at menarche, and gives rise to a condition known clinically as hematocolpos.

In the male, the vagina disappears when the müllerian ducts are resorbed. However, remnants of the vagina sometimes persist as a prostatic utricle.

The external genitalia of both sexes develop from common anlagen

Although anatomically separate precursors give rise to the internal genitalia, common anlagen give rise to the external genitalia of the two sexes (Fig. 53-8A). Knowledge of the common origins of the external genitalia during normal development facilitates understanding of the ambiguities of abnormal sexual development.


Figure 53-8 Development of the external genitalia. A, Genital folds and genital swellings surround the cloacal membrane. B, Early in the fourth week of development—in both sexes—the genital tubercle begins to enlarge to form the phallus. C, In males, the genital tubercle becomes the glans penis. The urogenital folds fuse to form the shaft of the penis. The labioscrotal swellings become the scrotum. D, In females, the genital tubercle becomes the clitoris. The urogenital folds remain separate as the labia minora. The labioscrotal swellings become the labia majora where they remain unfused. Ventrally, the labioscrotal swellings fuse to form the mons pubis. Dorsally they fuse to form the posterior labial commissure.

The genital tubercle (Fig. 53-8B) develops during the fourth week on the ventral side of the cloacal membrane. As a result of elongation of the genital tubercle, a phallus develops in both sexes. The genital tubercle of the primitive embryo develops into the glans penis in the male (Fig. 53-8C) and the clitoris in the female (Fig. 53-8D). Until about the end of the first trimester of pregnancy, the external genitalia of males and females are anatomically difficult to distinguish. The phallus undergoes rapid growth in the female initially, but its growth slows, and in the absence of androgens, the phallus becomes the relatively small clitoris in the female.

The paired urogenital folds give rise to the ventral aspect of the penis in the male (Fig. 53-8C) and the labia minora in the female (Fig. 53-8D). After formation of the urogenital opening, a groove—the urethral groove—forms on the ventral side of the phallus; this groove is continuous with the urogenital opening. The bilateral urogenital folds fuse over the urethral groove to form an enclosed spongy urethra; the line of fusion is the penile raphe. As the urogenital folds fuse to form the ventral covering of the penis, they do so in a posterior-to-anterior direction, thus displacing the urethral orifice to the tip of the penis. Elongation of the genital tubercle and fusion of the genital folds occur at the 12th to the 14th week of gestation. However, in the female, the urogenital folds normally remain separate as the labia minora.

In the male, the genital or labioscrotal swellings fuse to give rise to the scrotum. In females, however, the labioscrotal swellings fuse anteriorly to give rise to the mons pubis and posteriorly to form the posterior labial commissure. The unfused labioscrotal swellings give rise to the labia majora.


The SRY gene triggers development of the testis, which makes the androgens and AMH necessary for male sexual differentiation

I already noted that the female pattern of sexual differentiation occurs in the absence of testes. In fact, the embryo follows the female pattern even in the absence of all gonadal tissue. It thus appears that the male pattern of sexual differentiation is directed by endocrine and paracrine control mechanisms. Therefore, I successively examine the control of testicular development, the development of the male internal system of genital ducts, and the development of the male urogenital sinus and external genitalia.

Testicular development proceeds in the presence of TDF—the gene product of the SRY gene—before 9 weeks of gestation. If TDF is not present or if TDF is present only after the critical window of 9 weeks has passed, an ovary will develop instead of a testis. Further male-pattern sexual differentiation depends on the presence of three hormones, testosterone, DHT, and AMH. The testis directly produces both testosterone and AMH. Peripheral tissues convert testosterone to DHT.

Testosterone Production The primary sex steroid produced by both the fetal and the postnatal testis is testosterone. The testes also produce DHT and estradiol, although in lesser amounts. The Leydig cells are the source of sex steroid production in the testes. The Leydig cells differentiate from mesenchymal tissue that surround the testicular cords. This tissue makes up more than half the testicular volume by 60 days of gestation. The early increase in the number of Leydig cells and secretion of testosterone in humans could depend on either maternal human chorionic gonadotropin (hCG) or fetal luteinizing hormone (LH). The human testis has its greatest abundance of side-chain–cleavage enzyme—which catalyzes the first committed step in steroid synthesis (see Fig. 50-2)—at 14 to 15 weeks of gestation and low values by 26 weeks of gestation. Because hCG follows a similar temporal pattern, it may be hCG that supports early testosterone production. Late regulation of testosterone production by fetal LH is supported by the finding that the testes of anencephalic fetuses (see the box in Chapter 10 on abnormalities of neural tube closure) at term have few Leydig cells.

The Androgen Receptor Androgens diffuse into target cells and act by binding to androgen receptors, which are present in genital tissues. In the absence of adequate androgen production or functioning androgen receptors, sexual ambiguity occurs. The androgen receptor functions as a homodimer (AR/AR) and is a member of the family of nuclear receptors (see Chapter 3). The AR/AR receptor complex is a transcription factor that binds to hormone-response elements on DNA located 5′ from the genes controlled by the androgens (see Table 4-2). Interaction between the receptor-steroid complex and nuclear chromatin causes increased transcription of structural genes, the appearance of mRNA, and subsequent translation and production of new proteins. Congenital absence of the androgen receptor, or the production of abnormal androgen receptor, leads to a syndrome known as testicular feminization (see the box on Impaired Androgen Action in Target Tissues).

Dihydrotestosterone Formation In certain target tissues, cytoplasmic 5α-reductase converts testosterone to DHT (see Fig. 54-5), which binds to the same androgen receptor as does testosterone. However, DHT binds to the androgen receptor with an affinity that is ~100-fold greater than the binding of testosterone to the androgen receptor. Moreover, the DHT-receptor complex binds to chromatin more tightly than does the testosterone-receptor complex.

Antimüllerian Hormone As noted earlier, the Sertoli cells of the testis produce AMH, also known as MIS. AMH is a homodimer of two monomeric glycoprotein subunits that are linked by disulfide bonds.

Androgens direct the male pattern of sexual differentiation of the internal ducts, the urogenital sinus, and the external genitalia

Androgens play two major roles in male phenotypic differentiation: (1) they trigger conversion of the wolffian ducts to the male ejaculatory system, and (2) they direct the differentiation of the urogenital sinus and external genitalia. The wolffian phase of male sexual differentiation is regulated by testosterone itself and does not require conversion of testosterone to DHT. In contrast, virilization of the urogenital sinus, the prostate, the penile urethra, and the external genitalia during embryogenesis requires DHT, as does sexual maturation at puberty.

Differentiation of the Duct System After formation of the testicular cords, the Sertoli cells produce AMH, which causes the müllerian ducts to regress. The cranial end of the müllerian duct becomes the vestigial appendix testis at the superior pole of the testis. Shortly after the initiation of AMH production, the fetal Leydig cells begin producing testosterone. The embryonic mesenchyme contains androgen receptors and is the first site of androgen action during formation of the male urogenital tract. The Sertoli cells also produce a substance referred to as androgen-binding protein (ABP). It is possible that ABP binds and maintains a high concentration of testosterone locally. These high local levels of testosterone stimulate growth and differentiation of the medulla of the gonad into the rete testes, as well as differentiation of the wolffian ducts into the epididymis, the vas deferens, the seminal vesicles, and the ejaculatory duct. Testosterone also promotes development of the prostate from a series of endodermal buds located at the proximal aspect of the urethra. Cells of the wolffian ducts lack 5α-reductase and therefore cannot convert testosterone to DHT. Thus, the internal male ducts respond to testosterone per se and do not require the conversion of testosterone to DHT. In the absence of testosterone, the wolffian system remains rudimentary, and normal male internal ductal development does not occur.

Congenital Adrenal Hyperplasia

Ambiguous genitalia in genotypic females may result from disorders of adrenal function. Several forms of congenital adrenal hyperplasia have been described, including the deficiency of several enzymes involved in steroid synthesis (see Fig. 50-2): the side chain–cleavage enzyme, 17α-hydroxylase, 21α-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase. Deficiencies in 21α-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase all lead to virilization in females—and thus ambiguous genitalia—as a result of the hypersecretion of adrenal androgens. 21α-Hydroxylase deficiency, by far the most common, accounts for ~95% of cases. Some of the consequences of this deficiency are discussed in the box on 21α-hydroxylase deficiency in Chapter 50.

As summarized in Figure 50-2, 21α-hydroxylase deficiency reduces the conversion of progesterone to 11-deoxycorticosterone—which goes on to form aldosterone—and also reduces the conversion of 17α-hydroxyprogesterone to 11-deoxycortisol—which is the precursor of cortisol. As a result, adrenal steroid precursors are shunted into androgen pathways. In female infants, the result is sometimes called the adrenogenital syndrome. The external genitalia are difficult to distinguish from male genitalia on visual inspection. The clitoris is enlarged and resembles a penis, and the labioscrotal folds are enlarged and fused and resemble a scrotum. The genitalia thus have a male phenotype in an otherwise normal female infant.

Differentiation of the Urogenital Sinus and External Genitalia The cells of the urogenital sinus and external genitalia, unlike those of the wolffian duct, contain 5α-reductase and are thus capable of converting testosterone to DHT. Indeed, conversion of testosterone to DHT is required for normal male development of the external genitalia. Congenital absence of 5α-reductase (see the box titled Impaired Androgen Action in Target Tissues) is associated with normal development of the wolffian duct system but impaired virilization of the external genitalia.

At ~9 weeks’ gestation, soon after virilization of the internal genital ducts of the male, development of the external genitalia commences. It is completed by 13 weeks of gestation. In the presence of high intracellular concentrations of DHT, the genital tubercle, the bipotential predecessor to either a clitoris or a penis, elongates to become the glans penis, the corpus spongiosum, and the two corpora cavernosa. Formation of the penis and scrotum is complete by ~13 weeks, and even extremely high concentrations of testosterone after this time fail to cause midline fusion of the urethral groove or scrotum, although the clitoris will enlarge. The urogenital sinus gives rise to the prostate and the bulbourethral glands, also under the influence of DHT.

In the absence of androgen secretion by the fetal testis—or abnormal extragonadal sources—the indifferent external genitalia remain unfused and follow the female pattern of differentiation.

Androgen Dependence of Testicular Descent

In preparation for descent, the testes enlarge. In addition, the mesonephric kidneys and wolffian (mesonephric) ducts atrophy. This process frees the testes for their future move down the posterior abdominal wall and across the abdomen to the deep inguinal rings. Testicular descent occurs in three phases during the last two thirds of gestation. During the first stage of testicular descent, rapid growth of the abdominopelvic region causes relative movement of the testes down to the inguinal region (Fig. 53-9A). The role of the gubernaculum—the ligament attaching the inferior part of the testes to the lower segment of the labioscrotal fold—is uncertain. However, the gubernaculum shortens and appears to guide the testis to its place of ultimate functional residence in the scrotum. The second stage of testicular descent is herniation of the abdominal wall adjacent to the gubernaculum (Fig. 53-9B). This herniation, which occurs as a result of increasing abdominal pressure, forms the processus vaginalis; the processus vaginalis then folds around the gubernaculum and creates the inguinal canal. In the third stage, the gubernaculum increases to the approximate diameter of the testis. As its proximal portion degenerates, the gubernaculum draws the testis into the scrotum through the processus vaginalis (Fig. 53-9C).


Figure 53-9 Testicular descent.

The testes usually complete their descent by the seventh month of gestation; ~97.5% of full-term infants and 79% of premature infants have fully descended testes at birth. At 9 months of age, only 0.8% of male infants have undescended testes. The incidence of undescended testes in young men is 0.2%.

Testicular descent is an androgen-dependent process, and development of the structures involved in testicular descent depends on testosterone. Thus, in testosterone-deficient states caused by inadequate secretion or disordered androgen action, the testes of genetic males often fail to descend. This abnormality can be seen in individuals with both 5α-reductase deficiency and complete androgen resistance (i.e., testicular feminization syndrome).

Androgens and estrogens influence sexual differentiation of the brain

Anatomically sexually dimorphic nuclei have been identified in the diencephalons of rodents and lower primates. Gonadal steroids influence the development of these sexually dimorphic nuclei. Androgens do not act directly on the hypothalamus and other areas of the brain having to do with sex behavior and control of gonadotropin secretion. Rather, aromatase—which catalyzes the formation of estrone and estradiol (see Fig. 55-10)—converts androgens to estrogens in the brain. Thus, androgens in the brain serve as prohormones for estrogens. Therefore, estrogens are derived from androgens that appear to masculinize sexually dimorphic nuclei directly in the brain. It is not clear why, in females, estrogens do not masculinize the brain.

Gonadal steroids affect sex behavior in both males and females. In rodents, lordosis behavior in females and mounting behavior in males are examples of sex behavior. An example of functional sexual dimorphism in the human brain is the manner in which gonadotropin is released. Gonadotropin release has been described as cyclic in the female and tonic in the male inasmuch as females have midcycle cyclic release of gonadotropin before ovulation, whereas males seem to have a continuous tonic pattern of gonadotropin release. Although controversy continues over the role of prenatal virilization in the determination of sexual dimorphism, sex steroids clearly have an impact on sexual behavior and sexual reference in humans.

The appearance of secondary sex characteristics at puberty completes sexual differentiation and development

Although at birth humans have the primary and secondary sex organs necessary for procreation, final sexual maturity occurs only at puberty. Profound alterations in hormone secretion during the peripubertal period cause changes in the primary and secondary sex organs. The events occurring in puberty are discussed in more detail for both males (see Chapter 54) and females (see Chapter 55).

Impaired Androgen Action in Target Tissues

As already discussed, in the absence of androgens, male embryos follow a typically female pattern of sexual development. However, such a female developmental pattern can occur even if testosterone levels are normal or elevated. Any defect in the mechanisms by which androgens act on target tissues—in genotypic males—may lead to a syndrome of male pseudohermaphroditism. Affected individuals have a normal male karyotype (46, XY) and unambiguous male gonads but ambiguous external genitalia, or they may phenotypically appear as female. In principle, impaired androgen action could result from a deficiency of the enzyme that converts testosterone to DHT in target tissues, absent androgen receptors, qualitatively abnormal receptors, a quantitative deficiency in receptor levels, or postreceptor defects. The two major forms that have been identified clinically are defects in the conversion of testosterone to DHT (5α-reductase deficiency) and androgen receptor defects. (See Note: 5 αReductase DeficiencyAndrogen-Receptor Defects)

Female The vagina reflects the effects of estrogens on the vaginal mucosa. The uterus and cervix enlarge, and their secretory functions increase under the influence of estrogen. The uterine glands increase in number and length, and the endometrium and stroma proliferate in response to estrogen secretion. The cervical glands produce increasing quantities of cervical mucus, which serves to lubricate the vaginal vault. The mucous membranes of the female urogenital tract are made of stratified squamous epithelium; these membranes respond to hormones, particularly estrogens. Estrogen levels increase and cause increased epithelial proliferation with the formation of successive intermediate and superficial layers. The cells of the vaginal mucosa are transformed into superficial cells, and the thickness of the vaginal mucosa increases.

Development of the breasts occurs under the influence of a complex of hormones. Progesterone is primarily responsible for development of the alveoli, which are analogous to the acini of other exocrine glands. Estrogen is the primary stimulus for development of the duct system that connects the alveoli to the exterior. Insulin, growth hormone, glucocorticoids, and thyroxine contribute to breast development, but they are incapable of causing breast growth by themselves. Lactation is discussed in Chapter 56.

Male The penis undergoes rapid growth under the influence of testosterone secreted by the testes. The testes also increase dramatically in size in response to increasing androgen secretion at puberty.


Books and Reviews

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Haqq CM, Donahoe PK: Regulation of sexual dimorphism in mammals. Physiol Rev 1998; 78:1-33.

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Lee MM, Donahoe PK: Müllerian inhibiting substance: A gonadal hormone with multiple functions. Endocr Rev 1993; 14:152-164.

Naftolin F, Ryan KJ, Davie KJ, et al: The formation of estrogens by central neuroendocrine tissues. Recent Prog Horm Res 1975; 31:295-319.

Rebar RW: Normal and abnormal sexual differentiation and pubertal development. In Moore TR, Reiter RC, Rebar RW, Baker VV eds: Gynecology and Obstetrics: A Longitudinal Approach, New York: Churchill Livingstone, 1993: 97-146.

Journal Articles

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Judd HL, Hamilton CR, Barlow JJ, et al: Androgen and gonadotropin dynamics in testicular feminization syndrome. J Clin Endocrinol Metab 1972; 34:229-234.

New MI, Dupont B, Pang S, et al: An update of congenital adrenal hyperplasia. Recent Prog Horm Res 1981; 37:105-181.

Sinclair AH, Berta P, Palmer MS, et al: A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 1990; 346:240-244.

Turner HH: A syndrome of infantilism, congenital webbed neck, and cubitus valgus. Endocrinology 1938; 23:566-574.

Wilkins L: Masculinization of the female fetus due to the use of orally given progestins. JAMA 1960; 172:1028-1032.