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Chapter 4: Sexual differentiation.

CHAPTER OBJECTIVES

* Describe the sexual organization of mammalian bodies.

* Describe how sex is determined.

* Describe the development and differentiation of the gonads, genital tract, external genitalia, and secondary sex traits.

* Describe major anomalies in sexual differentiation.

OVERVIEW OF SEXUAL DIFFERENTIATION

The males and females of most animals can be distinguished by various anatomic features that are said to be sexually differentiated. A characteristic that differs in shape and function between males and females is said to be a sexually dimorphic trait. These characteristics are related to the reproductive roles of each sex. Such traits play either direct or indirect roles in sexual reproduction. Those that play direct roles include the gonads, genital ducts, and external genitalia.

The so-called secondary sex traits play indirect roles in the reproductive process. In other words, they are sexually differentiated traits that may facilitate sexual contact, but are not required for the production, transport, or fusion of gametes. Examples of secondary sex traits include sex-based differences in mammary gland development, body size, body shape, body composition, pattern of coloration, pattern of hair growth, and sexual behavior. You may recall that sexual reproduction requires the ability of individuals to recognize members of their own species as well as members of the other sex. It is likely that secondary sex traits allow males and females of a particular species to recognize each other in order to form mating pairs.

The sexual differentiation of animals involves several developmental steps that begin during embryogenesis (development of the embryo) and end with puberty (sexual maturation). In viviparous animals (i.e., most mammals) embryogenesis occurs in the uterus. In oviparous animals (birds, reptiles, amphibians, and monotreme mammals) embryogenesis occurs in the egg. Your understanding of sexual differentiation will be facilitated if you remember three important concepts.

* The sexual organization of an individual occurs in several steps.

* Each of these steps depends on the previous one.

* Almost all sexual characteristics arise from indifferent (neither male nor female) precursors.

Figure 4-1 summarizes the major steps in sexual differentiation. Briefly, chromosomal sex is determined at syngamy and reflects the genetic composition of the father's sperm cell and the mother's oocyte. The chromosomal sex determines what type of gonad develops in the embryo. This is commonly referred to as sex determination. Subsequent steps are referred to as sexual differentiation. In the first step of sexual differentiation, the differentiated gonad directs development of the genital ducts and external genitalia. By the time of birth, newborn mammals have fully differentiated genital ducts and external genitalia, but males and females are otherwise indistinguishable. However, during sexual maturation, the gonads begin producing large amounts of hormones that induce development of secondary sex traits. These characteristics are the most visible manifestations of sexual dimorphisms, and are the ones we typically rely on to identify a particular sex in humans and other animals.

A word of caution seems appropriate before we engage in a deeper discussion of sexual differentiation. Descriptions of this process typically emphasize anatomic and physiologic differences between males and females. This can promote the notion that the sexes are opposites; that is, that the sexes are somehow set against each other. Although this view has been popularized in our culture, it isn't consistent with what we know about the biology of sexual reproduction. Sexual reproduction requires cooperation between the sexes. Although it is true that the reproductive traits of males and females are clearly distinguishable, they promote complex interactions between a male and female, not antagonism. Moreover, sexually dimorphic traits usually serve similar biological functions in each sex and develop from the same embryonic structures. For example, the ovaries and testes of adult females and males serve similar physiologic functions and consist of analogous cell types that originate from the same embryonic precursor cells.

[FIGURE 4-1 OMITTED]

CHROMOSOMAL SEX

In some animals (e.g., some reptiles and fish), sex is determined by environmental conditions such as the ambient temperature that prevails during incubation of eggs. Sex determination in mammals is a more stable process; that is, sex ratios are the same regardless of environmental conditions. The sex of an individual mammal is determined by its genotype. More specifically, the type of primary and secondary sex traits expressed by an individual is due to particular genes that control sexual differentiation. A gene, the functional unit of heredity, consists of particular segment of DNA that makes up part of a chromosome. Chromosomes exist as homologous pairs; that is, two chromosomes that have similar size and shape. Chromosomes are usually studied by making a karyotype. A karyotype is produced by photographing the metaphase chromosomes of a single cell and then matching the chromosomes according to their sizes and shapes. Finally, the chromosomes are ordered according to size. Matching chromosomes is facilitated by using various imaging techniques that reveal similarities in DNA sequences. Homologous pairs of chromosomes have analogous gene sequences as well as similar sizes and shapes.

Sexually reproducing organisms have two major types of chromosomes; that is, sex chromosomes and autosomes. Sex chromosomes contain genes that are particularly important in determining whether an individual will develop ovaries or testes. There are two types of sex chromosomes in mammals: X and Y. Although the sex chromosomes are considered to be a homologous pair, there is typically a marked difference in size between the two types. The X chromosome is a medium-size chromosome with a submedial (almost in the middle) centromere. The Y chromosome resembles short, acrocentric autosomes (i.e., having the centromere near one end). The short arms (chromatids) of the X and Y chromosomes have homologous segments that pair during meiosis. This is the site at which the chiasmata form, permitting the exchange of DNA between these regions.

The standard way of making reference to an individual's karyotype is to note the total number of chromosomes followed by the type of sex chromosomes. For example, normal human males have the 46, XY karyotype, whereas normal human females have the 46, XX karyotype. The importance of the sex chromosomes in determining an individual's sex is revealed by studying various anomalies of sexual differentiation in humans. Table 4-1 lists the karyotypes and gonadal sexes of normal males and females as well as those of individuals with some of the most common anomalies. Each of these anomalies can be classified as aneuploidy; that is, the total number of chromosomes differs from that which is characteristic for a particular species. In these particular cases the discrepancy is due to variations in number of sex chromosomes. Aneuploidy can result from errors in mitosis in the zygote, or from errors in meiosis in development of the oocyte; that is, failure of chromatids or homologous pairs of chromosomes to separate.

After studying this table, it becomes clear that development of testes is associated with presence of a Y chromosome. Of particular importance is the observation that the presence of only one X chromosome results in development of ovaries. Based on this observation it is clear that a Y chromosome plays a pivotal role in testicular organogenesis. Interestingly, the ovaries of X0 individuals are not fully functional, suggesting that two X chromosomes are required for normal ovarian development. Moreover, the X chromosome contains genes that regulate vital processes; that is, embryos that lack an X chromosome (e.g., 45, 0Y) do not survive.

In somatic cells of 46, XX females, one of the X chromosomes is inactivated. The inactivation of an X chromosome is random. Gonadal cells that are precursors for gametes have only one active X chromosome, but both are active during meiosis and development of the oocyte.

Studies of human karyotypes and corresponding sex traits provide the basis for the hypothesis that the Y chromosome contains putative genes that induce development of the male gonad. Advances in molecular genetics research lead to identification of such a gene; that is, the sex-determining region of the Y chromosome (SRY). This area consists of a 35 kb region of DNA located on the short arm of the Y chromosome. Most scientists believe that this gene acts as a switch that initiates expression of other genes that direct development of the male gonad. It is likely that the genes that are activated by SRY reside on the Y chromosome as well as on autosomes. The actual gene products controlling testicular development are various peptide growth factors, some of which have been fully characterized.

The extent to which the X chromosome is involved in gonadogenesis is less clear. Apparently, the X chromosome of males is not necessary for normal testicular function. However, males with 44, XXY karyotypes have impaired spermatogenesis (production of sperm cells). In females, two X chromosomes are required for normal ovarian development. Based on these observations, it seems likely that there are particular genes that direct ovarian organogenesis, but such genes may be inhibited in the presence of genes expressed by the Y chromosome.

OVERVIEW OF EMBRYONIC DEVELOPMENT: THE PIG AS A MODEL

As noted earlier, phenotypic sex depends on gonadal sex. In order to understand how this occurs, you must become familiar with some of the major aspects of embryonic development. The pig serves as a useful model to study this process because embryogenesis in this species has been thoroughly characterized. Although the embryonic ages at which specific developmental events occur varies among mammals, the order in which they occur is similar across species.

Embryogenesis in the pig occurs between 12 days of gestation and birth (114 days). It is useful to divide this process into two periods: embryonic and fetal. The embryonic period refers to the time when the embryo prevails and begins with establishment of the body axis (i.e., distinguishable head and tail regions) and ends when males and females can be distinguished by their external genitalia; that is, between 12 and 36 days of gestation. The fetal period refers to the time after which the fetus develops. In a fetus the structures of major organ systems have differentiated and the species of the conceptus can be identified; for example, a pig embryo takes on the shape of a pig. Embryology can be an extremely difficult area of study, due to the fact that all of the anatomic systems are developing simultaneously. Our examination of embryogenesis will be simplified by the fact that we are concerned only with development of the urogenital system.

Day 17 Through 18

Figure 4-2 illustrates the major anatomic features of the pig embryo at 17 days of age. At this stage of development the embryo has rudimentary nervous, cardiovascular, urinary, and digestive systems and is intimately associated with the so-called extra-embryonic membranes; chorion, amnion, allantois, and yolk sac. Figure 4-2 shows only a portion of these membranes. A protective amniotic membrane directly surrounds the embryo, encasing it in an amniotic space. A prominent yolk sac (vitellus) protrudes from the ventral surface of the embryo and is important in providing nutrients. At this stage, an allantois is developing from the hindgut. Both the embryo and the aforementioned membranes are surrounded by the chorion (not shown). The allantois eventually grows to surround the amnion and fuses with the chorion to form the placenta in eutherian mammals.

[FIGURE 4-2 OMITTED]

Development of the reproductive system is closely related to development of the urinary system (Figure 4-3). At 17 days of age, the mesonephros, an early embryonic kidney, is a large organ consisting of a tight mass of convoluted tubules. One end of each tubule is blind and is richly supplied with capillaries that receive blood from the dorsal aorta. The other ends of these tubules drain into bilateral (one on each side) mesonephric ducts that empty into the cloaca, also known as the urogenital sinus. Two uretic buds can be seen immediately above the points where the mesonephric ducts enter the cloaca. These will develop into the metanephric kidneys (metanephroi) that become the permanent kidneys later in development. The metanephric ducts exit from these kidneys and enter the bladder. In adults these ducts are known as the ureters.

At the stage of development described in the previous paragraph, both male and female embryos have identical (undifferentiated) gonads; that is, the gonadal ridges (Figure 4-3). These appear as knots in the connective tissue located on either side of the central, dorsal aorta, above the hindgut in the lower thoracic (between neck and abdomen), and upper lumbar (lower back between the ribs and pelvis) region of the embryo. A layer of columnar-shaped cells covers the ventral surface of each genital ridge. This tissue layer is the germinal epithelium. The genital ridge is located superficial to and medial to the developing mesonephros. At this period of development, the gonads are devoid of cells that will become gametes. Primordial germ cells, the progenitors of gamete cells, originate in the inner lining of the yolk sac near the developing allantois (Figure 4-2). They migrate from the yolk sac to the genital ridges via the connective tissue of the hindgut and the mesentery which supports the hindgut. Primordial germ cells have well-defined pseudopodia (temporary protoplasmic processes) similar to amoeba, and move via amoeboid action.

[FIGURE 4-3 OMITTED]

The 18-day-old pig embryo has a well-defined genital tubercle (Figure 4-3), a swelling on the ventral surface between the umbilical cord and opening of the urogenital sinus. This will eventually form the male or female external genitalia.

Day 28

Figure 4-4a depicts major features of the genital system at day 28. Well-defined gonads appear along the medial face of each mesonephros. These are elongated structures and have a germinal epithelium that has been invaded by primordial germ cells. Microscopic examination reveals that the gonads have initiated differentiation. Two ducts can be seen along each mesonephros. The mesonephric (Wolffian) ducts drain the mesonephroi and empty into the urogenital sinus. On each side of the embryo, a smaller paramesonephric (Mullerian) duct appears between the mesonephros and mesonephric duct. At this point these ducts have blind, growing points directed toward the urogenital sinus. Finally, the genital tubercle enlarges and develops a furrow along its median (center) axis; that is, the urogenital slit (not shown).

Day 36

By day 36, the end of the embryonic period, the gonads have differentiated into either testes or ovaries (Figure 4-4b). In addition, two sets of genital ducts (Wolffian and Mullerian) are readily apparent and extend from the mesonephros to the urogenital sinus. The mesonephric kidneys have begun to retract and metanephric kidneys have enlarged and have migrated cranially (forward). A ureter can be seen draining each metanephros and emptying into the urogenital sinus. The urogenital sinus has elongated to form a tubular urethra that connects to the bladder. The external genitalia have just begun to differentiate.

[FIGURE 4-4 OMITTED]

Day 55

By 55 days of age (Figure 4-5) the mesonephros has regressed and the metanephros has begun producing urine. Each kidney is drained by a ureter that connects with the bladder. Urine is voided either through the urachus to the allantois, or through the urethra into the amniotic cavity. In the 55-day-old male fetus, (Figure 4-5a) the testes are located in the abdominal region near the lateral surface of the caudal (toward the rear) pole of the metanephroi. The paramesonephric ducts have regressed leaving only the mesonephric ducts that become connected with the testes via a few remaining tubules of the mesonephros. The mesonephric duct will become the epididymis and ductus deferens, the tubular system that allows sperm cells to be ejaculated into the urethra in adults. The genital tubercle of males has elongated and moved cranially toward the umbilical cord to form the penis and the ventral opening to the urogenital sinus has closed to form the penile urethra. The entire penis is embedded in the muscle of the ventral body wall.

[FIGURE 4-5 OMITTED]

At 55 days of age the ovaries of the female fetus are closely associated with the paramesonephric ducts (Figure 4-5b). The mesonephric ducts no longer exist. At the innermost region, the two paramesonephric ducts remain separate and form the left and right oviducts and uterine horns. In contrast, the outermost portions of the two paramesonephric ducts fuse to form the body of the uterus and part of the vagina. Changes in the genital tubercle of the female fetus is less dramatic that those of the male. The clitoris does not become closely associated with the ventral body wall, and the urogenital slit does not close. This allows formation of a vaginal opening, which is protected by the vulva.

[FIGURE 4-6 OMITTED]

Days 55 Through 114

By 55 days, the female pig fetus has assumed most of the particular form that is characteristic of its species. Although the male fetus is also recognizable as a pig, the shape of the male fetus changes dramatically during the last 20 to 25 days of pregnancy. This change is due to descent of the testes from the abdomen to the scrotum. Figure 4-6 traces the migration of the testes during this time period. Note that by day 80, the testes have moved to the bottom of the abdominal cavity in the area of the groin. A few days before birth, they have entered the scrotal swellings, which, in the pig, protrude noticeably beyond the buttocks. The details of this process will be considered later in this chapter.

DETAILS OF SEXUAL DIFFERENTIATION

The previous discussion provides a brief overview of the critical events in the sexual differentiation of mammals. Its purpose is to help you understand the temporal relationships among these developmental changes. In the next several sections, we will examine these changes in greater detail so you can understand the physiologic mechanisms that regulate them. However, before delving into these details it is helpful to review the overall regulation of sexual differentiation of the genital organs (Figure 4-7). As noted in an earlier section, differentiation of the gonads is determined by the chromosomal sex. In embryos that are genetically male, SRY induces development of testes, whereas ovaries develop in the absence of SRY. The presence of testes induces masculinization of the genital ducts and external genitalia. These effects are mediated by two testicular hormones. Testosterone, a steroid, stimulates development of the Wolffian ducts leading to formation of the epididymis and ductus deferens, the duct system that drains the testes. Anti-mullerian hormone (AMH) is a peptide that induces regression of the Mullerian ducts. Testosterone also induces masculinization of the external genitalia, but this effect depends on its conversion to dihydrotestosterone (DHT). Development of the female genitalia occurs in the absence of testosterone and AMH. Without AMH, the Mullerian ducts develop into the oviducts, uterus, and cranial vagina, and the external genitalia form the vulva, clitoris, and caudal vagina (vestibule). The lack of testosterone causes the Wolffian ducts to regress.

[FIGURE 4-7 OMITTED]
BOX 4-1 Focus on Fertility: The Jost Paradigm

Much of our current understanding of sexual
differentiation in mammals can be attributed to
the work of the French scientist, A. Jost. His work
in the late 1940s forms the basis of what is now
known as the "Jost Paradigm" of sexual
differentiation. More specifically, Jost and his
coworkers demonstrated that the embryonic
gonads influenced development of the genital
ducts via a local, humoral (relating to a body
fluid) mechanism. Figure 4-8 summarizes Jost's
experiments with rabbit embryos. As noted previously,
two indifferent genital ducts are present in
the non-differentiated embryo (Figure 4-8a). In
males (Figure 4-8b), the Wolffian ducts develop
and the Mullerian ducts regress. In females
(Figure 4-8c), the Wolffian ducts regress and the
Mullerian ducts develop. When either male or female
embryos are bilaterally castrated (both gonads are
removed), the Wolffian ducts regress and the
Mullerian ducts develop (Figure 4-8d). This observation
supports the idea that the testes are
required for Wolffian development and Mullerian
duct regression. If only one gonad is removed from
a male embryo (unilateral castration) different
duct systems develop on each side (Figure 4-8e).
More specifically, Wolffian ducts develop and
Mullerian ducts regress on the side ipsilateral to
the remaining gonad (testis), whereas Mullerian
ducts develop and Wolffian ducts regress on the
side contralateral to the gonad. Moreover, if an
embryonic testis is grafted onto one female gonad
(Figure 4-8f), Wolffian ducts develop and
Mullerian ducts regress on the side ipsilateral to
the graft; on the side without the grafted tissue,
Mullerian ducts and Wolffian ducts regress. These
two treatment groups reinforce the notion that the
testis is the source of factors that promote
Wolffian duct development and Mullerian duct
regression. They also lead to the hypothesis that
the effects are local. The idea that a humoral
mechanism is involved is supported by two
observations: 1) Mullerian duct regression does
not require direct contact between the testes and
Mullerian ducts, and 2) Mullerian duct regression
in male embryos is prevented when the testes and
Mullerian ducts are separated by dialysis membranes
that restrict diffusion of large substances
(e.g., peptides) such as AMH. Moreover, implanting
testosterone into a female gonad (not shown)
promotes development of the Wolffian ducts, but
fails to prevent development of the Mullerian
ducts. This lead Jost to propose that Wolffian duct
development is dependent on testosterone,
whereas Mullerian duct regression is caused by
some other testicular factor (i.e., a "Mullerian
duct-inhibiting substance," now known as AMH).
Based on these experiments, Jost proposed a theory
for sex determination and differentiation; that
is, that chromosomal sex determines gonadal sex
which in turn orchestrates the differentiation of
the genital ducts (part of the phenotypic sex).

[FIGURE 4-8 OMITTED]


Differentiation of the Gonads

Prior to invasion by the primordial germ cells, the embryonic gonad is sexually indifferent (Figure 4-9). It consists of mesenchymal tissue and epithelial cells that are arranged either in an outer layer covering the surface of the gonad (coelomic epithelium), or in tubules that are branches of the mesonephric duct (mesonephric tubules). Once they enter the genital ridges, the primitive germ cells induce formation of primitive sex chords; that is, columns of cells formed by proliferation and inward migration of cells from the mesonephros and coelomic epithelium. Development of the sex cords causes the genital ridges to enlarge and grow into the mesonephros. Once the primordial germ cells have entered the genital ridge, sexual differentiation of the gonad begins.

[FIGURE 4-9 OMITTED]

In the presence of the Y chromosome, mesenchymal cells located in the cortical (outer) region of the gonad condense to form the tunica albuginea, a thin layer of connective tissue that envelopes the gonad. At this time mesenchymal cells deep in the medullary (center) region of the gonad come in contact with the ingrowing tubules of the mesonephros to form seminiferous cords. The seminiferous cords engulf all of the primordial germ cells and produce a basement membrane which eventually forms a network of seminiferous tubules. The seminiferous tubules converge to form the rete testis, which connects to the mesonephric duct via the mesonephric tubules, which later become the efferent ducts. Within the cords, the primordial germ cells will give rise to spermatogonia (precursors for sperm cells), whereas the mesodermal cells from the mesonephros will develop into Sertoli cells. Clumps of mesenchymal cells between the sex cords will become vascularized and give rise to Leydig cells. It is important to note that the primordial germ cells proliferate via mitosis prior to making contact with the seminiferous cords, but cell divisions cease once these cells become engulfed by the sex cords. Mitosis resumes once spermatogonia develop.

In the absence of the Y chromosome, the primitive sex cords remain disorganized and eventually degrade in the medullary region. The primordial germ cells cluster and continue to divide in the cortical regions of the gonads and become surrounded by remaining clusters of mesenchymal cells. The primordial germ cells, with their surrounding layer of mesenchymal cells, form primordial follicles. The mesenchymal cells secrete an outer basement membrane and primordial germ cells stop dividing. Eventually, the primordial germ cells will develop into oogonia and ultimately become oocytes, whereas the mesenchymal cells within the membrane will become granulosa cells. Remaining clusters of mesenchymal cells located between follicles will become thecal cells. Unlike the developing testis, the mesonephric tubules regress away from the ovary. Remnants of these tubules remain in the adult female. Another important difference between the developing ovary and testis is that the paramesonephric duct does not invade the ovary; that is, there is no tubular system connecting the ovary with the paramesonephric duct.

The organization of sex cords and appearance of Sertoli cells in males occurs much earlier than formation of primordial follicles in females. For example, in humans signs of sexual dimorphism in the male appear at 6 weeks of gestation, whereas the female gonad resembles the indifferent gonad until the sixth month of pregnancy. The precise mechanism controlling differentiation of the gonad has not been fully characterized. However, it is clear that something other than the primordial germ cells determine the type of gonad that develops; destruction of primordial germ cells in the developing embryo does not impede development of testes or ovaries.

It is important to note that even though the male and female gonads follow different developmental paths, the organization of mesenchymal and primordial germ cells is similar for both sexes. In each case, gametes are located within a basement membrane and in close association with Sertoli or granulosa cells. Moreover, both gonads contain interstitial cells (Leydig and thecal cells, respectively).

Differentiation of the Genital Ducts

At the time of gonadal differentiation, male and female embryos have indistinguishable urogenital systems consisting of a set of two ducts (Figure 4-10). Sexual dimorphism of the genital ducts involves regression of one or the other of these ducts. Development of the male genital ducts depends on hormones produced by the testes and therefore cannot occur until differentiation of the gonad has been completed. In contrast, development of the female genital ducts is not dependent on production of hormones by the ovary. Thus it appears that there is an inherent tendency for the genital ducts to feminize.

[FIGURE 4-10 OMITTED]

Differentiation of the genital ducts in males begins shortly after gonadal differentiation (Figure 4-10). In the presence of testes, the Mullerian ducts regress and the Wolffian ducts develop into the epididymis and ductus deferens. In addition, the vesicular glands, prostate, and bulbourethral glands, accessory sex glands that contribute fluids to the ejaculate, develop at the lower sections of the Wolffian ducts near the urogenital sinus, which in the male contains the urethra.

As noted earlier, development of the male urogenital system is regulated by testicular hormones. Shortly after the organization of spermatic cords, the testes begin producing two hormones. Testosterone is produced by the interstitial Leydig cells, whereas the Sertoli cells produce AMH. Testosterone, a steroid, promotes the transformation of the Wolffian ducts into the epididymis, ductus deferens, and seminal vesicles as well as development of the prostate gland along the urogenital sinus. AMH, a peptide, causes regression of the Mullerian ducts by inducing apoptosis (programmed cell death). Development of the Wolffian ducts begins after onset of Mullerian duct regression. Testosterone and AMH influence differentiation of the genital ducts via localized actions. In other words, once released by the developing testes, they reach the genital ducts via diffusion, not by entry into the general circulatory system. Therefore, the hormones produced by a testis affect only the ducts ipsilateral to that testis.

In the presence of ovaries, and/or absence of testes, the Wolffian ducts degenerate and the Mullerian ducts differentiate to form the oviducts, uterus, and upper vagina (Figure 4-11). During this process, the rostral Mullerian ducts remain separate and form the oviducts and uterine horns, whereas the caudal ducts fuse to form the uterus and vagina. The fused ducts contact the urogenital sinus to form the uterovaginal plate, which lengthens to increase the distance between the developing uterus and the plate. At a later time the plate canalizes to form the lumen of the vagina. Interestingly, remnants of the regressing Wolffian ducts remain in the female.

Differentiation of the External Genitalia

Differentiation of the external genitalia is depicted in Figure 4-12. Development of male external genitalia begins soon after masculinization of the Wolffian ducts and is completed long before formation of external genitalia in females. As with the genital ducts, there is an inherent tendency for the external genitalia to feminize. Development of male genitalia requires a hormone which is a metabolite of testosterone; 5_-dihydrotestosterone (DHT). Both testosterone and DHT are members of a general class of steroid hormones known as androgens.

[FIGURE 4-11 OMITTED]

At the indifferent stage, the external genitalia consist of the genital tubercle, genital fold, and genital swellings (Figure 4-12). The cells of these tissues produce an enzyme (steroid 5_-reductase) that converts testosterone to the more potent DHT. In males testosterone produced by the testes diffuses into these cells and is converted to DHT. The DHT then acts to promote differentiation of these cells to form male external genitalia. Both testosterone and DHT are capable of producing these effects. However, the low concentrations of testosterone produced by the testes at this stage of development are insufficient to induce differentiation of these tissues. The more potent DHT is capable of inducing these changes at low concentrations. Cells of the Wolffian ducts do not express the 5_-reductase enzyme. Therefore it appears that masculinization of the Wolffian ducts is controlled by testosterone.

In the presence of DHT, the genital tubercle elongates and the genital folds fuse around the urethral groove to form the penis and penile urethra. These changes bring the genital swellings closer together to form the scrotum. In the absence of DHT, the genital folds do not fuse, leaving much of the urogenital sinus exposed. This results in formation of a cleft or vestibule, into which the vagina and urethra open. In females, the clitoris develops from the genital tubercle whereas the vulva, consisting of the labia majora and labia minora, develops from the genital swellings.

[FIGURE 4-12 OMITTED]

Testicular Descent

The testes descend into the scrotum late in development. In some cases (cattle and sheep) this occurs by the middle of pregnancy. In other cases, testicular descent occurs during late pregnancy, or soon after birth (pigs, humans, horses). This process can be divided into three phases; transabdominal movement, formation of the processus vaginalis, and transinguinal descent. Figure 4-13 illustrates the overall process in a schematic manner.

At the beginning of testicular descent, the testes are situated at the level of the ribs, along the mesonephros and are anchored cranially (toward the head) to the abdominal wall by a fold of peritoneum (i.e., a ligament). The testes lie in a retroperitoneal position (outside the peritoneum relative to the viscera). The caudal portion of the testis is attached to the gubernaculum, a ligament that connects the testis to the developing scrotum. Movement of the testes from the abdominal region to the inguinal (groin) region is due to three processes: degeneration of the peritoneal fold supporting the cranial part of the gonad, shortening of the gubernaculum, and increased intra-abdominal pressure due to rapid growth of the abdominal-pelvic tissues. These changes bring the testes to rest against the abdominal wall in the inguinal region (Figure 4-13a).

[FIGURE 4-13 OMITTED]

Formation of the inguinal canals is necessary for movement of the testes into the developing scrotum. As intra-abdominal pressure increases, there is a herniation of the abdominal wall near the gubernaculum. At this point a process of peritoneum pushes outward toward the scrotum (Figure 4-13a). This projection of peritoneum is called the vaginal process. Continued pressure causes the vaginal process to enlarge around the gubernaculum and form the inguinal canal. At this point the gubernaculum undergoes rapid expansion which pulls the testis toward the entrance of the inguinal canal (Figure 4-13a).

The final stage of testicular descent involves movement of the testis through the inguinal canal into the scrotum (Figure 4-13b and c). This is largely attributed to progressive degeneration of the proximal gubernaculum (near the testis). As the gubernaculum shortens, it pulls the testis into its final location. As the testis moves into the scrotum, the inguinal canals are constrained by developing inguinal rings; that is, openings in the abdominal oblique muscles. These prevent the testis from re-entering the abdominal cavity.

The testis and epididymis reside in the scrotum enveloped by two layers of peritoneum (Figure 4-13c). In the scrotum these tissues are known as the vaginal tunic. The layer that lines the interior of the scrotum is the parietal vaginal tunic. This is the abdominal peritoneum through which the testes are pushed during their descent. The layer of peritoneum in direct contact with the testis and epididymis is the visceral vaginal tunic. This is the peritoneum that covered the testis when it resided in the abdominal region. The thin space between these layers is the vaginal cavity.

Regulation of testicular descent is poorly understood. The entire process appears to be controlled by the testes, but the factor that regulates this has not been fully characterized. At one time there was consensus that testosterone and AMH regulate growth of the gubernaculum. However, recent work suggests that another hormone may direct this process. A factor that controls shortening of the gubernaculum has not been identified.

There are two common types of anomalies associated with testicular descent; cryptorchidism and inguinal hernias. Cryptorchidism is the failure of one or both testes to descend into the scrotum. Unilateral cryptorchids have only one undescended testis, whereas neither testis has descended in bilateral cryptorchids. Bilateral cryptorchids are infertile, due to the fact that sperm production by the testes is impeded at normal body temperature. However, these animals retain masculine sex traits since their undescended testes continue to produce testosterone. Inguinal hernias occur when a portion of the intestine penetrates the inguinal canal and enters the scrotum. Swine appear to be particularly prone to this condition compared to other livestock species. Approximately one in 200 male pigs develops an inguinal hernia. In young boars, these are usually repaired at the time of castration.

SECONDARY SEX TRAITS AND SEXUAL BEHAVIOR

At the time of birth, male and females possess all of the anatomic traits necessary to fulfill their reproductive roles. However, they remain incapable of reproducing until they reach puberty. Puberty refers to all the physiologic, morphologic, and behavioral changes that result from the transition of the gonads from the infantile to the adult phase. The adult gonad produces hormones known as sex steroids (e.g., testosterone and estradiol), which bring about the physical and behavioral changes associated with puberty. In individuals of both sexes a growth spurt is associated with puberty onset. This is partly dependent on the sex steroids, but other hormones are involved. Changes in body composition also occur at this time. Although such changes occur in both males and females, there are sex-related differences in these growth characteristics. Moreover, sex steroids bring about other physical changes that are sexually dimorphic; that is, secondary sex traits.

Secondary Sex Traits

You are undoubtedly familiar with development of secondary sex traits in humans. As girls and boys become sexually mature, they experience changes in the breasts, external genitalia, body hair, and voice. Other animals express comparable changes that make it possible to distinguish between males and females. Although the ages at which these changes occur vary among individuals, the sequence of these changes is consistent within a sex. For example, you are likely familiar with the fact that certain boys and girls express mature traits earlier than their peers. Nevertheless, in all children such changes follow a particular developmental sequence; for example, appearance of adult traits can only occur after the testes or ovaries show increases in testosterone or estrogen production.

Sexual Differentiation of the Brain

The brain regulates reproductive activity in two important ways. First, it controls the pituitary gland that produces hormones that govern production of gametes and hormones by the gonads. Second, the brain regulates sexual behavior, which coordinates mating. The neural mechanisms governing gonadal function and sexual behavior are sexually differentiated. More specifically, the secretory patterns of some pituitary hormones as well as behavior patterns associated with mating differ between males and females. Differentiation of the mechanisms controlling hormone secretion and behavior occurs during a so-called critical period of neuronal development. In most mammals this occurs prenatally. However, in rodents, sexual differentiation of the brain occurs during the first 5 days of life. The principles of sexual differentiation of the brain are similar to those governing differentiation of the genital ducts and external genitalia; that is, differentiation is mediated by gonadal hormones.

The brains of mammals are inherently female. If the developing brain is not exposed to testosterone during the critical period, neuronal centers controlling hormone release and behavior will develop in ways that result in female hormone patterns and female sexual behavior. Exposure to testosterone during the critical period masculinizes the brain resulting in neuronal architecture that evokes male hormone patterns and male behaviors later in life (after puberty). It is unlikely that testosterone per se induces these effects. It is generally agreed that testosterone is converted to estradiol in the brain and that it is this metabolite of testosterone that promotes development of sexual dimorphisms responsible for male behavior. This mechanism is analogous to the one controlling development of male external genitalia; that is, a metabolite of testosterone (DHT) induces development of a penis and scrotum.

Special considerations apply to discussions of sexual behavior in primates, especially humans. There is no doubt that the human central nervous system includes regions that are sexually dimorphic, and it is likely that sex steroids play a role in this differentiation. However, we are uncertain about the extent to which gonadal steroids determine the type of sexual behavior expressed by a person. Assessment of a person's sexual behavior involves four categories: 1) gender identity, 2) gender role, 3) gender orientation, and 4) cognitive differences. Gender identity refers to identification of the self as male or female. Gender role deals with differences between male and female behavior as defined by a particular culture in a particular time. Gender orientation refers to one's choice of sexual partners. Cognitive differences refer to differing cognitive abilities between males and females.

Psychosexual differences between male and female humans reflect much more than genetic differences. Environmental and social factors play important roles in determining one's sexual identity and behavior. According to early studies the play behaviors of girls who were exposed to androgens differed from girls who were not exposed to androgens. However, both groups readily identified themselves as female. In other studies, children who were reared as a sex opposite to their chromosomal and/or gonadal sex expressed a gender identity corresponding to their assigned sexes. These types of observations support the theory that gender identity corresponds to the assigned, not the biological sex. However, this notion has been challenged by a recent case involving a 46, XY identical twin whose penis was accidentally ablated during circumcision as an infant. The patient was castrated and assigned a female gender role, which he never accepted. As an adult, the patient underwent sex reassignment and now lives successfully in a male gender role. It should be noted that not all patients who undergo sex reassignment as infants reject their assigned gender roles, especially if reassignment occurs before 30 months of age. A reasonable conclusion from these cases is that androgens exert facultative (taking place under some conditions but not others) rather than deterministic (taking place under all circumstances) roles in establishing gender identity in humans.

ANOMALIES OF SEXUAL DIFFERENTIATION

A large portion of our understanding of sexual differentiation comes from studies of anomalies. Anomalies of sexual differentiation occur in all animal species, but they have been most thoroughly studied in humans. Disorders of sexual differentiation can be divided into four major categories: 1) disorders of gonadal differentiation, 2) female pseudohermaphroditism, 3) male pseudohermaphroditism, and 4) unclassified forms. We will consider only the first three types of disorders.

Disorders of gonadal differentiation are caused by irregularities in expression of genes regulating development of the gonads. Female pseudohermaphroditism occurs when the genital ducts, external genitalia, and other aspects of phenotypic sex virilize in XX females. Male pseudohermaphroditism occurs in XY males when there is a deficiency of and/or resistance to the testicular hormones that promote development of the male phenotypic sex.

Disorders of Gonadal Differentiation

These types of disorders include gonadal dysgenesis (incomplete development of the gonads) and hermaphroditism, presence of gonads that contain both ovarian and testicular tissues. Some of these disorders result in both reproductive and nonreproductive pathologies. However, we will restrict our discussion to the chromosomal, gonadal, and phenotypic sexes associated with these conditions.

Klinefelter's Syndrome

Klinefelter's syndrome is the most common form of gonadal dysgenesis (1 in 800 males). These individuals have a 47, XXY complement of chromosomes. This condition results from nondisjunction of the sex chromosomes during meiosis in parents. Although these individuals develop testes, the presence of an extra X chromosome causes malformation of the seminiferous tubules resulting in extremely low spermatozoa production. However, both the genital ducts and external genitalia are male and appear normal.

Turner's Syndrome

Turner's syndrome occurs in one of 5,000 newborn females. Over 90 percent of fetuses with this syndrome die within the first 28 weeks of pregnancy. These individuals have a 45, X complement of chromosomes. The ovaries of 45, X individuals are "streak like" and contain only fibrous stromal tissue that lacks follicles. Genital ducts and external genitalia are female, but remain infantile in appearance due to insufficient production of sex steroids by the ovaries. This also results in short stature and little to no development of secondary sex traits. Thus even adults with this condition appear to be sexually immature.

Other Types of Gonadal Dysgenesis

Gonadal dysgenesis can also occur in 46, XX and 46, XY individuals. These conditions are the result of various mutations of genes located on autosomes and/or sex chromosomes. For example, one type of ovarian dysgenesis is attributed to a mutation of an autosomal gene that regulates hormonal control of follicle growth. In contrast, mutation of the SRY gene on the Y chromosome has been associated with a particular type of testicular dysgenesis. In these cases, development of the genital ducts and external genitalia is consistent with the type of gonad present. However, maturation of the reproductive system is incomplete due to hormone deficiencies.

True Hermaphroditism

True hermaphrodites have both ovarian and testicular tissue. These tissues can be arranged in the following ways: 1) a testis on one side and an ovary on the other (20 percent); 2) two ovotestes (both ovarian and testicular tissues are present in both gonads; 30 percent); 3) testicular and ovarian tissues are present on one side and a testis or ovary is on the other (50 percent). Hermaphroditism is rare in humans; slightly more than 400 documented cases. Differentiation of the genital ducts and genitalia is quite variable. External genitalia may resemble those of normal males or females, or may be ambiguous (having characteristics of both males and females). Most hermaphrodites have a large phallus that resembles a penis more than a clitoris. However, in almost all cases there is no penile urethra; that is, the urethra is exposed on the ventral surface of the phallus (hypospadia). Labioscrotal folds are prominent on each side of the urethral opening and cryptorchidism is common. A vagina and uterus are present in most hermaphrodites, but the uterus is typically underdeveloped. In patients with ovotestes, the ovarian tissue contains follicles and is functional, whereas the testicular tissue is dysgenic. Thus these individuals express female phenotypes. In cases where the individual has a testis and ovary, genital duct development on each side is consistent with the type of gonad present. This is consistent with the hypothesis that testicular-induced differentiation of the genital ducts involves localized effects of AMH and testosterone. Although the ovaries of these individuals are usually functional, the testes do not usually support spermatogenesis.

Hermaphroditism can arise in several ways: 1) sex chromosome mosaicism, 2) chimerism, 3) Y-to-autosome or Y-to-X chromosome translocation, and 4) mutation of either X-linked or autosomal genes involved with genesis of the testis. Mosaics and chimeras have a mixture of XX and XY cell types. In mosaicism, the different cell types come from different cell lines originating from the same zygote. This is the result of errors in mitosis during early cell divisions. Chimeras also have different cell types, but these originate from different genetic sources. For example, fusion of two zygotes or transfer of cells from one twin to another can result in chimerism. The freemartin, commonly seen in cattle, is an example of this condition. This occurs when the placentas of a male and female twin fuse resulting in a conjoined circulation. This permits mixing of primordial germ cells and hemopoietic cells, causing both the male and female twins to become chimeric; that is, each possesses XX and XY cells. Sexual differentiation of the bull calf appears normal, but fertility may be suppressed once it reaches maturity. In contrast, sexual differentiation of the female twin (the freemartin) is clearly abnormal. Freemartins have dysgenic testes or ovotestes, Wolffian-duct derivatives and female external genitalia frequently characterized by an enlarged clitoris. The gonadal and phenotypic sexes of the freemartin can be explained in the following manner. The key to understanding the etiology of this condition is the fact that differentiation of the male gonad occurs before that of the female. By the time the placentas of the twins fuse and permit exchange of blood, the testes have begun to develop. In contrast the ovaries remain largely undifferentiated at this the time. Exposure of the female's presumptive ovaries to XY cells causes partial or complete virilization. Moreover, AMH and testosterone from the male fetus masculinize the genital duct system of the female twin, promoting development of the Wolffian system and degeneration of the Mullerian system.

In humans, most true hermaphrodites have 46, XX karyotypes. A small percentage of these patients are SRY positive, meaning that they have cells to which the SRY gene was translocated to an X chromosome or autosome during parental meiosis. The majority is 46, XX and SRY negative. In these cases hermaphroditism is due to mutations of genes that are activated by SRY to promote genesis of the testes.

Female Pseudohermaphroditism

Pseudohermaphroditism is characterized by discordance between an individual's gonadal and phenotypic sex. Female pseudohermaphrodites have ovaries, female genital ducts, and masculinized external genitalia. The most common cause of this condition is prenatal exposure to androgens resulting from an inherited deficiency in 21-hydroxylase, an enzyme regulating a key step in synthesis of cortisol by the adrenal glands. A deficiency of this enzyme leads to overproduction of androgens by the adrenals. The incidence of this condition is one in 50,000 persons. Virilization of the external genitalia in XX individuals can also result from other biochemical disorders, as well as exposure to exogenous androgens. If exposure by any means occurs early in the sexual differentiation process (before 12 weeks in humans) masculinization is prominent characterized by development of a penis and scrotum. Masculinizing effects are limited to hypertrophy of the clitoris when exposure occurs later in development. It is important to note that the effects of prenatal androgen exposure are limited to the external genitalia. This is due to the absence of testes. Without testes, there is no production of AMH. Thus Mullerian duct development proceeds unimpeded.

Male Pseudohermaphroditism

Pseudohermaphroditism in males is characterized by presence of testes without complete masculinization of the genital ducts and/or external genitalia. This is caused by either a deficiency in testosterone production or insensitivity to testosterone. Various conditions can result in a failure of the testes to produce testosterone. These will become apparent later when we discuss the hormonal control of reproduction. Without testosterone, neither the Wolffian ducts nor the penis and scrotum will develop. In addition, the testes will remain in the abdominal cavity. The same situation occurs in patients whose tissues do not respond to testosterone even though their testes produce the hormone. This latter condition is known as complete androgen resistance. The ability of a hormone to affect a particular cell (target cell) depends on the presence of receptors; that is, cellular proteins that specifically bind with a hormone to evoke particular biochemical responses. Resistance to androgens is due to an X-linked disorder that results in a deficiency of androgen receptors or an impaired interaction between androgen and its receptor. This type of male pseudohermaphroditism occurs in one of every 20,000 males.

Genetic males who do not produce testosterone or who are completely resistant to it have bilateral (undescended) testes, but the Wolffian ducts are either absent or underdeveloped. They also lack a uterus, but have a blind vagina. This can be explained by the fact that the testes produce AMH, which causes regression of the Mullerian ducts. Adults with this syndrome develop female secondary sex characteristics, but do not exhibit menstrual cycles.

Resistance to androgens can be incomplete (due to less pronounce disruption of androgen-receptor interactions), resulting in intermediate degrees of feminization, ranging from sexually ambiguous to underdeveloped male external genitalia. In all cases, Mullerian derivatives are absent and Wolffian ducts are underdeveloped.

Deficiencies in AMH can also occur, but this is rare compared to deficiencies in androgens; only 150 documented cases. The condition may be caused by lack of AMH production, and/or resistance to AMH. In either case, males have testes and normal male external genitalia. However, they also express Mullerian-derived genital ducts (oviducts and uterus), which are typically pulled into the inguinal canals and block full testicular descent. The condition is usually discovered when patients are undergoing repair of cryptorchidism or inguinal hernia.

One of the more striking types of male pseudohermaphroditism is 5[alpha]-reductase deficiency; that is, the inability to convert testosterone to DHT. Patients with this syndrome are genetic males with functional testes and male genital ducts. However, due to the inability to convert testosterone into the more potent DHT, the external genitalia remain feminized. At birth these individuals express external genitalia that consist of a small phallus with a ventral opening to a blind vaginal pouch. The testes are undescended and remain in the inguinal or labial regions. At puberty, testicular production of testosterone increases producing levels that are sufficient to masculinize the external genitalia. In addition to appearance of secondary sex traits, the phallus enlarges and the testes descend into the labioscrotal folds. Typically surgery is required to repair the hypospadia and to construct a scrotum.

It is not uncommon for students to experience feelings of skepticism or shock when they first learn of these anomalies in sexual differentiation. As noted earlier, many people are accustomed to thinking that there are only two sexes, male and female, and that these are completely separate and opposite conditions. Moreover, the fact that a person's phenotypic sex, the sex with which most of us identify ourselves and others, can be ambiguous or discordant with one's chromosomal and gonadal sex, can be quite disconcerting. Anomalies in sexual differentiation challenge the common, dualistic way of thinking about sex. They force us to view sex in a much more complicated manner. Is a hermaphrodite or pseudohermaphrodite male, female, both or neither? If they are neither, then do we require a new language that accepts more than two sexes?

SUMMARY OF MAJOR CONCEPTS

* The structures and activities of mammalian species are organized to fulfill the basic requirement of sexual reproduction; the production and fusion of two different types of gametes. In other words, mammalian bodies are sexually differentiated.

* The sexual organization of mammalian bodies occurs in a well-defined sequence of developmental events beginning at syngamy and ending at puberty; that is, chromosomal sex determines gonadal sex, which directs sexual differentiation of the genital ducts, external genitalia, and secondary sex traits.

* Initially, mammalian embryos have indifferent reproductive systems, which have the inherent tendency to feminize. In males, the presence of a Y chromosome induces development of testes, which then produces hormones that masculinize internal and external reproductive organs as well as specific regions of the brain.

* Anomalies associated with the sex chromosomes result in gonadal dysgenesis or hermaphroditism (presence of ovarian and testicular tissue), whereas anomalies associated with differentiation of the reproductive system result in pseudohermaphroditism (discordance between gonadal and phenotypic sex).

DISCUSSION

1. Construct a list of characteristics that you typically rely on to distinguish between men and women. Which of these traits arise from biological mechanisms of sexual differentiation? Which ones are social constructions; that is, characteristics we create in regards to prevailing norms concerning how men and women should look and/or behave? Discuss some of the ethical, social, and political implications of your analysis.

2. Describe the gonadal and phenotypic (genital ducts and external genitalia) sexes that would develop in an XX mouse that received a microinjection of the SRY DNA sequence when it was a single-celled embryo. Explain how these characteristics developed in this case.

3. In 1779, John Hunter provided a written account of "Mr. Wright's freemartin." His publication also included a precise drawing of the gonads and reproductive tract of an animal with this anomaly. The drawing depicts two (apparently undescended) testes, female external genitalia, a vagina, and a genital duct system that does not resemble a normal uterus and oviducts. Twentieth-century reproductive biologists who have examined this rendering agree that it is a representation of an anomaly of sexual differentiation, but assert that is not a freemartin in the sense that we use the term today. On what criteria is their skepticism based? What type of disorder might this actually be? Explain the basis of your answer.

REFERENCES

Diamond, M. and K. Sigmundson. 1997. Sex reassignment at birth. Archives of Pediatric and Adolescent Medicine. 151:248-302.

George, F.W. and J.D. Wilson. 1994. Sex Determination and Differentiation. In: E. Knobil and J.D. Neill. The Physiology of Reproduction Vol. 2. Second Edition. New York: Raven Press: 3-28.

Grumbach, M.M. and F.A. Conte. 1998. Disorders of Sex Differentiation. In: J.D. Wilson, D.W. Foster, H.M. Kronenberg, P.R. Reed. Williams Textbook of Endocrinology, 9th Edition. Philadelphia: W.B. Saunders Company: 1303-1425.

Hunter, R.H.F. 1995. Sex Determination, Differentiation and Intersexuality in Placental Mammals. Cambridge: Cambridge University Press.

Marrable, A.W. 1971. The Embryonic Pig: A Chronological Account. London: Pitman Medical.

Patten, B.M. Embryology of the Pig, Third Edition. New York: McGraw-Hill Book Co., Inc.

Keith K. Schillo, PhD

Department of Animal and Food Sciences

University of Kentucky

Lexington, Kentucky
TABLE 4-1 Karyotypes and gonadal sexes of various anomalies in human
sexual differentiation

Autosomes   Sex Chromosomes   Gonad     Syndrome Name

44          X0                Ovaries   Turner's
44          XX                Ovaries   Normal female
44          XXX               Ovaries   Superfemale
44          XY                Testes    Normal male
44          XXY               Testes    Klinfelter's
44          XYY               Testes    Supermale
66          XXX               Ovaries   Triploid (lethal)
66          XXY               Testes    Triploid (lethal)
44          [XX.sup.sxr]      Testes    Sex reversal (1)

(1) In this case a small piece of the Y chromosome is translocated
to an X chromosome.
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Author:Schillo, Keith K.
Publication:Reproductive Physiology of Mammals, From Farm to Field and Beyond
Geographic Code:1USA
Date:Jan 1, 2009
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Previous Article:Chapter 3: Organization and structure of mammalian reproductive systems.
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