Reproduction and Development

26 Reproduction and Development Sex Determination Sex Chromosomes Determine Genetic Sex Sexual Differentiation Occurs Early in Development Basic Patterns of Reproduction Gametogenesis Begins in Utero The Brain Directs Reproduction Environmental Factors Influence Reproduction Male Reproduction Testes Produce Sperm and Hormones Spermatogenesis Requires Gonadotropins and Testosterone Male Accessory Glands Contribute Secretions to Semen Androgens Influence Secondary Sex Characteristics Female Reproduction Females Have an Internal Uterus The Ovary Produces Eggs and Hormones A Menstrual Cycle Lasts about One Month Hormonal Control of the Menstrual Cycle Is Complex Hormones Influence Female Secondary Sex Characteristics Birth, and copulation, and death. That s all the facts when you come to brass tacks. T.S. Eliot, Sweeney Agonistes Background Basics Positive and negative feedback Flagella Steroids Agonist/antagonist Up-and down-regulation Prostaglandins Hypothalamic-pituitary axis Prolactin Oxytocin Spinal reflex Hot flashes 900 Procreation The Human Sexual Response Has Four Phases The Male Sex Act Includes Erection and Ejaculation Sexual Dysfunction Affects Males and Females Contraceptives Are Designed to Prevent Pregnancy Infertility Is the Inability to Conceive Pregnancy and Parturition Fertilization Requires Capacitation The Developing Embryo Implants in the Endometrium The Placenta Secretes Hormones During Pregnancy Pregnancy Ends with Labor and Delivery The Mammary Glands Secrete Milk During Lactation Prolactin Has Other Physiological Roles Growth and Aging Puberty Marks the Beginning of the Reproductive Years Menopause and Andropause Are a Consequence of Aging Cross-section of intestinal villi (outlined in red).

Imagine growing up as a girl, then at the age of 12 or so, finding that your voice is deepening and your genitals are developing into those of a man. This scenario actually happens to a small number of men who have a condition known as pseudohermaphroditism { pseudes, false + hermaphrodites, the dual-sex offspring of Hermes and Aphrodite}. These men have the internal sex organs of a male but inherit a gene that causes a deficiency in one of the male hormones. Consequently, they are born with external genitalia that appear feminine, and they are raised as girls. At puberty { pubertas, adulthood}, the period when a person makes the transition from being nonreproductive to being reproductive, pseudohermaphrodites begin to secrete more male hormones. As a result, they develop some, but not all, of the characteristics of men. Not surprisingly, a conflict arises: should these individuals change gender or remain female? Most choose to change and continue life as men. Reproduction is one area of physiology in which we humans like to think of ourselves as significantly advanced over other animals. We mate for pleasure as well as procreation, and women are always sexually receptive (that is, not only during fertile periods). But just how different are we? Like many other terrestrial animals, humans have internal fertilization that allows motile flagellated sperm to remain in an aqueous environment. To facilitate the process, we have mating and courtship rituals, as do other animals. Development is also internal, within the uterus, which protects the growing embryo from dehydration and cushions it in a layer of fluid. Humans are sexually dimorphic { di-, two + morphos, form}, meaning that males and females are physically distinct. This distinction is sometimes blurred by dress and hairstyle, but these are cultural acquisitions. Although everyone agrees that male and female humans are physically dimorphic, we are still debating whether we are behaviorally and psychologically dimorphic as well. RUNNING PROBLEM Infertility Peggy and Larry have just about everything to make them happy: successful careers, a loving marriage, a comfortable home. But one thing is missing: after five years of marriage, they have been unable to have a child. Today, Peggy and Larry have their first appointment with Dr. Coddington, an infertility specialist. Finding the cause of your infertility is going to require some painstaking detective work, Dr. Coddington explains. He will begin his workup of Peggy and Larry by asking detailed questions about their reproductive histories. Based on the answers to these questions, he will then order tests to pinpoint the problem. Sex hormones play a significant role in the behavior of other mammals, acting on adults as well as influencing the brain of the developing embryo. Their role in humans is more controversial. Human fetuses are exposed to sex hormones while in the uterus, but it is unclear how much influence these hormones have on behavior later in life. Does the preference of little girls for dolls and of little boys for toy guns have a biological basis or a cultural basis? We have no answer yet, but growing evidence suggests that at least part of our brain structure is influenced by sex hormones before we ever leave the womb. In this chapter we address the biology of human reproduction and development. We begin our discussion with gametes that fuse to form the fertilized egg, or zygote. As the zygote begins to divide (2-cell stage, 4-cell stage, etc.), it becomes first an embryo (weeks 0 8 of development), then a fetus (8 weeks until birth). Sex Determination The male and female sex organs consist of three sets of structures: the gonads, the internal genitalia, and the external genitalia. Gonads { gonos, seed} are the organs that produce gametes { gamein, to marry}, the eggs and sperm that unite to form a new individual. The male gonads are the testes (singular testis ), which produce sperm ( spermatozoa ). The female gonads are the ovaries, which produce eggs, or ova (singular ovum ). The undifferentiated gonadal cells destined to produce eggs and sperm are called germ cells. The internal genitalia consist of accessory glands and ducts that connect the gonads with the outside environment. The external genitalia include all external reproductive structures. Sexual development is programmed in the human genome. Each nucleated cell of the body except eggs and sperm contains 46 chromosomes. This set of chromosomes is called the diploid number because the chromosomes occur in pairs: 22 matched, or homologous, pairs of autosomes plus one pair of sex chromosomes ( Fig. 26.1 a). The 22 pairs of autosomal chromosomes direct development of the human body form and of variable characteristics such as hair color and blood type. The two sex chromosomes, designated as either X or Y, contain genes that direct development of internal and external sex organs. The X chromosome is larger than the Y chromosome and includes many genes that are missing from the Y chromosome. Eggs and sperm are haploid cells with 23 chromosomes, one from each matched pair and one sex chromosome. When egg and sperm unite, the resulting zygote then contains a unique set of 46 chromosomes, with one chromosome of each matched pair coming from the mother and the other from the father. Sex Chromosomes Determine Genetic Sex Th e sex chromosomes a person inherits determine the genetic sex of that individual. Genetic females are XX, and genetic males are XY ( Fig. 26.1 b). Females inherit one X chromosome from 26 901

HUMAN CHROMOSOMES (a) Humans have 23 pairs of chromosomes: 22 pairs of autosomes and one pair of sex chromosomes. X and Y chromosomes (lower right) mean that these chromosomes came from a male. The autosomes are arranged in homologous pairs in this figure. whether development proceeds along male or female lines. The presence of a Y chromosome means the embryo will become male, even if the zygote also has multiple X chromosomes. For instance, an XXY zygote will become male. A zygote that inherits only a Y chromosome (YO) will die because the larger X chromosome contains essential genes that are missing from the Y chromosome. In the absence of a Y chromosome, an embryo will develop into a female. For this reason, a zygote that gets only one X chromosome (XO; Turner s syndrome) will develop into a female. Two X chromosomes are needed for normal female reproductive function, however. Once the ovaries develop in a female fetus, one X chromosome in each cell of her body inactivates and condenses into a clump of nuclear chromatin known as a Barr body. (Barr bodies in females can be seen in stained cheek epithelium.) The selection of the X chromosome that becomes inactive during development is random: some cells will have an active maternal X chromosome and others have an active paternal X chromosome. Because inactivation occurs early in development before cell division is complete all cells of a given tissue will usually have the same active X chromosome, either maternal or paternal. Concept Check Answers: End of Chapter 1. Name the male and female gonads and gametes. (b) X and Y chromosomes determine sex. Each egg produced by a female (XX) has an X chromosome. Sperm produced by a male (XY) have either an X chromosome or a Y chromosome. X Fig. 26.1 Female parent XX Eggs X XX XY X Female offspring Male offspring Male parent XY Sperm each parent. Males inherit a Y chromosome from the father and an X chromosome from the mother. The Y chromosome is essential for development of the male reproductive organs. If sex chromosomes are abnormally distributed at fertilization, the presence or absence of a Y chromosome determines Y Sexual Differentiation Occurs Early in Development The sex of an early embryo is difficult to determine because reproductive structures do not begin to differentiate until the seventh week of development. Before differentiation, the embryonic tissues are considered bipotential because they cannot be morphologically identified as male or female. The bipotential gonad has an outer cortex and an inner medulla ( Fig. 26.2 a). Under the influence of the appropriate developmental signal (described below), the medulla will develop into a testis. In the absence of that signal, the cortex will differentiate into ovarian tissue. The bipotential internal genitalia consist of two pairs of accessory ducts: Wolffian ducts (mesonephric) derived from the embryonic kidney, and Müllerian ducts (paramesonephric ducts). As development proceeds along either male or female lines, one pair of ducts develops while the other degenerates ( Fig. 26.2 a 2 ). The bipotential external genitalia consist of a genital tubercle, urethral folds, urethral groove, and labioscrotal swellings ( Fig. 26.2 b). These structures differentiate into the male and female reproductive structures as development progresses. What directs some single-cell zygotes to become males, and others to become females? Sex determination depends on 902

Reproduction and Development CLI NI C AL F OCU S X-Linked Inherited Disorders Normally, a person inherits two copies of the gene for a given trait: one copy from each parent. However, many genes found on the X chromosome, called X-linked genes, have no matching gene on the much smaller Y chromosome. Females always get two copies of X-linked genes, so the expression of X-linked traits follows the usual pattern of gene dominance and recession. Males, however, receive only one copy of an X-linked gene on the X chromosome from their mother so males always exhibit the traits associated with an X-linked gene. If the maternally inherited X-linked gene is defective, male offspring will exhibit the mutation. Among the identified X-linked diseases are Duchenne muscular dystrophy, hemophilia, and color-blindness. the presence or absence of the sex-determining region of the Y chromosome, or SRY gene. In the presence of a functional SRY gene, the bipotential gonads develop into testes. In the absence of the SRY gene and under the direction of multiple femalespecific genes, the gonads develop into ovaries. Male Embryonic Development The SRY gene produces a protein (testis-determining factor or TDF) that binds to DNA and activates additional genes, including SOX9, WT1 (Wilms tumor protein), and SF1 (steroidogenic factor). The protein products of these genes direct development of the gonadal medulla into a testis ( Fig. 26.3). Note that testicular development does not require male sex hormones such as testosterone. The developing embryo cannot secrete testosterone until after the gonads differentiate into testes. Once the testes differentiate, they begin to secrete three hormones that influence development of the male internal and external genitalia. Testicular Sertoli cells secrete glycoprotein anti-müllerian hormone (AMH; also called Müllerianinhibiting substance). Testicular Leydig cells secrete testosterone and its derivative dihydrotestosterone (DHT). These two androgens {andro-, male} are the dominant steroid hormones in males. Testosterone and DHT both bind to the same androgen receptor, but the two ligands elicit different responses. In the developing fetus, anti-müllerian hormone causes the embryonic Müllerian ducts to regress (Fig. 26.2a, 2 male). Testosterone converts the Wolffian ducts into male accessory structures: epididymis, vas deferens, and seminal vesicle ( 3 male). Later in fetal development, testosterone controls migration of the testes from the abdomen into the scrotum, or scrotal sac. The remaining male sex characteristics, such as differentiation of the external genitalia, are controlled primarily by DHT. The importance of DHT in male development came to light in studies of the male pseudohermaphrodites described in the opening of this chapter. These men inherit a defective gene for 5a-reductase, the enzyme that catalyzes the conversion of testosterone to DHT ( Fig. 26.4). Despite normal testosterone secretion, these men have inadequate levels of DHT, and as a result the male external genitalia and prostate gland fail to develop fully during fetal development. At birth, the infants appear to be female and are raised as such. However, at puberty, the testes again begin to secrete testosterone, causing masculinization of the external genitalia, pubic hair growth (although scanty facial and body hair), and deepening voice. By studying the 5a-reductase defect in these individuals, scientists have been able to separate the effects of testosterone from those of DHT. Exposure of nongenital tissues to testosterone during embryonic development is known to have masculinizing effects, such as altering the brain s responsiveness to certain hormones. One controversial aspect of the masculinizing effects of testosterone is its influence on human sexual behavior and gender identity. It is well documented that in many nonhuman mammals, adult sexual behavior depends on the absence or presence of testosterone during critical periods of brain development. However, a similar cause-effect relationship has never been proved in humans. In human behavior, it is very difficult to separate biological influences from environmental factors, and it will probably be years before this question is resolved. 26 Female Embryonic Development In female embryos, which have no SRY gene, the cortex of the bipotential gonad develops into ovarian tissue (Fig. 26.2a 1 female). Research indicates that female development is more complex than originally thought, with multiple genes required for the development of functional ovaries. In the absence of testicular AMH, the Müllerian ducts develop into the upper portion of the vagina, the uterus, and the fallopian tubes, named after the anatomist Fallopius, who first described them (Fig. 26.2a 3 female). Fallopian tubes are also called oviducts. Without testosterone, the Wolffian ducts degenerate (Fig. 26.2a 2 female). Without DHT, the external genitalia take on female characteristics (Fig. 26.2b). Concept Check Answers: End of chapter 2. Where in a target cell would you expect to find receptors for androgens? Where would you expect to find receptors for AMH? 3. Why was King Henry VIII of England wrong to blame his wives when they were unable to produce a male heir to the throne? 4. Which sex will a zygote become if it inherits only one X chromosome (XO)? 5. If the testes are removed from an early male embryo, why does it develop a uterus and fallopian tubes rather than the normal male accessory structures? Will the embryo have male or female external genitalia? Explain. 903

(a) Development of Internal Organs Bipotential stage: 6 week fetus The internal reproductive organs have the potential to develop into male or female structures. Bipotential stage (6 week fetus) Müllerian duct Gonad (bipotential) Wolffian duct IF FEMALE: Kidney IF MALE: Gonad (cortex) forms ovary. Gonad (medulla) regresses. Wolffian duct regresses (testosterone absent). Müllerian duct becomes fallopian tube, uterus, cervix, and upper 1/2 of vagina (AMH absent). Cloacal opening Gonad (cortex) regresses. Gonad (medulla) forms testis. Wolffian duct forms epididymis, vas deferens, and seminal vesicle (testosterone present). Müllerian duct regresses (AMH present). FEMALE MALE 10 weeks 10 weeks 1 Gonadal cortex becomes ovary in the absence of SRY protein and under the influence of female-specific genes. Testis 1 SRY protein in a male embryo directs the medulla of the bipotential gonad to develop into testis. 2 Absence of testosterone causes Wolffian duct to degenerate. Uterus Müllerian duct Wolffian duct 2 Anti-Müllerian hormone from testis causes the Müllerian ducts to disappear. At birth At birth Ovary 3 Absence of anti- Müllerian hormone allows the Müllerian duct to become the fallopian tube, uterus, and upper part of the vagina. Uterus Fallopian tube (from Müllerian duct) Prostate Seminal vesicle Vas deferens Testis 3 Testosterone from testis converts Wolffian duct into seminal vesicle, vas deferens, and epididymis. DHT controls prostate development. Vagina Epididymis 904

(b) Development of External Genitalia Bipotential stage: The external genitalia of a 6-week fetus cannot be visually identified as male or female. Bipotential stage (6 week fetus) Genital tubercle Labioscrotal swelling Urethral groove Urethral fold IF FEMALE: Genital tubercle forms clitoris. Urethral folds and grooves form labia minora, opening of vagina and urethra. Labioscrotal swellings form labia majora. Anus IF MALE: Genital tubercle forms glans penis. Urethral folds and grooves form shaft of penis. Labioscrotal swellings form shaft of penis and scrotum. FEMALE MALE 10 weeks 10 weeks Clitoris Penis 26 Urethral fold Labioscrotal swelling Anus Anus Urethral fold Labioscrotal swelling 1 In the absence of androgens, the external genitalia are feminized. 1 DHT causes development of male external genitalia. At birth At birth Labia majora Labia minora Clitoris Urethral opening Vaginal opening Glans penis Shaft of penis Scrotum Anus Anus 2 The testes descend from the abdominal cavity into the scrotum. 905

The SRY gene directs male development. Leydig cells secrete Testosterone controls Sex-determining region of Y chromosome in embryonic germ cells (SRY gene) produces Testis-determining SRY protein initiates production of Multiple proteins that cause gonad medulla to differentiate into a testis which has Sertoli cells secrete Anti-Müllerian hormone causes CLINICAL FOCUS Determining Sex The first question new parents typically ask about their child is, Is it a boy or a girl? Sometimes the answer is not obvious because in approximately 1 in 3000 births, the sex of the child cannot easily be determined. Multiple criteria might be used to establish an individual s sex: genetic, chromosomal, gonadal, morphological, or even psychological characteristics. For example, presence of a Y chromosome with a functional SRY gene could be one criterion for maleness. However, it is possible for an infant to have a Y chromosome and not appear to be male because of a defect in some aspect of development. Currently there is ongoing debate about how best to decide sex in cases where there is doubt. Traditionally, sex determination has been based on appearance of the external genitalia at birth, but the idea that individuals should be allowed to choose their sex when they become old enough is gaining ground. The sex a person considers himself or herself to be is called the person s gender identity. You can read more about causes of ambiguous genitalia and the current criteria used to decide a child s sex in the American Academy of Pediatrics policy statement Evaluation of the Newborn with Developmental Anomalies of the External Genitalia, Pediatrics 106(1): 138 142, 2000 (July) (available online at http://pediatrics.aappublications.org ). Development of Wolffian duct into accessory structures Development of male external genitalia (via DHT) Fig. 26.3 Regression of Müllerian duct SYNTHESIS PATHWAYS FOR STEROID HORMONES The blank boxes represent intermediate compounds whose names have been omitted for simplicity. Cholesterol Basic Patterns of Reproduction Th e testis and ovary both produce hormones and gametes, and they share other similarities, as might be expected of organs having the same origin. However, male and female gametes are very different from each other. Eggs are some of the largest cells in the body. They are nonmotile and must be moved through the reproductive tract on currents created by smooth muscle contraction or the beating of cilia. Sperm, in contrast, are quite small. They are the only flagellated cells in the body and are highly motile so that they can swim up the female reproductive tract in their search for an egg to fertilize. The timing of gamete production, or gametogenesis, is also very different in males and females. Most evidence indicates that women are born with all the eggs, or oocytes, they will ever have, although recent reports suggest there may be stem cells in the ovary. During the reproductive years, eggs mature in a cyclic pattern and Progesterone Corticosterone Aldosterone Fig. 26.4 Cortisol Testosterone aromatase Estradiol * Dihydrotestosterone (DHT) KEY 5α-reductase * Intermediate steps 906

are released from the ovaries roughly once a month. After about 40 years, female reproductive cycles cease ( menopause ). Men, in contrast, manufacture sperm continuously from the time they reach reproductive maturity. Sperm production and testosterone secretion diminish with age but do not cease as women s reproductive cycles do. Gametogenesis Begins in Utero Figure 26.5 compares the male and female patterns of gametogenesis. In both sexes, germ cells in the embryonic gonads first undergo a series of mitotic divisions to increase their numbers 1. After that, the germ cells are ready to undergo meiosis, the cell division process that forms gametes. In the first step of meiosis, the germ cell s DNA replicates until each chromosome is duplicated (46 chromosomes duplicated = 92 chromosomes). The cell, now called a primary spermatocyte or primary oocyte, contains twice the normal amount of DNA 2. However, cell and chromosomal division do not take place as they do in mitosis. Instead, each duplicated chromosome forms two identical sister chromatids, linked together at a region known as the centromere. The primary gametes are then ready to undergo meiotic divisions to create four haploid cells. In the first meiotic division, one primary gamete divides into two secondary gametes ( secondary spermatocyte or secondary oocyte ) 3. Each secondary gamete gets one copy of each duplicated autosome plus one sex chromosome. In the second meiotic division, the sister chromatids separate 4. In males, the cells split during the second meiotic division, resulting in two haploid sperm from each secondary spermatocyte. In females, the second meiotic division creates one egg and one small cell called a polar body. What happens after that depends on whether or not the egg is fertilized. Th e timing of mitotic and meiotic divisions is very different in males and females. Let s take a closer look at gametogenesis in each sex. Male Gametogenesis At birth, the testes of a newborn boy have not progressed beyond mitosis and contain only immature germ cells ( Fig. 26.5 1 ). After birth, the gonads become quiescent (relatively inactive) until puberty, the period in the early teen years when the gonads mature. At puberty, germ cell mitosis resumes. From that point onward, the germ cells, known as spermatogonia (singular spermatogonium ), have two possible fates. Some continue to undergo mitosis throughout the male s reproductive life. Others are destined to start meiosis and become primary spermatocytes 2. Each primary spermatocyte creates four sperm. In the first meiotic division, a primary spermatocyte divides into two secondary spermatocytes 3. In the second meiotic division, each secondary spermatocyte divides into two spermatids. Each spermatid has 23 single chromosomes, the haploid number characteristic of a gamete 4. The spermatids then mature into sperm. Female Gametogenesis In the embryonic ovary, germ cells are called oögonia (singular oögonium ) ( Fig. 26.5 1 ). Oögonia complete mitosis and the DNA duplication stage of meiosis by the fifth month of fetal development 2. At this time, germ cell mitosis ceases and no further oocytes can be formed. At birth each ovary contains about half a million primary gametes, or primary oocytes. In the ovary, meiosis does not resume until puberty 3. Each primary oocyte divides into two cells, a large egg ( secondary oocyte ) and a tiny first polar body. Despite the size difference, the egg and polar body each contain 23 duplicated chromosomes. This first polar body disintegrates. Meanwhile, the egg begins the second meiotic division 4. After the sister chromatids separate from each other, meiosis pauses. The final step of meiosis, in which sister chromatids go to separate cells, does not take place unless the egg is fertilized. The ovary releases the mature egg during a process known as ovulation. If the egg is not fertilized, meiosis never goes to completion, and the egg disintegrates or passes out of the body 5. If fertilization by a sperm occurs, the final step of meiosis takes place 6. Half the sister chromatids remain in the fertilized egg (zygote), while the other half are released in a second polar body. The second polar body, like the first, degenerates. As a result of meiosis, each primary oocyte gives rise to only one egg. Gametogenesis in both males and females is under the control of hormones from the brain and from endocrine cells in the gonads. Some of these hormones are identical in males and females, but others are different. Concept Check Answers: End of chapter 6. At what stage of development is the gamete in a newborn male? In a newborn female? 7. Compare the amount of DNA in the first polar body with the amount of DNA in the second polar body. 8. How many gametes are formed from one primary oocyte? From one primary spermatocyte? The Brain Directs Reproduction Th e reproductive system has some of the most complex control pathways of the body, in which multiple hormones interact in an ever-changing fashion. The pathways that regulate reproduction begin with secretion of peptide hormones by the hypothalamus and anterior pituitary. These trophic hormones control gonadal secretion of the steroid sex hormones, including androgens, estrogens, and progesterone. The sex steroids are closely related to one another and arise from the same steroid precursors ( Fig. 26.4 ). Both sexes produce 26 907

GAMETOGENESIS Germ cells first duplicate themselves through mitosis. Then, through meiosis, they form gametes with one chromosome from each pair. For simplicity, this figure shows only one of the body s 22 pairs of autosomes in each cell. Female Stage of Cell Division Male Germ cell: Oögonium 1 MITOSIS Germ cell proliferation 46 chromosomes per cell (only two shown here) Embryo Germ cell: Spermatogonium.. Oogonia Embryo 46 (diploid) Spermatogonia Primary oocyte Sister chromatids MEIOSIS 2 DNA replicates but no cell division. 46 chromosomes, duplicated Sister chromatids Primary spermatocyte First polar body (may not occur) Disintegrates Secondary oocyte (egg) Egg released from ovary at ovulation. Reproductive adult 3 First meiotic division Primary gamete divides into two secondary gametes. 23 chromosomes, duplicated 4 Second meiotic division Secondary gamete divides. 23 chromosomes (haploid) Reproductive adult Secondary spermatocytes Spermatids develop into Sperm One primary oocyte yields 1 egg. 6 FERTILIZATION One primary spermatocyte yields 4 sperm. 5 Second polar body disintegrates. Fig. 26.5 Unfertilized egg passes out of body. Zygote both androgens and estrogens, but androgens predominate in males, and estrogens are dominant in females. In men, most testosterone is secreted by the testes, but about 5% comes from the adrenal cortex. Testosterone is converted in peripheral tissues to its more potent derivative DHT. Some of the physiological effects attributed to testosterone are actually the result of DHT activity. Males synthesize some estrogens, but the feminizing effects of these compounds are usually not obvious in males. Both testes and ovaries contain the enzyme aromatase, which converts 908

Reproduction and Development HORMONAL CONTROL OF REPRODUCTION (a) In both sexes, the brain controls reproduction through GnRH and pituitary gonadotropins (FSH and LH). KEY Internal and environmental stimuli CNS GnRH = gonadotropin- Stimulus releasing hormone Integrating center LH = luteinizing hormone Output signal GnRH Hypothalamus Short-loop negative feedback Target FSH = follicle-stimulating Tissue response hormone Anterior pituitary (b) Feedback effects of sex steroids on gonadotropin release Long-loop feedback may be negative or positive LH es al m Fe Steroid and peptide hormones Gonads (ovaries or testes) ly on Endocrine cells FSH Gamete production STEROID HORMONE EFFECT GONADOTROPIN LEVEL Low estrogen or androgen Absence of negative feedback Increases Moderate estrogen or androgen Negative feedback Decreases High androgen Negative feedback Decreases Sustained high estrogen Positive feedback Increases 26 Fig. 26.6 androgens to estrogens, the female sex hormones. A small amount of estrogen is also made in peripheral tissues. In women, the ovary produces estrogens (particularly estradiol and estrone) and progestins, particularly progesterone. The ovary and the adrenal cortex produce small amounts of androgens. Control Pathways The hormonal control of reproduction in both sexes follows the basic hypothalamus-anterior pituitary-peripheral gland pattern ( Fig. 26.6). Gonadotropin-releasing hormone (GnRH*) from the hypothalamus controls secretion of two anterior pituitary gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). FSH and LH in turn act on the gonads. FSH, along with steroid sex hormones, is required to initiate and maintain gametogenesis. LH acts primarily on endocrine cells, stimulating production of the steroid sex hormones. Although primary control of gonadal function arises in the brain, the gonads also influence their own function. Both *GnRH is sometimes called luteinizing hormone releasing hormone (LHRH) because it was first thought to have its primary effect on LH. ovary and testis secrete peptide hormones that feed back to act directly on the pituitary. Inhibins inhibit FSH secretion, and related peptides called activins stimulate FSH secretion. Activins also promote spermatogenesis, oocyte maturation, and development of the embryonic nervous system. These gonadal peptides are produced in nongonadal tissues as well, and their other functions are still being investigated. AMH, introduced earlier in the discussion of sexual differentiation during development, is also made by cells of both ovary and testis after birth. The inhibins, activins, and AMH are part of a large family of related growth and differentiation factors known as the transforming growth factor - b family. Feedback Pathways The feedback loops of the reproductive system also become quite complex. The feedback pathways for trophic hormones follow the general patterns for long-loop and short-loop feedback. Gonadal hormones alter secretion of GnRH, FSH, and LH in a long-loop response, and the pituitary gonadotropins inhibit GnRH release from the hypothalamus by a short-loop path (Fig. 26.6a). 909

When circulating levels of gonadal steroids are low, the pituitary secretes FSH and LH ( Fig. 26.6 b). As steroid secretion increases, negative feedback usually inhibits gonadotropin release. Androgens always maintain negative feedback on gonadotropin release: as androgen levels go up, FSH and LH secretion decreases. However, in an unusual twist, higher concentrations of estrogen can exert either positive or negative feedback. Low levels of estrogen have no feedback effect. Moderate concentrations of estrogen have a negative feedback effect. But if estrogen rises rapidly to a threshold level and remains high for at least 36 hours, feedback switches from negative to positive, and gonadotropin release (particularly LH) is stimulated. The paradoxical effects of estrogen on gonadotropin release play a significant role in the female reproductive cycle, as you will learn later in this chapter. Scientists still do not fully understand the mechanism underlying the change from negative to positive feedback with estrogen. Some evidence suggests that high levels of estrogen increase the number of GnRH receptors in the anterior pituitary, making it more sensitive to GnRH (up-regulation of receptors). Other evidence points to estrogen influencing GnRH release by altering the release of a peptide called kisspeptin from hypothalamic neurons. Pulsatile GnRH Release Tonic GnRH release from the hypothalamus occurs in small pulses every 1 3 hours in both males and females. The region of the hypothalamus that contains the GnRH neuron cell bodies has been called a GnRH pulse generator because it coordinates the periodic pulsatile secretion of GnRH. Scientists wondered why tonic GnRH release occurred in pulses rather than in a steady fashion, but several studies have shown the significance of the pulses. Children who suffer from a GnRH deficiency will not mature sexually in the absence of gonadotropin stimulation of the gonads. If treated with steady infusions of GnRH through drug-delivery pumps, these children still fail to mature sexually. But if the pumps are adjusted to deliver GnRH in pulses similar to those that occur naturally, the children will go through puberty. Apparently, steady high levels of GnRH cause down-regulation of the GnRH receptors on gonadotropin cells, making the pituitary unable to respond to GnRH. This receptor down-regulation is the basis for the therapeutic use of GnRH in treating certain disorders. For example, patients with prostate and breast cancers stimulated by androgens or estrogens may be given GnRH agonists to slow the growth of the cancer cells. It seems paradoxical to give these patients a drug that stimulates secretion of androgens and estrogens, but after a brief increase in FSH and LH, the pituitary becomes insensitive to GnRH. Then FSH and LH secretion decreases, and gonadal output of steroid hormones also falls. In essence, the GnRH agonist creates chemical castration that reverses when the drug is no longer administered. Environmental Factors Influence Reproduction Among the least-understood influences on reproductive hormones and gametogenesis are environmental effects. In men, factors that influence gametogenesis are difficult to monitor short of requesting periodic sperm counts. Disruption of the normal reproductive cycle in women is easier to study because physiological uterine bleeding in the menstrual cycle is easily monitored. Factors that affect reproductive function in women include stress, nutritional status, and changes in the day-night cycle, such as those that occur with travel across time zones or with shift work. The hormone melatonin from the pineal gland mediates reproduction in seasonally breeding animals, such as birds and deer, and researchers are investigating whether melatonin also plays a role in seasonal and daily rhythms in humans. Environmental estrogens are also receiving a lot of attention. These are naturally occurring compounds, such as the phytoestrogens of plants, or synthetic compounds that have been released into the environment. Some of these compounds bind to estrogen receptors in both sexes and mimic estrogen s effects. Others are anti-estrogens that block estrogen receptors or interfere with second messenger pathways or protein synthesis. Growing evidence suggests that some of these endocrine disruptors can adversely influence developing embryos and even have their effects passed down to subsequent generations. Now that you have learned the basic patterns of hormone secretion and gamete development, let s look in detail at the male and female reproductive systems. Concept Check 9. What does aromatase do? Answers: End of chapter 10. What do the following abbreviations stand for? (Spelling counts!) FSH, DHT, SRY, LH, GnRH, AMH 11. Name the hypothalamic and anterior pituitary hormones that control reproduction. Male Reproduction Th e male reproductive system consists of the testes, the internal genitalia (accessory glands and ducts), and the external genitalia. The external genitalia consist of the penis and the scrotum, a saclike structure that contains the testes. The 910

urethra serves as a common passageway for sperm and urine, although not simultaneously. It runs through the ventral aspect of the shaft of the penis ( Fig. 26.7 a) and is surrounded by a spongy column of tissue known as the corpus spongiosum { corpus, body; plural corpora }. The corpus spongiosum and two columns of tissue called the corpora cavernosa constitute the erectile tissue of the penis. Th e tip of the penis is enlarged into a region called the glans that at birth is covered by a layer of skin called the foreskin, or prepuce. In some cultures, the foreskin is removed surgically in a procedure called circumcision. In the United States, this practice goes through cycles of popularity. Proponents of the procedure claim that it is necessary for good hygiene, and they cite evidence suggesting that the incidence of penile cancer, sexually transmitted diseases, and urinary tract infections is lower in circumcised men. Studies from Africa indicate that circumcising heterosexual adult men helps prevent infection with the HIV virus that causes AIDS (acquired immunodeficiency syndrome). Opponents of circumcision claim that subjecting newborn boys to this surgical procedure is unnecessary. The scrotum is an external sac into which the testes migrate during fetal development. This location outside the abdominal cavity is necessary because normal sperm development requires a temperature that is 2 3 F lower than core body temperature. Men who have borderline or low sperm counts are advised to switch from jockey-style underwear, which keeps the scrotum close to the body, to boxer shorts, which allow the testes to stay cooler. The failure of one or both testes to descend is known as cryptorchidism { crypto, hidden + orchis, testicle} and occurs in 1 3% of newborn males. If left alone, about 80% of cryptorchid testes spontaneously descend later. Those that remain in the abdomen through puberty become sterile and are unable to produce sperm. Although cryptorchid testes lose their sperm-producing potential, they can produce androgens, indicating that hormone production is not as temperature sensitive as sperm production. Because undescended testes are prone to become cancerous, authorities recommend that they be moved to the scrotum with testosterone treatment or, if necessary, surgically. Th e male accessory glands and ducts include the prostate gland, the seminal vesicles, and the bulbourethral (Cowper s) glands ( Fig. 26.7 b). The bulbourethral glands and seminal vesicles empty their secretions into the urethra through ducts. The individual glands of the prostate open directly into the urethral lumen. The prostate gland is the best known of the three accessory glands because of its medical significance. Cancer of the prostate is the most common form of cancer in men, and benign prostatic hypertrophy (enlargement) creates problems for many men after age 50. Because the prostate gland completely encircles the urethra, its enlargement causes difficulty in urinating by narrowing the passageway. Fetal development of the prostate gland, like that of the external genitalia, is under the control of dihydrotestosterone. Discovery of the role of DHT in prostate growth led to the development of finasteride, a 5a -reductase inhibitor that blocks DHT production. This drug was the first nonsurgical treatment for benign prostatic hypertrophy. Th e Prostate Cancer Prevention Trial (PCPT) was a placebo-controlled study to see if finasteride could also prevent prostate cancer. Nearly 19,000 men participated, with half of them receiving the drug and half receiving a placebo. The trial was stopped a year early after analysis of the results showed that the risk of developing prostate cancer fell by 25% in the men taking the drug. Testes Produce Sperm and Hormones The human testes are paired ovoid structures about 5 cm by 2.5 cm ( Fig. 26.7 a). The word testis means witness in Latin, but the reason for its application to male reproductive organs is not clear. Testes are also called testicles. Th e testes have a tough outer fibrous capsule that encloses masses of coiled seminiferous tubules clustered into 250 300 compartments ( Fig. 26.7 c). Interstitial tissue consisting primarily of blood vessels and the testosterone-producing Leydig cells lies between the tubules ( Fig. 26.7 e). The seminiferous tubules constitute nearly 80% of the testicular mass in an adult. Each individual tubule is 0.3 1 meter long, and, if stretched out and laid end to end, the entire mass would extend for about the length of two and a half football fields. Th e seminiferous tubules leave the testis and join the epididymis { epi-, upon + didymos, twin}, a single duct that forms a tightly coiled cord on the surface of the testicular capsule ( Fig. 26.7 c). The epididymis becomes the vas deferens { vas, vessel + deferre, to carry away from}, also known as the ductus deferens. This duct passes into the abdomen, where it eventually empties into the urethra, the passageway from the urinary bladder to the external environment (see Fig. 26.7 a). Seminiferous Tubules The seminiferous tubules are the site of sperm production and contain two types of cells: spermatogonia in various stages of becoming sperm and Sertoli cells ( Fig. 26.7 d, e). The developing spermatocytes stack in columns from the outer edge of the tubule to the lumen. Between each column is a single Sertoli cell that extends from the outer edge of the tubule to the lumen. Surrounding the outside of the tubule is a basal lamina ( Fig. 26.7 e) that acts as a barrier, preventing certain large molecules in the interstitial fluid from entering the tubule but allowing testosterone to enter easily. Adjacent Sertoli cells in a tubule are linked to each other by tight junctions that form an additional barrier between the 26 911

Fig. 26.7 ANATOMY SUMMARY The Male Reproductive System (a) Reproductive anatomy of the male Ureter Urinary bladder Prostate gland surrounds the urethra. Urethra Bulbourethral gland Seminal vesicle Vas (ductus) deferens transports sperm from testes to urethra. Opening to ejaculatory duct Penis Corpus spongiosum Corpora cavernosa Glans Dorsal blood vessels Corpora cavernosa Central artery Prepuce (foreskin) The scrotum holds the testes outside the abdominal cavity to keep them below body core temperature. Testis Corpus spongiosum Urethra (b) Lateral view Ureter Rectum Pubic symphysis (cartilage) Vas deferens Ejaculatory duct Urethra Urinary bladder These accessory glands contribute secretions to semen. Seminal vesicle Prostate gland Bulbourethral gland Penis Epididymis Scrotum The testis is the site of sperm and hormone production. 912

(c) Cutaway view of a testis showing coiled tubules (d) Cross section of a seminiferous tubule Head of epididymis Seminiferous tubule Lumen Capillary Sertoli cell Leydig cell Spermatogonium Epididymis Vas deferens Scrotal cavity (e) Sperm development Germ cells Mature sperm Spermatozoa Spermatids Secondary spermatocyte Primary spermatocyte Spermatogonium Lumen of seminiferous tubule Luminal fluid composition is high in K + and steroid hormones. Sertoli cells secrete proteins to support sperm production. Tight junction between Sertoli cells Fibroblast Basal lamina Interstitial tissue Capillary Leydig cells secrete testosterone. (f) Semen is composed of sperm and secretions from the accessory glands. (g) A sperm consists of a head with enzymes and DNA, a long tail, and mitochondria. COMPONENT FUNCTION SOURCE Sperm Mucus Gametes Lubricant Seminiferous tubules Bulbourethral glands Water Provides liquid medium All accessory glands Head Mid piece Acrosome contains enzymes to aid fertilization. Nucleus Buffers Neutralize acidic environment of vagina Prostate, bulbourethral glands Nutrients Fructose Citric acid Vitamin C Carnitine Nourish sperm Seminal vesicles Prostate Seminal vesicles Epididymis Centrioles Mitochondrial spiral Enzymes Clot semen in vagina, then liquefy the clot Seminal vesicles and prostate Microtubules Zinc Unknown, possible association with fertility Unknown Tail (flagellum) Prostaglandins Smooth muscle Seminal vesicles FIGURE QUESTION contraction; may aid sperm transport What is the function of mitochondria in sperm? 913

Reproduction and Development lumen of the tubule and the interstitial fluid outside the tubule. These tight junctions are sometimes called the bloodtestis barrier because functionally they behave much like the impermeable capillaries of the blood-brain barrier, restricting movement of molecules between two compartments. The basal lamina and tight junctions create three compartments: the tubule lumen, a basal compartment on the basolateral side of the Sertoli cells, and the interstitial fluid. Because of the barriers between these compartments, the luminal fluid has a composition different from that of interstitial fluid, with low concentrations of glucose and high concentrations of K + and steroid hormones. HORMONAL CONTROL OF SPERMATOGENESIS Hypothalamus Anterior pituitary Sperm Production Spermatogonia, the germ cells that undergo meiotic division to become sperm, are found clustered near the basal ends of the Sertoli cells, just inside the basal lamina of the seminiferous tubules (Fig. 26.7d,e). In this basal compartment, they undergo mitosis to create additional germ cells. Some of the spermatogonia remain here to produce future spermatogonia. Other spermatogonia start meiosis and become primary spermatocytes. As spermatocytes differentiate into sperm, they move inward toward the tubule lumen, continuously surrounded by Sertoli cells. The tight junctions of the blood-testis barrier break and reform around the migrating cells, ensuring that the barrier remains intact. By the time spermatocytes reach the luminal ends of Sertoli cells, they have divided twice and become spermatids (Fig. 26.5). Spermatids remain embedded in the apical membrane of Sertoli cells while they complete the transformation into sperm, losing most of their cytoplasm and developing a flagellated tail (Fig. 26.7g). The chromatin of the nucleus condenses into a dense structure that fills most of the head, while a lysosome-like vesicle called an acrosome flattens out to form a cap over the tip of the nucleus. The acrosome contains enzymes essential for 914 FSH Sertoli Cells The function of Sertoli cells is to regulate sperm development. Another name for Sertoli cells is sustentacular cells because they provide sustenance, or nourishment, for the developing spermatogonia. Sertoli cells manufacture and secrete proteins that range from the hormones inhibin and activin to growth factors, enzymes, and androgen-binding protein (ABP). ABP is secreted into the seminiferous tubule lumen, where it binds to testosterone ( Fig. 26.8). Testosterone bound to protein is less lipophilic and cannot diffuse out of the tubule lumen. Leydig Cells Leydig cells, located in the interstitial tissue between seminiferous tubules (Fig. 26.7d,e), secrete testosterone. They first become active in the fetus, when testosterone is needed to direct development of male characteristics. After birth, the cells inactivate. At puberty they resume testosterone production. The Leydig cells also convert some testosterone to estradiol. GnRH LH Leydig cells Testosterone (T) Inhibin Spermatogonium To body for secondary effects Spermatocyte Testes Second messenger Sertoli cell Sertoli cell Cell products Androgen-binding protein (ABP) ABP T Fig. 26.8 fertilization. Mitochondria to produce energy for sperm movement concentrate in the midpiece of the sperm body, along with microtubules that extend into the tail. The result is a small, motile gamete that bears little resemblance to the parent spermatid. Sperm are released into the lumen of the seminiferous tubule, along with secreted fluid. From there, they are free to move out of the testis. The entire development process from spermatogonium division until sperm release takes about 64 days. At any given time, different regions of the tubule contain spermatocytes in different stages of development. The staggering of developmental stages allows sperm production to remain nearly constant at a rate of 200 million sperm per day. That may sound like an extraordinarily high number, but it is about the number of sperm released in a single ejaculation.

Sperm just released from Sertoli cells are not yet mature and are incapable of swimming. They are pushed out of the tubule lumen by other sperm and by bulk flow of the fluid secreted by Sertoli cells. Sperm entering the epididymis complete their maturation during the 12 or so days of their transit time, aided by protein secretions from epididymal cells. Spermatogenesis Requires Gonadotropins and Testosterone Th e hormonal control of spermatogenesis follows the general pattern described previously: hypothalamic GnRH promotes release of LH and FSH from the anterior pituitary ( Fig. 26.8 ). FSH and LH in turn stimulate the testes. The gonadotropins were named originally for their effect on the female ovary, but the same names have been retained in the male. GnRH release is pulsatile, peaking every 1.5 hours, and LH release follows the same pattern. FSH levels are not as obviously related to GnRH secretion because FSH secretion is also influenced by inhibin and activin. FSH targets Sertoli cells. Unlike oocytes, male germ cells do not have FSH receptors. Instead, FSH stimulates Sertoli RUNNING PROBLEM Infertility can be caused by problems in either the man or the woman. Sometimes, however, both partners have problems that contribute to their infertility. In general, male infertility is caused by low sperm counts, abnormalities in sperm morphology, or abnormalities in the reproductive structures that carry sperm. Female infertility may be caused by problems in hormonal pathways that govern maturation and release of eggs or by abnormalities of the reproductive structures (cervix, uterus, ovaries, oviducts). Because tests of male fertility are simple to perform, Dr. Coddington first analyzes Larry s sperm. In this test, trained technicians examine a fresh sperm sample under a microscope. They note the shape and motility of the sperm and estimate the concentration of sperm in the sample. Q1: Name (in order) the male reproductive structures that carry sperm from the testes to the external environment. Q2: A new technique for the treatment of male infertility involves retrieval of sperm from the epididymis. The retrieved sperm can be used to fertilize an egg, which is then implanted in the uterus. Which causes of male infertility might make this treatment necessary? synthesis of paracrine molecules needed for spermatogonia mitosis and spermatogenesis. In addition, FSH stimulates production of androgen-binding protein and inhibin. Th e primary target of LH is the Leydig cells, which produce testosterone. In turn, testosterone feeds back to inhibit LH and GnRH release. Testosterone is essential for spermatogenesis, but its actions appear to be mediated by Sertoli cells, which have androgen receptors. Spermatocytes lack androgen receptors and cannot respond directly to testosterone. Spermatogenesis is a very difficult process to study in vivo or in vitro, and the available animal models may not accurately reflect the situation in the human testis. For these reasons, it may be some time before we can say with certainty how testosterone and FSH regulate spermatogenesis. Concept Check 12. What do Sertoli cells secrete? What do Leydig cells secrete? Answers: End of chapter 13. Because GnRH agonists cause down-regulation of GnRH receptors, what would be the advantages and disadvantages of using these drugs as a male contraceptive? 14. Name another important lipophilic molecule that binds to protein to make it more soluble in body fluid. Male Accessory Glands Contribute Secretions to Semen The male reproductive tract has three accessory glands bulbourethral glands, seminal vesicles, and prostate whose primary function is to secrete various fluid mixtures ( Fig. 26.7 b). When sperm leave the vas deferens during ejaculation, they are joined by these secretions, resulting in a sperm-fluid mixture known as semen. About 99% of the volume of semen is fluid added from the accessory glands. Accessory gland contributions to the composition of semen are listed in Figure 26.7 f. Semen provides a liquid medium for delivering sperm. The bulbourethral glands contribute mucus for lubrication and buffers to neutralize the usually acidic environment of the vagina. Seminal vesicles contribute prostaglandins that appear to influence sperm motility and transport in both male and female reproductive tracts. Prostaglandins were originally believed to come from the prostate gland, and the name was well established by the time their true source was discovered. Both the prostate and seminal vesicles contribute nutrients for sperm metabolism. In addition to providing a medium for sperm, accessory gland secretions help protect the male reproductive tract from pathogens that might ascend the urethra from the external environment. The secretions physically flush out the urethra and supply immunoglobulins, lysozyme, and other compounds with 26 915

antibacterial action. One interesting component of semen is zinc. Its role in reproduction is unclear, but concentrations of zinc below a certain level are associated with male infertility. Androgens Influence Secondary Sex Characteristics Androgens have a number of effects on the body in addition to gametogenesis. These effects are divided into primary and secondary sex characteristics. Primary sex characteristics are the internal sexual organs and external genitalia that distinguish males from females. As you have already learned, androgens are responsible for the differentiation of male genitalia during embryonic development and for their growth during puberty. The secondary sex characteristics are other traits that distinguish males from females. The male body shape is sometimes described as an inverted triangle, with broad shoulders and narrow waist and hips. The female body is usually more pear shaped, with broad hips and narrow shoulders. Androgens are responsible for such typically male traits as beard and body hair growth, muscular development, thickening of the vocal chords with subsequent lowering of the voice, and behavioral effects, such as the sex drive, also called libido { libido, desire, lust]. Androgens are anabolic hormones that promote protein synthesis, which gives them their street name of anabolic steroids. The illicit use of these drugs by athletes has been widespread despite possible adverse side effects such as liver tumors, infertility, and excessive aggression ( roid rage ). One of the more interesting side effects is the apparent addictiveness of anabolic steroids. Withdrawal from the drugs may be associated with behavioral changes that include depression, psychosis, or aggression. These psychiatric disturbances suggest that human brain function can be modulated by sex steroids, just as the brain function of other animals can. Fortunately, many side effects of anabolic steroids are reversible once their use is discontinued. Concept Check Answers: End of chapter 15. Explain why the use of exogenous anabolic steroids might shrink a man s testes and make him temporarily infertile. Female Reproduction Female reproduction is an example of a physiological process that is cyclic rather than steady state. The cycles of gamete production in the ovary and the interactions of reproductive hormones and feedback pathways are part of one of the most complex control systems of the human body. Females Have an Internal Uterus The female external genitalia are known collectively as either the vulva or the pudendum {vulva, womb; pudere, to be ashamed}. They are shown in Figure 26.9c, the view seen by a healthcare worker who is about to do a pelvic exam or take a Pap smear. Starting at the periphery are the labia majora {labium, lip}, folds of skin that arise from the same embryonic tissue as the scrotum. Within the labia majora are the labia minora, derived from embryonic tissues that in the male give rise to the shaft of the penis (see Fig. 26.2b). The clitoris is a small bud of erectile, sensory tissue at the anterior end of the vulva, enclosed by the labia minora and an additional fold of tissue equivalent to the foreskin of the penis. In females, the urethra opens to the external environment between the clitoris and the vagina { vagina, sheath}, the cavity that acts as receptacle for the penis during intercourse. At birth, the external opening of the vagina is partially closed by a thin ring of tissue called the hymen, or maidenhead. The hymen is external to the vagina, not within it, so the normal use of tampons during menstruation will not rupture the hymen. However, it can be stretched by normal activities such as cycling and horseback riding and therefore is not an accurate indicator of a woman s virginity. Now let s follow the path of sperm deposited in the vagina during intercourse. To continue into the female reproductive tract, sperm must pass through the narrow opening of the cervix, the neck of the uterus that protrudes slightly into the upper end of the vagina ( Fig. 26.9 a). The cervical canal is lined with mucous glands whose secretions create a barrier between the vagina and uterus. Sperm that make it through the cervical canal arrive in the lumen of the uterus, or womb, a hollow, muscular organ slightly smaller than a woman s clenched fist. The uterus is the structure in which fertilized eggs implant and develop during pregnancy. It is composed of three tissue layers ( Fig. 26.9 d): a thin outer connective tissue covering, a thick middle layer of smooth muscle known as the myometrium, and an inner layer known as the endometrium {metra, womb}. The endometrium consists of an epithelium with glands that dip into a connective tissue layer below. The thickness and character of the endometrium vary during the menstrual cycle. Cells of the epithelial lining alternately proliferate and slough off, accompanied by a small amount of bleeding in the process known as menstruation {menstruus, monthly}. Sperm swimming upward through the uterus leave its cavity through openings into the two fallopian tubes ( Fig. 26.9 a). The fallopian tubes are 20 25 cm long and about the diameter of a drinking straw. Their walls have two layers of smooth muscle, longitudinal and circular, similar to the walls of the intestine. A ciliated epithelium lines the inside of the tubes. Fluid movement created by the cilia and aided by muscular contractions transports an egg along the fallopian tube toward 916

the uterus. If sperm moving up the tube encounter an egg moving down the tube, fertilization may occur. Pathological conditions in which ciliary function is absent are associated with female infertility and with pregnancies in which the embryo implants in the fallopian tube rather than the uterus. The flared open end of the fallopian tube divides into fingerlike projections called fimbriae { fimbriae, fringe}. The fimbriae ( Fig. 26.9 a) are held close to the adjacent ovary by connective tissue, which helps ensure that eggs released from the surface of the ovary will be swept into the tube rather than floating off into the abdominal cavity. The Ovary Produces Eggs and Hormones The ovary is an elliptical structure, about 2 4 cm long ( Fig. 26.9 e). It has an outer connective tissue layer and an inner connective tissue framework known as the stroma { stroma, mattress}. Most of the ovary consists of a thick outer cortex filled with ovarian follicles in various stages of development or decline. The small central medulla contains nerves and blood vessels. Th e ovary, like the testis, produces both gametes and hormones. As mentioned earlier, about 7 million oögonia in the embryonic ovary develop into half a million primary oocytes. Each primary oocyte is enclosed in a primary follicle with a single layer of granulosa cells separated by a basement membrane from an outer layer of cells known as the theca { theke, case or cover}. A Menstrual Cycle Lasts about One Month Female humans produce gametes in monthly cycles (average 28 days; normal range 24 35 days). These cycles are commonly called menstrual cycles because they are marked by a 3 7 day period of bloody uterine discharge known as the menses { menses, months}, or menstruation. The menstrual cycle can be described by following changes that occur in follicles of the ovary, the ovarian cycle, or by following changes in the endometrial lining of the uterus, the uterine cycle. Figure 26.10 is a summary figure showing a typical menstrual cycle and its phases. Notice that the ovarian cycle is divided into three phases: 1 Follicular phase. The first part of the ovarian cycle, known as the follicular phase, is a period of follicular growth in the ovary. This phase is the most variable in length and lasts from 10 days to 3 weeks. 2 Ovulation. Once one or more follicles have ripened, the ovary releases the oocyte(s) during ovulation. 3 Luteal phase. The phase of the ovarian cycle following ovulation is known as the postovulatory or luteal phase. The second name comes from the transformation of a ruptured follicle into a corpus luteum { corpus, body + luteus, yellow}, named for its yellow pigment and lipid deposits. The corpus luteum secretes hormones that continue the preparations for pregnancy. If a pregnancy does not occur, the corpus luteum ceases to function after about two weeks, and the ovarian cycle begins again. Th e endometrial lining of the uterus also goes through a cycle the uterine cycle regulated by ovarian hormones: 1 Menses. The beginning of the follicular phase in the ovary corresponds to menstrual bleeding from the uterus. 2 Proliferative phase. The latter part of the ovary s follicular phase corresponds to the proliferative phase in the uterus, during which the endometrium adds a new layer of cells in anticipation of pregnancy. 3 Secretory phase. After ovulation, hormones from the corpus luteum convert the thickened endometrium into a secretory structure. This means that the luteal phase of the ovarian cycle corresponds to the secretory phase of the uterine cycle. If no pregnancy occurs, the superficial layers of the secretory endometrium are lost during menstruation as the uterine cycle begins again. Hormonal Control of the Menstrual Cycle Is Complex The ovarian and uterine cycles are under the primary control of various hormones: GnRH from the hypothalamus FSH and LH from the anterior pituitary Estrogen, progesterone, inhibin, and AMH from the ovary During the follicular phase, the dominant steroid hormone is estrogen ( Fig. 26.10 ). Ovulation is triggered by surges in LH and FSH. In the luteal phase, progesterone is dominant, although estrogen is still present. Anti-Müllerian hormone (AMH) was first known for its role in male development, but scientists have discovered that AMH is also produced by ovarian follicles in the first part of the ovarian cycle. AMH apparently acts as a brake to keep too many follicles from developing at one time. Now let s go through an ovarian cycle in detail. Early Follicular Phase Th e first day of menstruation is day 1 of a cycle. This point was chosen to start the cycle because the bleeding of menstruation is an easily observed physical sign. Just before the beginning of each cycle, gonadotropin secretion from the anterior pituitary increases. Under the influence of FSH, several follicles in the ovaries begin to mature (second row of Fig. 26.10 and Fig. 26.11 ). As the follicles grow, their granulosa cells (under the influence of FSH) and their thecal cells (under the influence of LH) start to produce steroid hormones ( Fig. 26.12 ). Granulosa cells also begin to secrete AMH. This AMH decreases follicle 26 917

Fig. 26.9 ANATOMY SUMMARY The Female Reproductive System (a) Internal reproductive structures Uterine cavity Fallopian tube Ovary Fimbriae Mammary glands Uterus Cervical canal Cervix Vagina (b) Cross-sectional view of pelvis Ovary Fallopian tube Uterus Urinary bladder Cervix Pubic symphysis Rectum Urethra Vagina Clitoris Labium minus Labium majus Anus 918

(c) Female external genitalia This is the view seen by a healthcare provider doing a pelvic exam. Clitoris Labium minus Labium majus Urethral opening Vagina Hymen (stretched) Anus 26 (d) Structure of the uterus Endometrium is glandular epithelium whose structure varies with phases of the menstrual cycle. Myometrium is smooth muscle. Outer connective tissue (e) Cross section of an ovary, showing all different stages of follicular development. Secondary follicle Oocyte Primary follicles Uterine cavity Mature follicle Uterine artery Ruptured follicle Stroma Artery Vein Ovulated oocyte Corpus luteum Regressing corpus luteum 919

THE MENSTRUAL CYCLE This 28-day menstrual cycle is divided into phases based on events in the ovary (ovarian cycle) and in the uterus (uterine cycle). PHASES OF THE OVARIAN CYCLE Gonadotrophic hormone levels FOLLICULAR PHASE OVULATION LUTEAL PHASE LH FSH Ovarian cycle Primary follicle Theca Antrum Ovulation Corpus luteum formation Mature corpus luteum Corpus albicans Ovarian hormone levels Progesterone Estrogen Inhibin Uterine cycle PHASES OF THE UTERINE CYCLE MENSES PROLIFERATIVE PHASE SECRETORY PHASE Basal body temperature 36.7 ( C) 36.4 Fig. 26.10 DAYS 28/0 7 14 21 28/0 920

FOLLICULAR DEVELOPMENT Surface epithelium Theca Basal lamina Granulosa cells Antral fluid Antrum Primary follicle Secondary follicle Tertiary follicle Ovulation Corpus luteum formation Corpus albicans OVARIAN PHASE BEFORE FSH STIMULATION EARLY FOLLICULAR PHASE LATE FOLLICULAR PHASE LUTEAL PHASE POST-LUTEAL PHASE Follicle stage Primary follicle Secondary follicle Tertiary follicle Corpus luteum Corpus albicans Ovum Primary oocyte Primary oocyte Becomes secondary oocyte with division arrested None None Zona pellucida* Minimal Increased in width Present None None Granulosa cells Single layer 2 6 cell layer 3 4 cell layer Converted to luteal cells Cells degenerate Antrum None None Develops within granulosa layer and fills with fluid; swells to 15 20 mm in diameter Fills with migrating cells None 26 Basal lamina Separates granulosa and theca Present Present Disappears None Theca Single cell layer plus blood vessels Single cell layer Inner layer: secretory and small blood vessels Outer layer: connective tissue, smooth muscle cells, large blood vessels Converted to luteal cells Cells degenerate * The zona pellucida is a glycoprotein coat that protects the ovum. Fig. 26.11 sensitivity to FSH, which apparently prevents recruitment of additional primary follicles once one group has started developing. Physicians now use blood AMH levels as an indicator of how many follicles are developing early in a cycle and as a marker for the condition known as polycystic ovary syndrome (PCOS), in which ovarian follicles form fluid-filled cysts. Thecal cells synthesize androgens that diffuse into the neighboring granulosa cells, where aromatase converts them to estrogens ( Fig. 26.12 a). Gradually increasing estrogen levels in the circulation have several effects. Estrogen exerts negative feedback on pituitary FSH and LH secretion, which prevents the development of additional follicles in the same cycle. At the same time, estrogen stimulates additional estrogen production by the granulosa cells. This positive feedback loop allows the follicles to continue estrogen production even though FSH and LH levels decrease. In the uterus, menstruation ends during the early follicular phase (Fig 26.10). Under the influence of estrogen from developing follicles, the endometrium begins to grow, or proliferate. This period is characterized by an increase in cell number and by enhanced blood supply to bring nutrients and oxygen to the thickening endometrium. Estrogen also causes mucous glands of the cervix to produce clear, watery mucus. Mid to Late Follicular Phase As the follicles enlarge, granulosa cells begin to secrete fluid that collects in a central cavity in 921

Reproduction and Development HORMONAL CONTROL OF THE MENSTRUAL CYCLE LH FSH Ovum Follicle Corpus luteum Estrogen Inhibin Progesterone (a) Early to mid-follicular phase (b) Late follicular phase and ovulation (c) Early to mid-luteal phase (d) Late luteal phase Low levels of estrogen exert negative feedback to GnRH, FSH, LH. Estrogen promotes more estrogen secretion by the follicle. AMH prevents more follicles from developing. Rising levels of estrogen plus increasing progesterone cause the LH surge. FSH is suppressed by inhibin. Combined estrogen and progesterone shut off FSH and LH. Estrogen and progesterone fall when corpus luteum dies. Gonadotropins start follicular development for a new cycle. + GnRH Pituitary + GnRH Hypothalamus FSH LH AMH Estrogens Granulosa cells Thecal cells Androgens High estrogen output Thecal cells Androgens Inhibin FSH LH Corpus luteum (from ovulated follicle) Follicle Granulosa cells Tonic secretion resumes + Follicle + GnRH LH FSH GnRH secretes Estrogen Progesterone Inhibin FSH New follicles begin to develop LH Corpus luteum dies Estrogen and progesterone Small amount of progesterone Fig. 26.12 the follicle known as the antrum {antron, cave} (Fig. 26.11). Antral fluid contains hormones and enzymes needed for ovulation. At each stage of follicular development, some follicles undergo atresia (hormonally regulated cell death). Only a few follicles reach the final stage, and usually only one dominant follicle develops until ovulation. As the follicular phase nears its end, ovarian estrogen secretion peaks (Fig. 26.12b). By this point of the cycle, only one 922 follicle is still developing. As the follicular phase ends, granulosa cells of the dominant follicle begin to secrete inhibin and progesterone in addition to estrogen. Estrogen, which had exerted a negative feedback effect on GnRH earlier in the follicular phase, changes to positive feedback, leading to a preovulatory GnRH surge. Immediately before ovulation, the persistently high levels of estrogen, aided by rising levels of progesterone, enhance

pituitary responsiveness to GnRH. As a result, LH secretion increases dramatically, a phenomenon known as the LH surge. FSH surges also, but to a lesser degree, presumably because it is being suppressed by inhibin and estrogen. Th e LH surge is an essential part of ovulation. Without it, the final steps of oocyte maturation cannot take place. Meiosis resumes in the developing follicle with the first meiotic division, which converts the primary oocyte into a secondary oocyte (egg) and a polar body, which is extruded ( Fig. 26.5 ). While this division is taking place, antral fluid collects and the follicle grows to its greatest size, preparing to release the egg. High levels of estrogen in the late follicular phase prepare the uterus for a possible pregnancy. The endometrium grows to a thickness of 3 4 mm ( Fig. 26.10 ). Just before ovulation, the cervical glands produce copious amounts of thin, stringy mucus to facilitate sperm entry. The stage is set for ovulation. Ovulation About 16 24 hours after LH peaks, ovulation occurs ( Fig. 26.10 ). The mature follicle secretes collagenase, an enzyme that dissolves collagen in the connective tissue holding the follicular cells together. The breakdown products of collagen create an inflammatory reaction, attracting leukocytes that secrete prostaglandins into the follicle. The prostaglandins may cause smooth muscle cells in the outer theca to contract, rupturing the follicle wall at its weakest point. Antral fluid spurts out along with the egg, which is surrounded by two to three layers of granulosa cells. The egg is swept into the fallopian tube and carried away to be fertilized or to die. In addition to promoting follicular rupture, the LH surge causes follicular thecal cells to migrate into the antral space, mingling with the former granulosa cells and filling the cavity. Both cell types then transform into luteal cells of the corpus luteum. This process, known as luteinization, involves biochemical and morphological changes. Early to Mid-Luteal Phase After ovulation, newly formed luteal cells accumulate lipid droplets and glycogen granules in their cytoplasm and begin to secrete progesterone. Estrogen synthesis diminishes initially but as the luteal phase progresses, the corpus luteum produces steadily increasing amounts of progesterone and estrogen. Progesterone is the dominant hormone of the luteal phase. Estrogen levels increase but never reach the peak seen before ovulation. The combination of estrogen and progesterone exerts negative feedback on the hypothalamus and anterior pituitary ( Fig. 26.12 c). Gonadotropin secretion, further suppressed by luteal inhibin production, remains shut down throughout most of the luteal phase. Under the influence of progesterone, the endometrium continues its preparation for pregnancy and becomes a secretory structure. Endometrial glands coil, and additional blood vessels grow into the connective tissue layer. Endometrial cells deposit lipids and glycogen in their cytoplasm. These deposits RUNNING PROBLEM The results of Larry s sperm analysis are normal. Dr. Coddington is therefore able to rule out sperm abnormalities as a cause of Peggy and Larry s infertility. Peggy is instructed to take her body temperature daily and record the results on a chart. This temperature tracking is intended to determine whether or not she is ovulating. Following ovulation, body temperature rises slightly and remains elevated through the remainder of the menstrual cycle. Q3: For which causes of female infertility is temperature tracking useful? For which causes is it not useful? will provide nourishment for a developing embryo while the placenta, the fetal-maternal connection, is developing. Progesterone also causes cervical mucus to thicken. Thicker mucus creates a plug that blocks the cervical opening, preventing bacteria as well as sperm from entering the uterus. One interesting effect of progesterone is its thermogenic ability. During the luteal phase of an ovulatory cycle, a woman s basal body temperature, taken immediately upon awakening and before getting out of bed, jumps 0.3 0.5 F and remains elevated until menstruation. Because this change in the temperature setpoint occurs after ovulation, it cannot be used effectively to predict ovulation. However, it is a simple way to assess whether a woman is having ovulatory or anovulatory (nonovulating) cycles. Late Luteal Phase and Menstruation Th e corpus luteum has an intrinsic life span of approximately 12 days. If pregnancy does not occur, the corpus luteum spontaneously undergoes apoptosis to become an inactive structure called a corpus albicans { albus, white}. As the luteal cells degenerate, progesterone and estrogen production decrease ( Fig. 26.12 d). This fall removes the negative feedback signal to the pituitary and hypothalamus, so secretion of FSH and LH increases. Maintenance of a secretory endometrium depends on the presence of progesterone. When the corpus luteum degenerates and hormone production decreases, blood vessels in the surface layer of the endometrium contract. Without oxygen and nutrients, the surface cells die. About two days after the corpus luteum ceases to function, or 14 days after ovulation, the endometrium begins to slough its surface layer, and menstruation begins. Menstrual discharge from the uterus totals about 40 ml of blood and 35 ml of serous fluid and cellular debris. There are usually few clots of blood in the menstrual flow because of the presence of plasmin, which breaks up clots. 26 923

Menstruation continues for 3 7 days, well into the follicular phase of the next ovulatory cycle. Hormones Influence Female Secondary Sex Characteristics Estrogens control the development of primary sex characteristics in females, just as androgens control them in males. Estrogens also control the most prominent female secondary sex traits: breast development and the female pattern of fat distribution (hips and upper thighs). Other female secondary sex characteristics, however, are governed by androgens produced in the adrenal cortex. Pubic and axillary (armpit) hair growth and libido (sex drive) are under the control of adrenal androgens. Concept Check Answers: End of chapter 16. Name the phases of the ovarian cycle and the corresponding phases of the uterine cycle. 17. What side effects would you predict in female athletes who take anabolic steroids to build muscles? 18. Aromatase converts testosterone to estrogen. What would happen to the ovarian cycle of a woman given an aromatase inhibitor? 19. On what day of the menstrual cycle will a woman with the following cycle lengths ovulate? (a) 28 days (b) 23 days (c) 31 days Procreation Reproduction throughout the animal kingdom is marked by species-specific behaviors designed to ensure that egg and sperm meet. For aquatic animals that release gametes into the water, coordinated timing is everything. Interaction between males and females of these species may be limited to chemical communication by pheromones. In terrestrial vertebrates, internal fertilization requires interactive behaviors and specialized adaptations of the genitalia. For example, the female must have an internal receptacle for sperm (the vagina in humans), and the male must possess an organ (the penis in humans) that can place sperm in the receptacle. The human penis is flaccid (soft and limp) in its resting state, not capable of penetrating the narrow opening of the vagina. In the male sex act, the penis first stiffens and enlarges during erection, and then releases sperm from the ducts of the reproductive tract during ejaculation. Without these events, fertilization cannot take place. The Human Sexual Response Has Four Phases Th e human sex act also known as sexual intercourse, copulation, or coitus { coitio, a coming together} is highly variable in some ways and highly stereotypical in other ways. Human sexual response in both sexes is divided into four phases: (1) excitement, (2) plateau, (3) orgasm, and (4) resolution. In the excitement phase, various erotic stimuli prepare the genitalia for the act of copulation. For the male, excitement involves erection of the penis. For the female, it includes erection of the clitoris and vaginal lubrication. In both sexes, erection is a state of vasocongestion in which arterial blood flow into spongy erectile tissue exceeds venous outflow. Erotic stimuli include sexually arousing tactile stimuli as well as psychological stimuli. Because the latter vary widely among individuals and among cultures, what is erotic to one person or in one culture may be considered disgusting by another individual or in another culture. Regions of the body that possess receptors for sexually arousing tactile stimuli are called erogenous zones and include the genitalia as well as the lips, tongue, nipples, and ear lobes. In the plateau phase, changes that started during excitement intensify and peak in an orgasm (climax). In both sexes, orgasm is a series of muscular contractions accompanied by intense pleasurable sensations and increased blood pressure, heart rate, and respiration rate. In females, the uterus and walls of the vagina contract. In males, the contractions usually result in the ejaculation of semen from the penis. Female orgasm is not required for pregnancy. Th e final phase of the sexual response is resolution, a period during which the physiological parameters that changed in the first three phases slowly return to normal. The Male Sex Act Includes Erection and Ejaculation A key element to successful copulation is the ability of the male to achieve and sustain an erection. Sexual excitement from either tactile or psychological stimuli triggers the erection reflex, RUNNING PROBLEM Results of the temperature tracking for several months reveal that Peggy is ovulating regularly. Dr. Coddington therefore believes that her ovaries are functioning normally. Other possible causes for this couple s infertility include abnormalities in Peggy s cervix, fallopian tubes, or uterus. Dr. Coddington next decides to order a postcoital test. In this test, the couple is instructed to have intercourse 12 hours before the physician visit. Cervical mucus is then analyzed. This test will also analyze the interaction between sperm and mucus. Q4: What abnormalities in the cervix, fallopian tubes, and uterus could cause infertility? 924

a spinal reflex that is subject to control from higher centers in the brain. The urination and defecation reflexes are similar types of reflexes. In its simplest form, the erection reflex begins with tactile stimuli sensed by mechanoreceptors in the glans penis or other erogenous zones ( Fig. 26.13 ). Sensory neurons signal the spinal integration center, which inhibits vasoconstrictive sympathetic input on penile arterioles. Simultaneously, nitric oxide produced by increased parasympathetic input actively dilates the penile arterioles. As arterial blood flows into the open spaces of the erectile tissue, it passively compresses the veins and traps blood. The erectile tissue becomes engorged, stiffening and lengthening the penis within 5 10 seconds. Th e climax of the male sexual act coincides with emission and ejaculation. Emission is the movement of sperm out of the vas deferens and into the urethra, where they are joined by secretions from the accessory glands to make semen. The average semen volume is 3 ml (range 2 6 ml), of which less than 10% is sperm. During ejaculation, semen in the urethra is expelled to the exterior by a series of rapid muscular contractions accompanied by sensations of intense pleasure the orgasm. A sphincter at the base of the bladder contracts to prevent sperm from entering the bladder and urine from joining the semen. Both erection and ejaculation can occur in the absence of mechanical stimulation. Sexually arousing thoughts, sights, sounds, emotions, and dreams can all initiate sexual arousal and even lead to orgasm in both men and women. In addition, nonsexual penile erection accompanies rapid eye movement (REM) sleep. THE ERECTION REFLEX Erection can take place without input from higher brain centers. It can also be stimulated (and inhibited) by descending pathways from the cerebral cortex. Spontaneous erections occur during REM sleep. Thoughts about sex!! KEY Stimulus Sensor Afferent pathway Erotic stimuli Higher brain centers 26 Integrating center Output signal Target Tissue response Descending autonomic pathways Ascending sensory pathway + Parasympathetic stimulated Penile arterioles vasodilate. Sympathetic inhibited Erection Penis Spinal cord Tactile stimuli Sensory neuron Mechanoreceptor Fig. 26.13 925

Sexual Dysfunction Affects Males and Females The inability to achieve or sustain a penile erection is known as erectile dysfunction (ED) or impotence. Erectile dysfunction is a matter of global concern because inability to achieve and sustain an erection disrupts the sex act for both men and women. Organic (physiological and anatomical) causes of ED include neural and hormonal problems, vascular insufficiency, and drug-induced ED. A variety of psychological causes can also contribute to ED. Alcohol inhibits sexual performance in both men and women, as noted by Shakespeare in Macbeth (II, iii). When Macduff asks, What three things does drink especially provoke? the porter answers, Marry, sir, nose-painting, sleep, and urine. Lechery, sir, it provokes and unprovokes: it provokes the desire, but it takes away the performance. Several antidepressant drugs list loss of libido among their side effects. Erectile dysfunction in men over age 40 is now considered a marker for cardiovascular disease and atherosclerosis, and sometimes ED is the first clinical sign of these conditions. Erections occur when neurotransmitters from pelvic nerves increase endothelial production of nitric oxide (NO), which increases cgmp and results in vasodilation of penile arterioles. Endothelial dysfunction and failure to produce adequate NO occur in atherosclerosis and diabetes mellitus, making ED an early manifestation of vascular pathology. In 1998 the U.S. Food and Drug Administration (FDA) approved sildenafil (Viagra ) for the treatment of erectile dysfunction. Sildenafil and similar drugs in the same class prolong the effects of nitric oxide by blocking phosphodiesterase-5 (PDE-5), the enzyme that degrades cgmp. Clinical trials have shown that phosphodiesterase inhibitors are very effective in correcting ED but are not without side effects. The U.S. Federal Aviation Administration issued an order that pilots should not take sildenafil within six hours of flying because 3% of men report impaired color vision (a blue or greenish haze). This impairment occurs because sildenafil also inhibits an enzyme in the retina. When the FDA approved PDE-5 inhibitors for male erectile dysfunction, women wondered if the drug, which promotes the erection reflex, would improve their sexual response. Although women do have clitoral erections, the female sexual response is more complicated. Studies on the efficacy of PDE-5 inhibitors for orgasmic dysfunction in women have had mixed results. Instead, pharmaceutical companies are testing other drugs for female sexual dysfunction. The most promising candidates, now in late clinical trials, are based on testosterone, the androgen that creates libido in both sexes. Contraceptives Are Designed to Prevent Pregnancy One disadvantage of sexual intercourse for pleasure rather than reproduction is the possibility of an unplanned pregnancy. On average, 85% of young women who have sexual intercourse without using any form of birth control will get pregnant within a year. Many women, however, get pregnant after just a single unprotected encounter. Couples who hope to avoid unwanted pregnancies generally use some form of birth control, or contraception. Contraceptive practices fall into several broad groups. Abstinence, the total avoidance of sexual intercourse, is the surest method to avoid pregnancy (and sexually transmitted diseases). Some couples practice abstinence only during times of suspected fertility calculated using fertility-awareness methods of birth control. Sterilization is the most effective contraceptive method for sexually active people, but it is a surgical procedure and is not easily reversed. Female sterilization is called tubal ligation. It consists of tying off and cutting the fallopian tubes. A woman with a tubal ligation still ovulates, but the eggs remain in the abdomen. The male form of sterilization is the vasectomy, in which the vas deferens is tied and clipped. Sperm are still made in the seminiferous tubules, but because they cannot leave the reproductive tract, they are reabsorbed. Interventional methods of contraception include (1) barrier methods, which prevent union of eggs and sperm; (2) methods that prevent implantation of the fertilized egg; and (3) hormonal treatments that decrease or stop gamete production. The efficacy of interventional contraceptives depends in part on how consistently and correctly they are used ( Tbl. 26.1 ). Barrier Methods Contraceptive methods based on chemical or physical barriers are among the earliest recorded means of birth control. Once people made the association between pregnancy and semen, they concocted a variety of physical barriers and spermicides { cida, killer} to kill sperm. An ancient Egyptian papyrus with the earliest known references to birth control describes the use of vaginal plugs made of leaves, feathers, figs, and alum held together with crocodile and elephant dung. Sea sponges soaked in vinegar and disks of oiled silk have also been used at one time or another. In subsequent centuries women used douches of garlic, turpentine, and rose petals to rinse the vagina after intercourse. As you can imagine, many of these methods also caused vaginal or uterine infections. Modern versions of the female barrier include the diaphragm, introduced into the United States in 1916. These rubber domes and a smaller version called a cervical cap are usually filled with a spermicidal cream, then inserted into the top of the vagina so they cover the cervix. One advantage to the diaphragm is that it is nonhormonal. When used properly and regularly, diaphragms are highly effective (97 99%). However, they are not always used because they must be inserted close to the time of intercourse, and consequently about 20% of women who depend on diaphragms for contraception are pregnant within the first year. Another female barrier contraceptive that was recently reintroduced is the contraceptive sponge, which contains a spermicidal chemical. 926

Efficacy of Various Contraceptive Methods Table 26.1 low failure rates (0.5% per year) but side effects that range from pain and bleeding to infertility caused by pelvic inflammatory disease and blockage of the fallopian tubes. Method No contraception 85% Spermicides 29% Abstinence during times of predicted fertility Diaphragm, cervical cap, or sponge Pregnancy Rate With Typical Use * 25% Oral contraceptive pills 8% 16 32% Intrauterine devices (IUDs) < 1% Contraceptive hormone injection < 1% Male condom 15% Female condom 21% Sterilization < 1% * Rates reflect unintentional pregnancies in the first year of using the method. Data are from www.contraceptivetechnology.org/table.html (Accessed 7/22/11). Lower rates are in women who have never delivered a child. The male barrier contraceptive is the condom, a closed sheath that fits closely over the penis to catch ejaculated semen. Males have used condoms made from animal bladders and intestines for centuries. Condoms lost popularity when oral contraceptives came into widespread use in the 1960s and 1970s, but in recent years they have regained favor because they combine pregnancy protection with protection from many sexually transmitted diseases. However, latex condoms may cause allergic reactions, and there is evidence that HIV can pass through pores in some condoms currently produced. A female version of the condom is also commercially available. It covers the cervix and completely lines the vagina, providing more protection from sexually transmitted diseases. Implantation Prevention Some contraceptive methods do not prevent fertilization but do keep a fertilized egg from establishing itself in the endometrium. They include intrauterine devices (IUDs) as well as chemicals that change the properties of the endometrium. IUDs are copper-wrapped plastic devices that are inserted into the uterine cavity, where they create a mild inflammatory reaction that prevents implantation. They have Hormonal Treatments Techniques for decreasing gamete production depend on altering the hormonal milieu of the body. In centuries past, women would eat or drink various plant concoctions for contraception. Some of these substances actually worked because the plants contained estrogen-like compounds. Modern pharmacology has improved on this method, and now women can choose between oral contraceptive pills, injections lasting three months, or a vaginal contraceptive ring (NuvaRing ). Th e oral contraceptives, also known as birth control pills, first became available in 1960. They rely on various combinations of estrogen and progesterone that inhibit gonadotropin secretion from the pituitary. Without adequate FSH and LH, ovulation is suppressed. In addition, progesterones in the contraceptive pills thicken the cervical mucus and help prevent sperm penetration. These hormonal methods of contraception are highly effective when used correctly but also carry some risks, including an increased incidence of blood clots and strokes, especially in women who smoke. Development of a male hormonal contraceptive has been slow because of undesirable side effects. Contraceptives that block testosterone secretion or action are also likely to decrease the male libido or even cause impotence. Both side effects are unacceptable to men who would be most interested in using the contraceptive. Some early male oral contraceptives irreversibly suppressed sperm production, which was also unacceptable. It now appears, however, that a combination of oral progestin to suppress sperm production plus injected testosterone to maintain libido is a promising candidate for a male hormonal contraceptive. Contraceptive vaccines are based on antibodies against various components of the male and female reproductive systems, such as antisperm or antiovum antibodies. These contraceptives can be administered as shots. However, clinical trials of human vaccines have been disappointing and vaccines may not be a practical contraceptive for humans. Infertility Is the Inability to Conceive While some couples are trying to prevent pregnancy, others are spending thousands of dollars trying to get pregnant. Infertility is the inability of a couple to conceive a child after a year of unprotected intercourse. For years, infertile couples had no choice but adoption if they wanted to have a child, but incredible strides have been made in this field since the 1970s. As a result, many infertile couples today are able to have children. Infertility can arise from a problem in the male, the female, or both. Male infertility usually results from a low sperm count or an abnormally high number of defective sperm. Female 26 927

infertility can be mechanical (blocked fallopian tubes or other structural problems) or hormonal, leading to decreased or absent ovulation. One problem involving both partners is that the woman may produce antibodies to her partner s sperm. In addition, not all pregnancies go to a successful conclusion. By some estimates, as many as a third of all pregnancies spontaneously terminate many within the first weeks, before the woman is even aware that she was pregnant. Some of the most dramatic advances have been made in the field of assisted reproductive technology (ART), strategies in which both sperm and eggs are manipulated. For in vitro fertilization, a woman s ovaries are manipulated with hormones to ovulate multiple eggs at one time. The eggs are collected surgically and fertilized outside the body. The developing embryos are then placed in the woman s uterus, which has been primed for pregnancy by hormonal therapy. Because of the expense and complicated nature of the procedure, multiple embryos are usually placed in the uterus at one time, which may result in multiple births. In vitro fertilization has allowed some infertile couples to have children, with a 2009 success rate in the United States averaging 31%. Success varies significantly with age, ranging from 41% for women younger than 35 to 12% for women older than 40. Pregnancy and Parturition Now let s return to a recently ovulated egg and some sperm deposited in the vagina and follow them through fertilization, pregnancy, and parturition, the birth process. Fertilization Requires Capacitation Once an egg is released from the ruptured follicle, it is swept into the fallopian tube by beating cilia. Meanwhile, sperm deposited in the vagina must go through their final maturation step, capacitation, which enables the sperm to swim rapidly and fertilize an egg. The process apparently involves the reorganization of molecules in the outer membrane of the sperm head. RUNNING PROBLEM Analysis of Peggy s postcoital cervical mucus shows that sperm are present but not moving. Dr. Coddington explains that it is likely that Peggy s cervical mucus contains antibodies that destroy Larry s sperm. Q 5 : Speculate on how this kind of infertility problem might be treated. Normally, capacitation takes place in the female reproductive tract, which presents a problem for in vitro fertilization. Those sperm must be artificially capacitated by placing them in physiological saline supplemented with human serum. Much of what we know about human fertilization has come from infertility research aimed at improving the success rate of in vitro fertilization. Fertilization of an egg by a sperm is the result of a chance encounter, possibly aided by chemical attractants produced by the egg. An egg can be fertilized for only about 12 24 hours after ovulation. Sperm in the female reproductive tract remain viable for 5 6 days. Fertilization normally takes place in the distal part of the fallopian tube. Of the millions of sperm in a single ejaculation, only about 100 reach this point. To fertilize the egg, a sperm must penetrate both an outer layer of loosely connected granulosa cells (the corona radiata ) and a protective glycoprotein coat called the zona pellucida ( Fig. 26.14 b). To get past these barriers, capacitated sperm release powerful enzymes from the acrosome in the sperm head, a process known as the acrosomal reaction. The enzymes dissolve cell junctions and the zona pellucida, allowing the sperm to wiggle their way toward the egg. The first sperm to reach the egg quickly finds sperm-binding receptors on the oocyte membrane and fuses its membrane to the egg membrane ( Fig. 26.14 c). The fused section of membrane opens, and the sperm nucleus sinks into the egg s cytoplasm. Fusion of the egg and sperm membranes signals the egg to resume meiosis and complete its second division. The final meiotic division creates a second polar body, which is ejected. At this point, the 23 chromosomes of the sperm join the 23 chromosomes of the egg, creating a zygote nucleus with a full set of genetic material. The fusion of sperm and oocyte membrane triggers a chemical reaction called the cortical reaction. Membranebound cortical granules in the peripheral cytoplasm of the egg release their contents into the space just outside the egg membrane. These chemicals rapidly alter the membrane and surrounding zona pellucida so that additional sperm cannot penetrate or bind. The cortical reaction prevents polyspermy, in which more than one sperm fertilizes an egg. Once an egg is fertilized and becomes a zygote, it begins mitosis as it slowly makes its way along the fallopian tube to the uterus, where it will settle for the remainder of the gestation period { gestare, to carry in the womb}. The Developing Embryo Implants in the Endometrium Th e dividing embryo takes four or five days to move through the fallopian tube into the uterine cavity ( Fig. 26.14 d). Under the influence of progesterone, smooth muscle of the tube relaxes, and transport proceeds slowly. By the time the developing 928

Fertilization must occur within 24 hours of ovulation. (a) This photograph shows the tremendous difference in the sizes of human sperm and egg. (b) Capacitated sperm release enzymes from their acrosomes in order to penetrate the cells and zona pellucida surrounding the egg. Egg Sperm Cells of corona radiata Egg First polar body Second meiotic division suspended Capacitated sperm Zona pellucida (c) The first sperm to fuse with the egg fertilizes it. Sperm and egg plasma membranes fuse. Sperm nucleus moves into cytoplasm of egg. Oocyte nucleus completes meiotic division. Sperm and egg nuclei fuse to form zygote nucleus. Egg First polar body Egg Second polar body is expelled. Sperm nucleus Sperm nucleus (d) Timing of ovulation, fertilization, and implantation 2 Day 1: Fertilization 3 Days 2 4: Cell 4 division takes place. Day 4 5: Blastocyst reaches uterus. Inner cell mass Zygote Fallopian tube 1 Egg Ovulation Ovary Uterus 5 Blastocyst Days 5 9: Blastocyst implants. 929

embryo reaches the uterus, it consists of a hollow ball of about 100 cells called a blastocyst. Some of the outer layer of blastocyst cells will become the chorion, an extraembryonic membrane that will enclose the embryo and form the placenta ( Fig. 26.15 a). The inner cell mass of the blastocyst will develop into the embryo and into other extraembryonic membranes. These membranes include the amnion, which secretes amniotic fluid in which the developing embryo floats; the allantois, which becomes part of the umbilical cord that links the embryo to the mother; and the yolk sac, which degenerates early in human development. Implantation of the blastocyst into the uterine wall normally takes place about 7 days after fertilization. The blastocyst secretes enzymes that allow it to invade the endometrium, like a parasite burrowing into its host. As it does so, endometrial cells grow out around the blastocyst until it is completely engulfed. As the blastocyst continues dividing and becomes an embryo, cells that will become the placenta form fingerlike chorionic villi that penetrate into the vascularized endometrium. Enzymes from the villi break down the walls of maternal blood vessels until the villi are surrounded by pools of maternal blood ( Fig. 26.15 b). The blood of the embryo and that of the mother do not mix, but nutrients, gases, and wastes exchange across the membranes of the villi. Many of these substances move by simple diffusion, but some, such as maternal antibodies, must be transported across the membrane. The placenta continues to grow during pregnancy until, by delivery, it is about 20 cm in diameter (the size of a small dinner plate). The placenta receives as much as 10% of the total maternal cardiac output. The tremendous blood flow to the placenta is one reason sudden, abnormal separation of the placenta from the uterine wall is a medical emergency. The Placenta Secretes Hormones During Pregnancy As the blastocyst implants in the uterine wall and the placenta begins to form, the corpus luteum is nearing the end of its preprogrammed 12-day life span. Unless the developing embryo sends a hormonal signal, the corpus luteum disintegrates, progesterone and estrogen levels drop, and the embryo is flushed from the body along with the surface layers of endometrium during menstruation. Several hormones that prevent menstruation during pregnancy are secreted by the placenta, including THE PLACENTA (a) The developing embryo floats in amniotic fluid. It obtains oxygen and nutrients from the mother through the placenta and umbilical cord. (b) Some material is exchanged across placental membranes by diffusion, but other material must be transported. Umbilical cord Placenta Umbilical vein carries well-oxygenated blood to the embryo. Umbilical arteries return embryonic blood to placenta. Chorionic villi contain embryonic blood vessels. Amniotic fluid Extraembryonic membranes enclose the embryo and form the placenta. Yolk sac Chorion Amnion Umbilical cord Maternal blood bathes the chorionic villi. WEEK 10 Maternal blood vessels Fig. 26.15 Amnion 930

Reproduction and Development human chorionic gonadotropin, human placental lactogen, estrogen, and progesterone. Human Chorionic Gonadotropin The corpus luteum remains active during early pregnancy because of human chorionic gonadotropin (hcg), a peptide hormone secreted by the chorionic villi and developing placenta. Human chorionic gonadotropin is structurally related to LH, and it binds to LH receptors. Under the influence of hcg, the corpus luteum keeps producing progesterone to keep the endometrium intact. By the seventh week of development, however, the placenta has taken over progesterone production, and the corpus luteum is no longer needed. At that point, it finally degenerates. Human chorionic gonadotropin production by the placenta peaks at three months of development, then diminishes. A second function of hcg is stimulation of testosterone production by the developing testes in male fetuses. As you learned in the opening sections of this chapter, fetal testosterone and its metabolite DHT are essential for expression of male characteristics and for descent of the testes into the scrotum before birth. Human chorionic gonadotropin is the chemical detected by pregnancy tests. Because hcg can induce ovulation in rabbits, years ago rabbits were used for pregnancy testing. If a woman suspected she was pregnant, her urine was injected into a rabbit. The rabbit s ovaries were then inspected for signs of ovulation. It took several days for women to learn the results of this test. Today, with modern biochemical techniques, women can perform their own pregnancy tests in a few minutes in the privacy of their home. RUNNING PROBLEM Assisted reproductive technologies (ART) are one treatment option currently available to infertile couples. All ART techniques involve either artificially stimulating the ovaries to produce eggs or using an egg from an egg donor. The eggs are harvested surgically and are fertilized in vitro. The zygote may be placed in the fallopian tube immediately or may be allowed to develop into an early embryo before being placed into the uterus. A different technique used to overcome infertility is intrauterine insemination. In this procedure, sperm that have been washed to remove antigenic material are introduced into the uterus through a tube inserted through the cervix so that fertilization takes place in vivo. Q6: Based on the results of their infertility workup, which intervention ART or intrauterine insemination should be recommended for Peggy and Larry? Why? Human Placental Lactogen (hpl) Another peptide hormone produced by the placenta is human placental lactogen (hpl), also known as human chorionic somatomammotropin (hcs). This hormone, structurally related to growth hormone and prolactin, was initially believed to be necessary for breast development during pregnancy and for milk production (lactation). Although hpl probably does contribute to lactation, women who do not make hpl during pregnancy because of a genetic defect still have adequate breast development and milk production. A second role for hpl is alteration of the mother s glucose and fatty acid metabolism to support fetal growth. Maternal glucose moves across the membranes of the placenta by facilitated diffusion and enters the fetal circulation. During pregnancy, about 4% of women develop gestational diabetes mellitus, with elevated blood glucose levels caused by insulin resistance, similar to type 2 diabetes. After delivery, glucose metabolism in most of these women returns to normal, but these mothers and their babies are at higher risk of developing type 2 diabetes later in life. Estrogen and Progesterone Estrogen and progesterone are produced continuously during pregnancy, first by the corpus luteum under the influence of hcg and then by the placenta. With high circulating levels of these steroid hormones, feedback suppression of the pituitary continues throughout pregnancy, preventing another set of follicles from beginning development. During pregnancy, estrogen contributes to the development of the milk-secreting ducts of the breasts. Progesterone is essential for maintaining the endometrium and in addition helps suppress uterine contractions. The placenta makes a variety of other hormones, including inhibin and prorenin, but the function of most of them remains unclear. 26 Pregnancy Ends with Labor and Delivery Parturition normally occurs between the 38th and 40th week of gestation. What triggers this process? For many years, researchers developed animal models of the signals that initiate parturition, only to discover recently that there are no good non-primate models that apply to humans. Parturition begins with labor, the rhythmic contractions of the uterus that push the fetus out into the world. Signals that initiate these contractions could begin with either the mother or the fetus, or they could be a combination of signals from both. In many nonhuman mammals, a decrease in estrogen and progesterone levels marks the beginning of parturition. A decrease in progesterone levels is logical, as progesterone inhibits uterine contractions. In humans, however, levels of these hormones do not decrease until labor is well under way. Another possible labor trigger is oxytocin, the peptide hormone that causes uterine muscle contraction. As a pregnancy nears full term, the number of uterine oxytocin receptors increases. However, studies have shown that oxytocin secretion does not increase until after labor begins. Synthetic oxytocin is 931

often used to induce labor in pregnant women, but it is not always effective. Apparently, the start of labor requires something more than adequate amounts of oxytocin. Another possibility is that the fetus somehow signals that it has completed development. One theory supported by clinical evidence is that corticotropin-releasing hormone (CRH) secreted by the placenta is the signal to begin labor. (CRH is also a hypothalamic releasing factor that controls release of ACTH from the anterior pituitary.) In the weeks prior to delivery, maternal blood CRH levels increase rapidly. In addition, women with elevated CRH levels as early as 15 weeks of gestation are more likely to go into premature labor. Although we do not know for certain what initiates parturition, we do understand the sequence of events. In the days prior to the onset of active labor, the cervix softens ( ripens ) and ligaments holding the pelvic bones together loosen as enzymes destabilize collagen in the connective tissue. The control of these processes is not clear and may be due to estrogen or the peptide hormone relaxin, which is secreted by ovaries and the placenta. Once the contractions of labor begin, a positive feedback loop consisting of mechanical and hormonal factors is set into motion. The fetus is normally oriented head down ( Fig. 26.16 a). At the beginning of labor it repositions itself lower in the abdomen ( the baby has dropped ) and begins to push on the softened cervix ( Fig. 26.16 b). Cervical stretch triggers uterine contractions that move in a wave from the top of the uterus down, pushing the fetus farther into the pelvis. The lower portion of the uterus stays relaxed, and the cervix stretches and dilates. Cervical stretch starts a positive feedback cycle of escalating contractions ( Fig. 26.16 d). The contractions are reinforced by secretion of oxytocin from the posterior pituitary, with continued cervical stretch reinforcing oxytocin secretion. Prostaglandins are produced in the uterus in response to oxytocin and CRH secretion. Prostaglandins are very effective at causing uterine muscle contractions at any time. They are the primary cause of menstrual cramps and have been used to induce abortion in early pregnancy. During labor and delivery, prostaglandins reinforce the uterine contractions induced by oxytocin ( Fig. 26.16 d). As the contractions of labor intensify, the fetus moves down though the vagina and out into the world ( Fig. 26.16 c), still attached to the placenta. The placenta then detaches from the uterine wall and is expelled a short time later. Uterine contractions clamp the maternal blood vessels and help prevent excessive bleeding, although typically the mother loses about 240 ml of blood. The Mammary Glands Secrete Milk During Lactation A newborn has lost its source of maternal nourishment through the placenta and must rely on an external source of food instead. Primates, who normally have only one or two offspring at a time, have two functional mammary glands. A mammary gland is composed of 15 20 milk-secreting lobes ( Fig. 26.17 a ). Each lobe branches into lobules, and the lobules terminate in secretory structures called alveoli or acini. Each alveolus is composed of secretory epithelium that secretes into a duct, similar to the exocrine secretions of the pancreas. Each alveolus is surrounded by contractile myoepithelium. Interestingly, the mammary gland epithelium is closely related to the secretory epithelium of sweat glands, so milk secretion and sweat secretion share some common features. During puberty, the breasts begin to develop under the influence of estrogen. The milk ducts grow and branch, and fat is deposited behind the glandular tissue. During pregnancy, the glands develop further under the direction of estrogen, growth hormone, and cortisol. The final development step also requires progesterone, which converts the duct epithelium into a secretory structure. This process is similar to progesterone s effect on the uterus, in which progesterone makes the endometrium into a secretory tissue during the luteal phase. Although estrogen and progesterone stimulate mammary development, they inhibit secretion of milk. Milk production is stimulated by prolactin from the anterior pituitary. Prolactin is an unusual pituitary hormone in that its secretion is primarily controlled by prolactin-inhibiting hormone (PIH) from the hypothalamus. Good evidence suggests that PIH is actually dopamine, an amine neurohormone related to epinephrine and norepinephrine. During the later stages of pregnancy, PIH secretion falls, and prolactin reaches levels 10 or more times those found in nonpregnant women. Prior to delivery, when estrogen and progesterone are also high, the mammary glands produce only small amounts of a thin, low-fat secretion called colostrum. After delivery, when estrogen and progesterone decrease, the glands produce greater amounts of milk that contains 4% fat and substantial amounts of calcium. Proteins in colostrum and milk include maternal immunoglobulins, secreted into the duct and absorbed by the infant s intestinal epithelium. This process transfers some of the mother s immunity to the infant during its first weeks of life. Suckling, the mechanical stimulus of the infant nursing at the breast, reinforces the inhibition of PIH begun in the last weeks of pregnancy ( Fig. 26.17 b). In the absence of PIH, prolactin secretion increases, resulting in milk production. Pregnancy is not a requirement for lactation, and some women who have adopted babies have been successful in breast-feeding. The ejection of milk from the glands, known as the letdown reflex, requires the presence of oxytocin from the posterior pituitary. Oxytocin initiates smooth muscle contraction in the uterus and breasts. In the postpartum (after delivery) uterus, oxytocin-induced contractions help return the uterus to its prepregnancy size. 932

PARTURITION: THE BIRTH PROCESS (a) Fully developed fetus. As labor begins, the fetus is normally head down in the uterus. (d) The process of labor is controlled by a positive feedback loop that ends with delivery. Umbilical cord Fetus drops lower in uterus. Placenta Cervix Vagina Cervical canal + Cervical stretch + Oxytocin from posterior pituitary + Uterine contractions + + Prostaglandins from uterine wall (b) Cervical dilation. Uterine contractions push the head against the softened cervix, stretching and dilating it. Delivery of baby stops the cycle. 26 (c) Delivery. Once the cervix is fully dilated and stretched, the uterine contractions push the fetus out through the vagina. Fig. 26.16 933

LACTATION (a) Mammary glands Epithelial cells of the mammary glands secrete milk into the ducts of the gland. Contraction of the myoepithelium forces fluid out of the ducts through openings in the nipple. (b) The hormonal control of milk secretion and release Prolactin controls milk secretion, and oxytocin causes smooth muscle contraction to eject milk. Pectoralis major muscle Sound of child's cry Higher brain centers Pectoral fat pad Suspensory ligaments Lobes of glandular tissue Oxytocin neuron Hypothalamus + - PIH cell Milk duct Nipple Areola Portal system Anterior pituitary PIH Posterior pituitary Mammary gland lobule Inhibition of prolactin cells is removed. Prolactin Milk secretion Oxytocin Ascending sensory information Milk duct Muscle cells in wall of duct Milk ejected Smooth muscle contraction Epithelial milk-secreting cells Myoepithelial cells Baby suckling Mechanoreceptors in nipple Mammary gland alveolus Fig. 26.17 In the lactating breast, oxytocin causes contraction of myoepithelial cells surrounding the alveoli and in the walls of the ducts. Contraction creates high pressure in the ducts that sends the milk squirting into the infant s mouth. Although prolactin release requires the mechanical stimulus of suckling, oxytocin release can be stimulated by various cerebral stimuli, including the thought of the child. Many nursing mothers experience inappropriate milk release triggered by hearing someone else s child cry. 934