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Reproduction is the process by which a species is
perpetuated. As opposed to most of the physiological processes you have learned about in this book, reproduction is one of the few that is not necessary for the survival of an individual. However, normal reproductive function is essential for the production of healthy offspring and, therefore, for survival of the species. Sexual reproduction and the merging of parental chromosomes provide the biological variation of individuals that is necessary for adaptation of the species to our changing environment. Reproduction includes the processes by which the male gamete (the sperm) and the female gamete (the ovum) develop, grow, and unite to produce a new and unique combination of genes in their offspring. This new entity, the zygote, develops into an embryo and then a fetus within the maternal uterus. The gametes are produced by gonads—the testes in the male and the ovaries in the female. Reproduction also includes the process by which a fetus is born. Over the course of a lifetime, reproductive functions also include sexual maturation (puberty), as well as pregnancy and lactation in women. The gonads produce hormones that influence development of the offspring into male or female phenotypes. The gonadal hormones are controlled by and influence the secretion of hormones from the hypothalamus and the anterior pituitary gland. Together with the nervous system, these hormones regulate the cyclical activities of female reproduction, including the menstrual cycle, and provide a striking example of the general principle of physiology that most physiological processes are controlled by multiple regulatory systems, often working in opposition. The process of gamete maturation requires communication and feedback between the gonads, anterior pituitary gland, and brain, demonstrating the importance of two related general principles of physiology, namely, that information flow between cells, tissues, and organs is an essential feature of homeostasis and allows for integration of physiological processes; and that the functions of organ systems are coordinated with each other.!
S ECT ION A
Gametogenesis, Sex Determination, and Sex
Differentiation;
General Principles of Reproductive Endocrinology
The primary reproductive organs are known as the gonads: the testes (singular, testis ) in the male and the ovaries (singular, ovary ) in the female. In both sexes, the gonads serve dual functions. The first of these is gametogenesis, which is the production of the reproductive cells, or gametes. These are spermatozoa (singular, spermatozoan, usually shortened to sperm ) in males and ova (singular, ovum ) in females. Secondly, the gonads secrete steroid hormones, often termed sex hormones or gonadal steroids. The major sex hormones are androgens (including
testosterone and dihydrotestosterone [DHT] ) , estrogens (primarily estradiol ) , and progesterone. Both sexes have each of these hormones, but androgens predominate in males and estrogens and progesterone predominate in females.
17.1 Gametogenesis
The process of gametogenesis is depicted in Figure 17.1. At any point in gametogenesis, the developing gametes are called germ cells. The first stage in gametogenesis is proliferation of the primordial (undifferentiated) germ cells by mitosis. With the exception of the gametes, the DNA of each nucleated human cell is contained in 23 pairs of chromosomes, giving a total of 46. The two corresponding chromosomes in each pair are said to be homologous to each other, with one coming from each parent. In mitosis, the 46 chromosomes of the dividing cell are replicated. The cell then divides into two new cells called daughter cells. Each of the two daughter cells resulting from the division receives a full set of 46 chromosomes identical to those of the original cell. Therefore, each daughter cell receives identical genetic information during mitosis. In this manner, mitosis of primordial germ cells, each containing 46 chromosomes, provides a supply of identical germ cells for the next stages. The timing of mitosis in germ cells differs greatly in females and males. In the male, some mitosis occurs in the embryonic testes to generate the population of primary spermatocytes present at birth, but mitosis really begins in earnest in the male at puberty and usually continues throughout life. In the female, mitosis of germ cells in the ovary occurs primarily during fetal development, generating primary oocytes. The second stage of gametogenesis is meiosis, in which each resulting gamete receives only 23 chromosomes from a 46-chromosome germ cell, one chromosome from each homologous pair. Meiosis consists of two cell divisions in succession (see Figure 17.1). The events preceding the first meiotic division are identical to those preceding a mitotic division. During the interphase period, which precedes a mitotic division, chromosomal DNA is replicated. Therefore, after DNA replication, an interphase cell has 46 chromosomes, but each chromosome consists of two identical strands of DNA, called sister chromatids, which are joined together by a centromere. As the first meiotic division begins, homologous chromosomes, each consisting of two identical sister chromatids, come together and line up adjacent to each other. This results in the formation of 23 pairs of homologous chromosomes called bivalents. The sister chromatids of each chromosome condense into thick, rodlike structures. Then, within each homologous pair, corresponding segments of homologous chromosomes align closely. This allows two nonsister chromatids to undergo an exchange of sites of breakage in a process called crossing-over (see Figure 17.1). Crossing-over results in the recombination of genes on homologous chromosomes. As a result, the two sister chromatids are no longer identical. Recombination is one of the most significant features of sexual reproduction that creates genetic diversity. Following crossing-over, the homologous chromosomes line up in the center of the cell. The orientation of each pair on the 606 Chapter 17 equator is random, meaning that sometimes the maternal portion
clarity instead of the normal 46 in humans. The typical designations are 46,XY male or 46,XX female. The number indicates the total number of chromosomes in each nucleated somatic cell, the letters indicate the sex chromosomes present, and male or female is the physical appearance (phenotype). Chromosomes from one parent are purple, and those from the other parent are green. The size of the cells can vary quite dramatically in ova development. Reproduction 607
17.3 Sex Differentiation
The multiple processes involved in the development of the reproductive system in the fetus are collectively called sex differentiation. It is not surprising that people with atypical chromosomal combinations can manifest atypical sex differentiation. However, there are individuals with chromosomal combinations that do not match their sexual appearance and function ( phenotype ). In these people, sex differentiation has been atypical, and their sexual phenotype may not correspond with the presence of XX or XY chromosomes. The genes directly determine only whether the individual will have testes or ovaries. The rest of sex differentiation depends upon the presence or absence of substances produced by the genetically determined gonads, in particular, the testes. Differentiation of the Gonads The male and female gonads derive embryologically from the same site—an area called the urogenital (or gonadal) ridge. Until the sixth week of uterine life, primordial gonads are undifferentiated (see Figure 17.2). In the genetic male, the testes begin to develop during the seventh week. A gene on the Y chromosome (the SRY gene, for s ex-determining r egion of the Y chromosome) is expressed at this time in the urogenital ridge cells and triggers this development. In the absence of a Y chromosome and, consequently, the SRY gene, testes do not develop. Instead, ovaries begin to develop in the same area. The SRY gene codes for the SRY protein, a DNA-binding transcription factor that sets into motion a sequence of gene activations ultimately leading to the formation of testes from the various embryonic cells in the urogenital ridge. Differentiation of Internal and External Genitalia The internal duct system and external genitalia of the fetus are capable of developing into either sexual phenotype ( Figure 17. and Figure 17.3 ). Before the fetal gonads are functional, the undifferentiated reproductive tract includes a double genital duct system, comprised of the Wolffian ducts and Müllerian ducts, and a common opening to the outside for the genital ducts and urinary system. Usually, most of the reproductive tract develops from only one of these duct systems. In the male, the Wolffian ducts persist and the Müllerian ducts regress, whereas in the female, the opposite happens. The external genitalia in the two sexes and the outer part of the vagina do not develop from these duct systems, however, but from other structures at the body surface. Which of the two duct systems and types of external genitalia develops depends on the presence or absence of fetal testes. The fetal testes secrete testosterone and a protein hormone called anti-mu¨llerian hormone (AMH), which used to be called Müllerian-inhibiting substance (MIS) (see Figure 17.2). SRY protein induces the expression of the gene for AMH; AMH then causes the
degeneration of the Müllerian duct system. Simultaneously, testosterone causes the Wolffian ducts to differentiate into the epididymis, vas deferens, ejaculatory duct, and seminal vesicles. Externally and somewhat later, under the influence primarily of dihydrotestosterone (DHT) produced from testosterone in target tissue, a penis forms and the tissue near it fuses to form the scrotum (see Figure 17.3). The testes will ultimately descend into the scrotum, stimulated to do so by testosterone. Failure of the testes to descend is called cryptorchidism and is common in infants with decreased androgen 23 one-chromatid chromosomes. Although the concept is the same, the timing of the second meiotic division is different in males and females. In males, this occurs continuously after puberty with the production of spermatids and ultimately mature sperm cells described in detail in the next section. In females, the second meiotic division does not occur until after fertilization of a secondary oocyte by a sperm. This results in production of the zygote, which contains 46 chromosomes—23 from the oocyte (maternal) and 23 from the sperm (paternal)—and the second polar body, which, like the first polar body, has no function and will degrade. To summarize, gametogenesis produces daughter cells having only 23 chromosomes, and two events during the first meiotic division contribute to the enormous genetic variability of the daughter cells: (1) crossing-over and (2) the random distribution of maternal and paternal chromatid pairs between the two daughter cells.
17.2 Sex Determination
The complete genetic composition of an individual is known as the genotype. Genetic inheritance sets the sex of the individual, or sex determination, which is established at the moment of fertilization. Sex is determined by genetic inheritance of two chromosomes called the sex chromosomes. The larger of the sex chromosomes is called the X chromosome and the smaller, the Y chromosome. Males possess one X and one Y, whereas females have two X chromosomes. Therefore, the key difference in genotype between males and females arises from this difference in one chromosome. As you will learn in the next section, the presence of the Y chromosome leads to the development of the male gonads— the testes; the absence of the Y chromosome leads to the development the female gonads—the ovaries. The ovum can contribute only an X chromosome, whereas half of the sperm produced during meiosis are X and half are Y. When the sperm and the egg join, 50% should have XX and 50% XY. Interestingly, however, sex ratios at birth are not exactly 1:1; rather, there tends to be a slight preponderance of male births, possibly due to functional differences in sperm carrying the X versus Y chromosome. When two X chromosomes are present, only one is functional; the nonfunctional X chromosome condenses to form a nuclear mass called the sex chromatin, or Barr body, which can be observed with a light microscope. Scrapings from the cheek mucosa or white blood cells are convenient sources of cells to be examined. The single X chromosome in male cells rarely condenses to form sex chromatin. A more exacting technique for determining sex chromosome composition called a karyotype employs tissue culture visualization of all the chromosomes. This technique can be used to identify
Urethra Epididymis Testis Penis Uterine tube Ovary Uterus Urinary bladder (moved aside) Vagina Urethra Hymen Vestibule Testes 5- to 6-week embryo; sexually indifferent stage 7 to 8 weeks At birth At birth 8 to 9 weeks Cloaca Absence of Y chromosome Presence of Y chromosome Male Female Reproduction 609
Figure 17.3 Development of the external genitalia in males and females. The major signal for sex
differentiation of the external genitalia is the presence of testosterone in the male (produced by the testes shown in Figure 17.2) and its local conversion to dihydrotestosterone (DHT) in target tissue. By about 6 weeks of development, the three primordial structures of the embryo that will become the male or female external genitalia are the genital tubercle, the urogenital fold, and the labioscrotal fold. Sexual differentiation becomes apparent at 10 weeks of fetal life and is unmistakable by 12 weeks of fetal life. The female phenotype develops in the absence of testosterone and DHT. Matching colors identify homologous structures in the male and female. 6 weeks 8 weeks Male Female 10 weeks 10 weeks 12 weeks 12 weeks Genital tubercle In the absence of testosterone In the presence of testosterone Urogenital fold Labioscrotal fold Tail Developing glans of penis Phallus: Glans of penis Scrotum Prepuce Prepuce Urethral orifice Urethral orifice Anus Anus Urethral groove Urethral groove Anus Anus Developing glans of clitoris
Labia minora Labia majora Glans of clitoris Vaginal orifice Perineal raphe Perineal raphe 610 Chapter 17 secretion. Because sperm production requires about 2°C lower temperature than normal core body temperature, sperm production is usually decreased in cryptorchidism. Treatments include hormone therapy and surgical approaches to move the testes into the scrotum. In contrast, the female fetus, not having testes (because of the absence of the SRY gene), does not secrete testosterone and AMH. In the absence of AMH, the Müllerian system does not degenerate but rather develops into fallopian tubes and a uterus (see Figure 17.2). In the absence of testosterone, the Wolffian ducts degenerate and a vagina and female external genitalia develop from the structures at the body surface (see Figure 17.3). Contrary to previous thought, there are ovarian-determining genes on the X chromosome, the expression of which are repressed by the presence of the SRY protein. Therefore, the development of normal ovaries in the 46,XX embryo and fetus is due to the absence of the SRY gene and the presence of ovarian-determining genes. The events in sex determination and sex differentiation in males and females are summarized in Figure 17.. Disorders of Sexual Differentiation There are various conditions in which normal sex differentiation does not occur. For example, in androgen insensitivity syndrome (formerly called testicular feminization ), the genotype is XY and testes are present but the phenotype (external genitalia and vagina) is female (46, XY female). It is caused by a mutation in the androgen-receptor gene that renders the receptor incapable of normal binding to testosterone. Under the influence of SRY protein, the fetal testes differentiate as usual and they secrete both AMH and testosterone. AMH causes the Müllerian ducts to regress, but the inability of the Wolffian ducts to respond to testosterone also causes them to regress, and so no duct system develops. The tissues that develop into external genitalia are also unresponsive to androgen, so female external genitalia and a vagina develop. The testes do not descend, and they are usually removed when the diagnosis is made. The syndrome is typically not detected until menstrual cycles fail to begin at puberty. Whereas androgen insensitivity syndrome is caused by a failure of the developing fetus to respond to fetal androgens, congenital adrenal hyperplasia is caused by the production of too much androgen in the fetus. Rather than the androgen coming from the fetal testes, it is caused by adrenal androgen overproduction due to a partial defect in the ability of the fetal adrenal gland to synthesize cortisol. This is almost always due to a mutation in the gene for an enzyme in the cortisol synthetic pathway ( Figure 17.5 ) leading to a partial decrease in the activity of the enzyme. The resultant decrease in cortisol in the fetal blood leads to an increase in the secretion of ACTH from the fetal anterior pituitary gland due to a loss of glucocorticoid negative feedback. The increase in fetal plasma ACTH stimulates the fetal adrenal cortex to make more cortisol to overcome the partial enzyme dysfunction. Remember, however, that the adrenal cortex can
intensive research that will hopefully lead to new therapies to help prevent the inheritance of adult diseases that are not due to specific gene mutations but, rather, to changes in gene expression that were due to epigenetic modifications. Sexual Differentiation of the Brain With regard to sexual behavior, differences in the brain may form during fetal and neonatal development. For example, genetic female monkeys treated with testosterone during their late fetal life manifest evidence of masculine sex behavior as adults, such as mounting. In this regard, a potentially important difference in human brain anatomy has been reported; the size of a particular nucleus (neuronal cluster) in the hypothalamus is significantly larger in men. There is also an increase in gonadal steroid secretion in the first year of postnatal life in the male that contributes to the sexual differentiation of the brain. Sex-linked differences in appearance or form within a species are called sexual dimorphisms.
17.4 General Principles
of Reproductive Endocrinology
This is a good place to review the synthesis of gonadal steroid hormones introduced in Chapter 11 ( Figure 17.6 ). These steroidogenic pathways are excellent examples of how the understanding of physiological control is aided by an appreciation of fundamental chemical principles. Each step in this synthetic pathway is catalyzed by enzymes encoded by specific genes. Mutations in these enzymes can lead to atypical gonadal steroid synthesis and secretion and can have profound consequences on sexual development and function. As in the adrenal gland, steroid synthesis starts with cholesterol (see Figures 11.6 and 11.8). Androgens Testosterone belongs to a group of steroid hormones that have similar masculinizing actions and are collectively called androgens. In the male, most of the circulating testosterone is synthesized in the testes. Other circulating androgens are produced by the adrenal cortex, but they are much less potent than testosterone and are unable to maintain male reproductive function if testosterone secretion is inadequate. Furthermore, these adrenal androgens are also secreted by women. Some adrenal androgens, like dehydroepiandrosterone (DHEA) and androstenedione, are sold as dietary supplements and touted as miracle drugs with limited data showing effectiveness. Finally, some testosterone is converted to the more potent androgen dihydrotestosterone in target tissue by the action of the enzyme 5-α-reductase. Estrogens and Progesterone Estrogens are a class of steroid hormones secreted in large amounts by the ovaries and placenta. There are three major estrogens in humans. As noted earlier, estradiol is the predominant estrogen in the plasma. It is produced by the ovary and placenta and is often used synonymously with the generic term estrogen. Estrone is also produced by the ovary and placenta. Estriol is found primarily in pregnant women in whom it is produced by the placenta. In all cases, estrogens are produced from androgens by the enzyme aromatase (see Figure 17.6). Because plasma Plasma adrenal
androgens Plasma ACTH Cortisol Enzyme mutation Begin Adrenal cortex Cholesterol transport into mitochondria Hypothalamus–pituitary ACTH secretion Target cells for androgens Virilization Negative feedback Plasma cortisol
Figure 17.5 Mechanism of virilization in female fetuses with
congenital adrenal hyperplasia. An enzyme defect (usually partial) in the steroidogenic pathway leads to decreased production of cortisol and a shift of precursors into the adrenal androgen pathway. Because cortisol negative feedback is decreased, ACTH release from the fetal pituitary gland increases. Although cortisol can eventually be normalized, it is at the expense of ACTH-stimulated adrenal hyperplasia and excess fetal adrenal androgen production. PHYSIOLOGICAL INQUIRY ■ Explain how this figure illustrates the general principle of physiology described in Chapter 1 that homeostasis is essential for health and survival. In what way can the figure also be considered an exception to this principle? Answer can be found at end of chapter. Rarely, unequal crossing over (Figure 17.1) can result in the insertion of the SRY gene from the Y chromosome into the X chromosome. Although there are variations in the phenotype, an XX fetus who inherits an X-chromosome containing the SRY gene has an XX karyotype with a male phenotype (46,XX male). An individual who inherits the Y-chromosome missing the SRY gene will have an XY karyotype but a female phenotype (46,XY female). Fetal and Neonatal Programming Classic Mendelian inheritance teaches us that one’s genetic attributes are established at conception when the maternal and paternal gametes join together. It is now known that early life experiences can alter the expression of many genes in later life. This is called epigenetics or epigenetic programming. Among the causes of these changes in gene expression are changes in intrauterine environment caused by, for example, maternal malnutrition. Neonatal stressors such as a premature birth are also known to affect the adult phenotype through epigenetic mechanisms. The mechanisms of this effect include changes in methylation of specific genes, histone modifications, and the presence of alternate forms of RNA that affect the translation of messenger RNA into protein (see Section 3.4 in Chapter 3). Among the adult phenotypes that have been shown to be influenced by early life stressors include the incidence of high blood pressure (Chapter 12) and type 2 diabetes mellitus (Chapter 16). Another fascinating aspect of this is that these epigenetic changes can be transmitted to the next generation; that is, they can be inherited by the offspring of the affected adult. Although the field of epigenetics is relatively new, there is 612 Chapter 17
the many external differences between males and females, is also under the influence of gonadal steroids. Examples are hair distribution, body shape, and average adult height. The secondary sexual characteristics are not directly involved in reproduction. Hypothalamo–Pituitary–Gonadal Control Reproductive function is largely controlled by a chain of hormones ( Figure 17.7 ). The first hormone in the chain is gonadotropin-releasing hormone ( GnRH ). As described in Chapter 11, GnRH is one of the hypophysiotropic hormones involved in the control of anterior pituitary gland function. It is secreted by neuroendocrine cells in the hypothalamus, and it reaches the anterior pituitary gland via the hypothalamo– pituitary portal blood vessels. In the anterior pituitary gland, GnRH stimulates the release of the pituitary gonadotropins — follicle- stimulating hormone ( FSH ) and luteinizing hormone ( LH ) , which in turn stimulate gonadal function. The brain is, therefore, the primary regulator of reproduction. The cell bodies of the GnRH neurons receive input from throughout the brain as well as from hormones in the blood. This is why certain stressors, emotions, and trauma to the central nervous system can inhibit reproductive function. It has recently been discovered that neurons in discrete areas of the hypothalamus synapse on GnRH neurons and release a peptide called kisspeptin that is intimately involved in the activation of GnRH neurons. Secretion of GnRH is triggered by action potentials in GnRHproducing hypothalamic neuroendocrine cells. These action potentials occur periodically in brief bursts, with little secretion in between. The pulsatile pattern of GnRH secretion is important because the cells of the anterior pituitary gland that secrete the Reproduction 613 they come as well as on other parts of the body. In addition, the gonadal steroids exert feedback effects on the secretion of GnRH, FSH, and LH. It is currently thought that gonadal steroids exert negative feedback effects on GnRH both directly and through inhibition of kisspeptin neuron cell bodies in the hypothalamus that have input to the GnRH neurons. Gonadal protein hormones such as inhibin also exert feedback effects on the anterior pituitary gland. Each link in this hormonal chain is essential. A decrease in function of the hypothalamus or the anterior pituitary gland can result in failure of gonadal steroid secretion and gametogenesis just as if the gonads themselves were diseased. As a result of changes in the amount and pattern of hormone secretions, reproductive function changes markedly during a person’s lifetime and may be divided into the stages summarized in Table 17.. SECTION A SUMMARY Gametogenesis I. The first stage of gametogenesis is mitosis of primordial germ cells. II. This is followed by meiosis, which is a sequence of two cell divisions resulting in each gamete receiving 23 chromosomes. III. Early life (fetal and neonatal) experiences can alter the expression of many genes in later life and in the subsequent offspring. This is called epigenetics or epigenetic programming. IV. Crossing-over and random distribution of maternal and paternal chromatids to the daughter cells during meiosis cause genetic
variability in the gametes. Sex Determination I. Sex is determined by the two sex chromosomes; males are XY, and females are XX. Sex Differentiation I. The SRY gene on the Y chromosome is responsible for the development of testes. In the absence of a Y chromosome, testes do not develop and ovaries do instead. II. When functioning male gonads are present, they secrete testosterone and AMH, so a male reproductive tract and external genitalia develop. In the absence of testes, the female system develops. Fetal life to infancy: GnRH and the gonadotropins (in males and females), and gonadal sex hormones (in males) are secreted at relatively high levels. Childhood to the onset of puberty: GnRH, the gonadotropins, and gonadal sex hormones are low and reproductive function is quiescent. Puberty to adulthood: GnRH, the gonadotropins, and gonadal sex hormones increase markedly, showing large cyclical variations in women during the menstrual cycle. This is the time of fertility. Aging: Reproductive function diminishes largely because the gonads become less responsive to the gonadotropins. The ability to reproduce ceases entirely in women.
TABLE 17.1 Stages in the Control of Reproductive
Function Gonads Sex hormones Secrete sex hormones Gametogenesis FSH and LH Anterior pituitary Secretes FSH and LH Hypothalamus Secretes GnRH GnRH (in hypothalamo–pituitary portal vessels) + Reproductive tract and other organs Respond to sex hormones Begin
Figure 17.7 Pattern of reproduction control in both
males and females. GnRH, like all hypothalamic–hypophysiotropic hormones, reaches the anterior pituitary gland via the hypothalamo–hypophyseal portal vessels. The arrow within the box marked “gonads” denotes the fact that the sex hormones act locally as paracrine agents to influence the gametes. indicates negative feedback inhibition. indicates estrogen stimulation of FSH and LH in the middle of the menstrual cycle in women (positive feedback). PHYSIOLOGICAL INQUIRY ■ What would be the short- and long-term effects of removal of one of the two gonads in an adult? Answer can be found at end of chapter. gonadotropins lose sensitivity to GnRH if the concentration of this hormone remains constantly elevated. This phenomenon is exploited by the administration of synthetic analogs of GnRH to men with androgen-sensitive prostate cancer and to women with estrogen-sensitive breast cancer. Although one may think that administration of a GnRH analog would stimulate FSH and LH,
17.3 Sex Differentiation ambiguous genitalia androgen insensitivity syndrome congenital adrenal hyperplasia cryptorchidism virilization III. Early life (fetal and neonatal) experiences can alter the expression of many genes in later life and in the subsequent offspring. This is called epigenetics or epigenetic programming. IV. A sexually dimorphic brain region exists in humans and certain experimental animals that may be linked with male-type or female-type sexual behavior. General Principles of Reproductive Endocrinology I. The gonads have a dual function—gametogenesis and secretion of sex hormones. II. The male gonads are the testes, which produce sperm and secrete the steroid hormone testosterone. III. The female gonads are the ovaries, which produce ova and secrete the steroid hormones estrogen and progesterone. IV. Gonadal function is controlled by the gonadotropins (FSH and LH) from the anterior pituitary gland whose release is controlled by pulsatile gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus. SECTION A REVIEW QUESTIONS
- Describe the stages of gametogenesis and how meiosis results in genetic variability.
- State the genetic difference between males and females and a method for identifying genetic sex.
- Describe the sequence of events, the timing, and the control of the development of the gonads and the internal and external genitalia.
- Explain how administration of glucocorticoids to a pregnant woman would treat congenital adrenal hyperplasia in her fetus. SECTION A KEY TERMS androgens dihydrotestosterone (DHT) estradiol estrogens gametes gametogenesis gonadal steroids gonads ova (ovum) ovaries (ovary) progesterone sex hormones
S ECT ION B
Male Reproductive Physiology
17.5 Anatomy
The male reproductive system includes the two testes, the system of ducts that store and transport sperm to the exterior, the glands that empty into these ducts, and the penis ( Figure 17.8 ). The duct system, glands, and penis constitute the male accessory reproductive organs. The testes are suspended outside the abdomen in the scrotum, which is an outpouching of the abdominal wall and is divided internally into two sacs, one for each testis. During early fetal development, the testes are located in the abdomen; but during later gestation (usually in the seventh month of pregnancy),
they usually descend into the scrotum (see Figure 17.2). This descent is essential for normal sperm production during adulthood, because sperm formation requires a temperature approximately 2° C lower than normal internal body temperature. Cooling is achieved by air circulating around the scrotum and by a heatexchange mechanism in the blood vessels supplying the testes. In contrast to spermatogenesis, testosterone secretion can usually occur normally at internal body temperature, so failure of testes descent usually does not impair testosterone secretion. The sites of spermatogenesis (sperm formation) in the testes are the many tiny, convoluted seminiferous tubules ( Figure 17.9 ). The combined length of these tubes is 250 m (the length of over 2.5 football fields). The seminiferous tubules from different areas of a testis converge to form a network of interconnected tubes, the rete testis (see Figure 17.9). Small ducts called efferent ductules leave the rete testis, pierce the fibrous covering of the testis, and empty into a single duct within a structure called the epididymis (plural, epididymides ). The epididymis is loosely attached to the outside of the testis. The duct of the epididymis is so convoluted that, when straightened out at dissection, it measures 6 m. The epididymis draining each testis leads to a vas deferens (plural, vasa deferentia ), a large, thick-walled tube lined with smooth muscle. Not shown in Figure 17.9 is that the vas deferens and the blood Reproduction 615 Rete testis Seminiferous tubule Epididymis Efferent ductules Vas deferens
Figure 17.9 Section of a testis. The upper portion of the
testis has been removed to show its interior. Vas deferens Ejaculatory duct Urinary bladder Ureter Seminal vesicle Prostate gland Bulbourethral gland Epididymis Penis Urethra Testis Pubic bone
Figure 17.8 Anatomical organization of the male reproductive tract. This
figure shows the testis, epididymis, vas deferens, ejaculatory duct, seminal vesicle, and bulbourethral gland on only one side of the body, but they are all paired structures. The urinary bladder and a ureter are shown for orientation but are not part of the reproductive tract. Once the ejaculatory ducts join the urethra in the prostate, the urinary and reproductive tracts have merged. vessels and nerves supplying the testis are bound together in the spermatic cord, which passes to the testis through a slitlike passage, the inguinal canal, in the abdominal wall.
of undifferentiated spermatogonia is maintained. Each primary spermatocyte increases markedly in size and undergoes the first meiotic division (see Figure 17.10) to form two secondary spermatocytes, each of which contains 23 two- chromatid chromosomes. Each secondary spermatocyte undergoes the second meiotic division (see Figure 17.1) to form spermatids. In this way, each primary spermatocyte, containing 46 two-chromatid chromosomes, produces four spermatids, each containing 23 one-chromatid chromosomes. The final phase of spermatogenesis is the differentiation of the spermatids into spermatozoa (sperm). This process involves extensive cell remodeling, including elongation, but no further cell divisions. The head of a sperm cell ( Figure 17.11 ) consists almost entirely of the nucleus, which contains the genetic information (DNA). The tip of the nucleus is covered by the acrosome, a proteinfilled vesicle containing several enzymes that are important in fertilization. Most of the tail is a flagellum—a group of contractile filaments that produce whiplike movements capable of propelling the sperm at a velocity of 1 to 4 mm per min. Mitochondria form the midpiece of the sperm and provide the energy for movement. The entire process of spermatogenesis, from primary spermatocyte to sperm, takes approximately 64 days. The typical human male manufactures approximately 30 million sperm per day. Sertoli Cells Each seminiferous tubule is bounded by a basement membrane. In the center of each tubule is a fluid-filled lumen containing the mature sperm cells, called spermatozoa. The tubular wall is composed of Head Midpiece Flagellum (tail) Acrosome Cell membrane Nucleus (a) (b) Mitochondria
Figure 17.11 (a) Diagram of a human mature sperm.
(b) A close-up of the head drawn from a different angle. The acrosome contains enzymes required for fertilization of the ovum. developing germ cells and their supporting cells, called Sertoli cells (also known as sustentacular cells). Each Sertoli cell extends from the basement membrane all the way to the lumen in the center of the tubule and is joined to adjacent Sertoli cells by means of tight junctions ( Figure 17.12 ). Thus, the Sertoli cells form an unbroken ring around the outer circumference of the seminiferous tubule. The tight junctions divide the tubule into two compartments—a basal compartment, between the basement membrane and the tight junctions, and a central compartment, beginning at the tight junctions and including the lumen. The ring of interconnected Sertoli cells forms the Sertoli cell barrier (blood–testes barrier), which prevents the movement of many chemicals from the blood into the lumen of the seminiferous tubule and
helps retain luminal fluid. This ensures proper conditions for germ cell development and differentiation in the tubules. The arrangement of Sertoli cells also permits different stages of spermatogenesis to take place in different compartments and, therefore, in different environments. Leydig Cells The Leydig cells, or interstitial cells, which lie in small, connective-tissue spaces between the tubules, synthesize and release testosterone. Therefore, the sperm-producing and testosterone-producing functions of the testes are carried out by different structures—the seminiferous tubules and Leydig cells, respectively. Production of Mature Sperm As shown in Figure 17.12, spermatogenesis is ultimately controlled by the gonadotropins that stimulate local testosterone secretion from Leydig cells and increase the activity of Sertoli cells. Mitotic cell divisions and differentiation of spermatogonia to yield primary spermatocytes take place entirely in the basal Spermatogonia Mitosis Differentiation Primary spermatocytes Secondary spermatocytes 2nd meiotic division 1st meiotic division Differentiation Chromosomes per cell 46 46 23 23 Chromatid(s) per chromosome 2 2 1 1 Spermatids Spermatozoa 23 2
Figure 17.10 Summary of spermatogenesis, which begins at puberty.
Each spermatogonium yields, by mitosis, a clone of spermatogonia; for simplicity, the figure shows only two such cycles, with a third mitotic cycle generating two primary spermatocytes. The arrow from one of the spermatogonia back to a stem cell spermatogonium denotes the fact that one cell of the clone does not go on to generate primary spermatocytes but reverts to an undifferentiated spermatogonium that gives rise to a new clone. Each primary spermatocyte produces four spermatozoa. Reproduction 617 compartment. The primary spermatocytes then move through the tight junctions of the Sertoli cells (which open in front of them while at the same time forming new tight junctions behind them) to gain entry into the central compartment. In this central compartment, the meiotic divisions of spermatogenesis occur, and the spermatids differentiate into sperm while contained in recesses formed by invaginations of the Sertoli cell plasma membranes. When sperm formation is complete, the cytoplasm of the Sertoli
