Mamawawa

Hormones and Sex What’s Wrong with the Mamawawa?

13.1 Neuroendocrine System

13.2 Hormones and Sexual Development of the Body

13.3 Hormones and Sexual Development of Brain and Behavior

13.4 Three Cases of Exceptional Human Sexual Development

13.5 Effects of Gonadal Hormones on Adults

13.6 Neural Mechanisms of Sexual Behavior

13.7 Sexual Orientation and Sexual Identity

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the fact that this approach to hormones and sex is inconsis- tent with the evidence, its simplicity, symmetry, and com- fortable social implications draw us to it. That’s why this chapter grapples with it throughout. In so doing, this chapter encourages you to think about hormones and sex in new ways that are more consistent with the evidence.

Developmental and Activational Effects of Sex Hormones Before we begin discussing hormones and sex, you need to know that hormones influence sex in two fundamentally different ways (see Phoenix, 2008): (1) by influencing the development from conception to sexual maturity of the anatomical, physiological, and behavioral characteristics that distinguish one as female or male; and (2) by activat- ing the reproduction-related behavior of sexually mature adults. Both the developmental (also called organizational) and activational effects of sex hormones are discussed in different sections of this chapter. Although the distinction between the developmental and activational effects of sex hormones is not always as clear as it was once assumed to be—for example, because the brain continues to develop into the late teens, adolescent hormone surges can have both effects—the distinction is still useful (Cohen-Bendahan, van de Beek, & Berenbaum, 2005).

13.1 Neuroendocrine System

This section introduces the general principles of neuroen- docrine function. It intro- duces these principles by focusing on the glands and hormones that are directly in- volved in sexual development and behavior.

The endocrine glands are il- lustrated in Figure 13.1. By con- vention, only the organs whose primary function appears to be the release of hormones are re- ferred to as endocrine glands. However, other organs (e.g., the

This chapter is about hormones and sex, a topic thatsome regard as unfit for conversation but that fasci-nates many others. Perhaps the topic of hormones and sex is so fascinating because we are intrigued by the fact that our sex is so greatly influenced by the secretions of a small pair of glands. Because we each think of our gender as fundamental and immutable, it is a bit disturb- ing to think that it could be altered with a few surgical snips and some hormone injections. And there is some- thing intriguing about the idea that our sex lives might be enhanced by the application of a few hormones. For whatever reason, the topic of hormones and sex is always a hit with my students. Some remarkable things await you in this chapter; let’s go directly to them.

Men-Are-Men-and-Women-Are-Women Assumption Many students bring a piece of excess baggage to the topic of hormones and sex: the men-are-men-and-women-are- women assumption—or “mamawawa.” This assumption is seductive; it seems so right that we are continually drawn to it without considering alternative views. Unfor- tunately, it is fundamentally flawed.

The men-are-men-and-women-are-women assumption is the tendency to think about femaleness and maleness as discrete, mutually exclusive, opposite categories. In thinking about hormones and sex, this general attitude leads one to assume that females have female sex hormones that give them female bodies and make them do “female” things, and that males have male sex hormones that give them male bodies and make them do opposite “male” things. Despite

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Pineal

Hypothalamus

Pituitary

Thyroid

Parathyroid

Thymus

Adrenal

Pancreas

Ovary

Testis FIGURE 13.1 The endocrine glands.

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stomach, liver, and intestine) and body fat also release hor- mones into general circulation (see Chapter 12), and they are thus, strictly speaking, also part of the endocrine system.

Glands There are two types of glands: exocrine glands and en- docrine glands. Exocrine glands (e.g., sweat glands) re- lease their chemicals into ducts, which carry them to their targets, mostly on the surface of the body. Endocrine glands (ductless glands) release their chemicals, which are called hormones, directly into the circulatory system. Once released by an endocrine gland, a hormone travels via the circulatory system until it reaches the targets on which it normally exerts its effect (e.g., other endocrine glands or sites in the nervous system).

Gonads Central to any discussion of hormones and sex are the gonads—the male testes (pronounced TEST-eez) and the female ovaries (see Figure 13.1). As you learned in Chapter 2, the primary function of the testes and ovaries is the pro- duction of sperm cells and ova, respectively. After copulation (sexual intercourse), a single sperm cell may fertilize an ovum to form one cell called a zygote, which contains all of the information necessary for the normal growth of a complete adult organism in its natural envi- ronment (see Primakoff & Myles, 2002). With the excep- tion of ova and sperm cells, each cell of the human body has 23 pairs of chromosomes. In contrast, the ova and sperm cells contain only half that number, one member of each of the 23 pairs. Thus, when a sperm cell fertilizes an ovum, the resulting zygote ends up with the full com- plement of 23 pairs of chromosomes, one of each pair from the father and one of each pair from the mother.

Of particular interest in the context of this chapter is the pair of chromosomes called the sex chromosomes, so named because they contain the genetic programs that di- rect sexual development. The cells of females have two large sex chromosomes, called X chromosomes. In males, one sex chromosome is an X chromosome, and the other is called a Y chromosome. Consequently, the sex chromo- some of every ovum is an X chromosome, whereas half the sperm cells have X chromosomes and half have Y chromo- somes. Your sex with all its social, economic, and personal ramifications was determined by which of your father’s sperm cells won the dash to your mother’s ovum. If a sperm cell with an X sex chromosome won, you are a fe- male; if one with a Y sex chromosome won, you are a male.

You might reasonably assume that X chromosomes are X-shaped and Y chromosomes are Y-shaped, but this is incorrect. Once a chromosome has duplicated, the two products remain joined at one point, producing an X shape. This is true of all chromosomes, including Y chromo- somes. Because the Y chromosome is much smaller than

the X chromosome, early investigators failed to discern one small arm and thus saw a Y. In humans, Y-chromo- some genes encode only 27 proteins; in comparison, about 1,500 proteins are encoded by X-chromosome genes (see Arnold, 2004).

Writing this section reminded me of my seventh-grade basketball team, the “Nads.” The name puzzled our teacher because it was not at all like the names usually fa- vored by pubescent boys—names such as the “Avengers,” the “Marauders,” and the “Vikings.” Her puzzlement ended abruptly at our first game as our fans began to chant their support. You guessed it: “Go Nads, Go! Go Nads, Go!” My 14-year-old spotted-faced teammates and I considered this to be humor of the most mature and so- phisticated sort. The teacher didn’t.

Classes of Hormones Vertebrate hormones fall into one of three classes: (1) amino acid derivatives, (2) peptides and proteins, and (3) steroids. Amino acid derivative hormones are hormones that are synthesized in a few simple steps from an amino acid molecule; an example is epinephrine, which is released from the adrenal medulla and synthesized from tyrosine. Peptide hormones and protein hormones are chains of amino acids—peptide hormones are short chains, and protein hormones are long chains. Steroid hormones are hormones that are synthesized from cholesterol, a type of fat molecule.

The hormones that influence sexual development and the activation of adult sexual behavior (i.e., the sex hor- mones) are all steroid hormones. Most other hormones produce their effects by binding to receptors in cell mem- branes. Steroid hormones can influence cells in this fash- ion; however, because they are small and fat-soluble, they can readily penetrate cell membranes and often affect cells in a second way. Once inside a cell, the steroid mole- cules can bind to receptors in the cytoplasm or nucleus and, by so doing, directly influence gene expression (amino acid derivative hormones and peptide hormones affect gene expression less commonly and by less direct mechanisms). Consequently, of all the hormones, steroid hormones tend to have the most diverse and long-lasting effects on cellular function (Brown, 1994).

Sex Steroids The gonads do more than create sperm and egg cells; they also produce and release steroid hormones. Most people are surprised to learn that the testes and ovaries release the very same hormones. The two main classes of gonadal hormones are androgens and estrogens; testosterone is the most common androgen, and estradiol is the most common estrogen. The fact that adult ovaries tend to re- lease more estrogens than they do androgens and that adult testes release more androgens than they do estrogens

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has led to the common, but misleading, practice of refer- ring to androgens as “the male sex hormones” and to es- trogens as “the female sex hormones.” This practice should be avoided because of its men-are-men-and- women-are-women implication that androgens produce maleness and estrogens produce femaleness. They don’t.

The ovaries and testes also release a third class of steroid hormones called progestins. The most common progestin is progesterone, which in women prepares the uterus and the breasts for pregnancy. Its function in men is unclear.

Because the primary function of the adrenal cortex— the outer layer of the adrenal glands (see Figure 13.1)—is the regulation of glucose and salt levels in the blood, it is not generally thought of as a sex gland. However, in addi- tion to its principal steroid hormones, it does release small amounts of all of the sex steroids that are released by the gonads.

Hormones of the Pituitary The pituitary gland is frequently referred to as the master gland because most of its hormones are tropic hormones. Tropic hormones are hormones whose primary function is to influence the release of hormones from other glands (tropic means “able to stimulate or change something”). For example, gonadotropin is a pituitary tropic hormone that travels through the circulatory system to the gonads, where it stimulates the release of gonadal hormones.

The pituitary gland is really two glands, the posterior pituitary and the anterior pituitary, which fuse during the

course of embryological development. The posterior pituitary develops from a small outgrowth of hypothala- mic tissue that eventually comes to dangle from the hypothalamus on the end of the pituitary stalk (see Figure 13.2). In contrast, the anterior pituitary begins as part of the same embryonic tissue that eventually devel- ops into the roof of the mouth; during the course of de- velopment, it pinches off and migrates upward to assume its position next to the posterior pituitary. It is the ante- rior pituitary that releases tropic hormones; thus, it is the anterior pituitary in particular, rather than the pituitary in general, that qualifies as the master gland.

Female Gonadal Hormone Levels Are Cyclic; Male Gonadal Hormone Levels Are Steady Although men and women possess the same hormones, these hormones are not present at the same levels, and they do not necessarily perform the same functions. The major difference between the endocrine function of women and men is that in women the levels of gonadal and go- nadotropic hormones go through a cycle that repeats itself every 28 days or so. It is these more-or-less regular hor- mone fluctuations that control the female menstrual cycle. In contrast, human males are, from a neuroendocrine per- spective, rather dull creatures; males’ levels of gonadal and gonadotropic hormones change little from day to day.

Because the anterior pituitary is the master gland, many early scientists assumed that an inherent difference between the male and female anterior pituitary was the

basis for the difference in male and female patterns of gonadotropic and gonadal hormone release. However, this hypothesis was discounted by a series of clever trans- plant studies conducted by Geoffrey Harris in the 1950s (see Raisman, 1997). In these studies, a cycling pituitary re- moved from a mature female rat became a steady-state pituitary when trans- planted at the appropriate site in a male, and a steady-state pituitary removed from a mature male rat began to cycle once transplanted into a female. What these studies established was that anterior pi- tuitaries are not inherently female (cycli- cal) or male (steady-state); their patterns

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Hypothalamus

Anterior commissure

Massa intermedia (connects the two lobes of the thalamus)

Optic chiasm

Anterior pituitary

Posterior pituitary

Mammillary body

FIGURE 13.2 A midline view of the pos- terior and anterior pituitary and surrounding structures.

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of hormone release are controlled by some other part of the body. The master gland seemed to have its own master. Where was it?

Neural Control of the Pituitary The nervous system was implicated in the control of the anterior pituitary by behavioral research on birds and other animals that breed only during a specific time of the

year. It was found that the seasonal varia- tions in the light–dark cycle triggered many of the breeding-related changes in

hormone release. If the lighting conditions under which the animals lived were reversed, for example, by having the animals transported across the equator, the breeding seasons were also reversed. Somehow, visual input to the nervous system was controlling the release of tropic hor- mones from the anterior pituitary.

The search for the particular neural structure that con- trolled the anterior pituitary turned, naturally enough, to the hypothalamus, the structure from which the pituitary is suspended. Hypothalamic stimulation and lesion exper- iments quickly established that the hypothalamus is the regulator of the anterior pituitary, but how the hypothala- mus carries out this role remained a mystery. You see, the

anterior pituitary, unlike the posterior pituitary, receives no neural input whatsoever from the hypothalamus, or from any other neural structure (see Figure 13.3).

Control of the Anterior and Posterior Pituitary by the Hypothalamus There are two different mechanisms by which the hypothal- amus controls the pituitary: one for the posterior pituitary and one for the anterior pituitary. The two major hormones of the posterior pituitary, vasopressin and oxytocin, are peptide hormones that are synthesized in the cell bodies of neurons in the paraventricular nuclei and supraoptic nuclei on each side of the hypothalamus (see Figure 13.3 and Appendix VI). They are then transported along the axons of these neurons to their terminals in the posterior pi- tuitary and are stored there until the arrival of action poten- tials causes them to be released into the bloodstream. (Neurons that release hormones into general circulation are called neurosecretory cells.) Oxytocin stimulates contrac- tions of the uterus during labor and the ejection of milk during suckling. Vasopressin (also called antidiuretic hor- mone) facilitates the reabsorption of water by the kidneys.

The means by which the hypothalamus controls the re- lease of hormones from the neuron-free anterior pituitary was more difficult to explain. Harris (1955) suggested that the release of hormones from the anterior pituitary was it- self regulated by hormones released from the hypothala- mus. Two findings provided early support for this hypothesis. The first was the discovery of a vascular net- work, the hypothalamopituitary portal system, that seemed well suited to the task of carrying hormones from the hypothalamus to the anterior pituitary. As Figure 13.4 on page 332 illustrates, a network of hypothalamic capillar- ies feeds a bundle of portal veins that carries blood down the pituitary stalk into another network of capillaries in the anterior pituitary. (A portal vein is a vein that connects one capillary network with another.) The second finding was the discovery that cutting the portal veins of the pituitary stalk disrupts the release of anterior pituitary hormones until the damaged veins regenerate (Harris, 1955).

Discovery of Hypothalamic Releasing Hormones It was hypothesized that the release of each anterior pitu- itary hormone is controlled by a different hypothalamic hormone. The hypothalamic hormones that were thought to stimulate the release of an anterior pituitary hormone were referred to as releasing hormones; those thought to inhibit the release of an anterior pituitary hormone were referred to as release-inhibiting factors.

Efforts to isolate the putative (hypothesized) hypothal- amic releasing and inhibitory factors led to a major breakthrough in the late 1960s. Guillemin and his col- leagues isolated thyrotropin-releasing hormone from

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Anterior pituitary

Posterior pituitary

Pituitary stalk

Supraoptic nucleus of the hypothalamus

Paraventricular nucleus of the hypothalamus

FIGURE 13.3 The neural connections between the hypothal- amus and the pituitary. All neural input to the pituitary goes to the posterior pituitary; the anterior pituitary has no neural connections.

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the hypothalamus of sheep, and Schally and his colleagues isolated the same hormone from the hypothalamus of pigs.

Thyrotropin-releasing hormone triggers the release of thyrotropin from the anterior pi- tuitary, which in turn stimulates the release

of hormones from the thyroid gland. For their efforts, Guillemin and Schally were awarded Nobel Prizes in 1977.

Schally’s and Guillemin’s isolation of thyrotropin- releasing hormone confirmed that hypothalamic releasing hormones control the release of hormones from the ante- rior pituitary and thus provided the major impetus for the isolation and synthesis of several other releasing hor- mones. Of direct relevance to the study of sex hormones was the subsequent isolation of gonadotropin-releasing hormone by Schally and his group (Schally, Kastin, & Arimura, 1971). This releasing hormone stimulates the release of both of the anterior pituitary’s gonadotropins: follicle-stimulating hormone (FSH) and luteinizing hormone (LH). All hypothalamic releasing hormones, like all tropic hormones, have proven to be peptides.

Regulation of Hormone Levels Hormone release is regulated by three different kinds of signals: signals from the nervous system, signals from hormones, and signals from nonhormonal chemicals in the blood.

Regulation by Neural Signals All endocrine glands, with the exception of the anterior pituitary, are directly regulated by signals from the nervous system. Endocrine glands located in the brain (i.e., the pituitary and pineal glands) are regulated by cerebral neurons; those located outside the CNS are innervated by the autonomic nervous system—usually by both the sympathetic and parasympa- thetic branches, which often have opposite effects on hor- mone release.

The effects of experience on hormone release are usu- ally mediated by signals from the nervous system. It is ex- tremely important to remember that hormone release can be regulated by experience—for example, many species that breed only in the spring are often prepared for repro- duction by the release of sex hormones triggered by the in- creasing daily duration of daylight. This means that an explanation of any behavioral phenomenon in terms of a hormonal mechanism does not neces- sarily rule out an explanation in terms of an experiential mechanism. Indeed, hormonal and experiential explanations may merely be different aspects of the same hypothetical mechanism.

332 Chapter 13 ■ Hormones and Sex

1 Releasing and inhibiting hormones are released from hypothalamic neurons into the hypothalamo- pituitary portal system.

2 Hypothalamic-releasingand hypothalamic-inhibiting hormones are carried down the pituitary stalk by the hypothalamopituitary portal system.

3 Hypothalamic-releasingand hypothalamic-inhibiting hormones increase or decrease, respectively, the release of anterior pituitary hormones into general circulation.

1 Oxytocin and vasopressin are synthesized in the paraventricular and supraoptic nuclei of the hypothalamus.

2 Oxytocin and vasopressinare carried by axonal transport down the pituitary stalk.

3 Oxytocin and vasopressinare released into general circulation from terminal buttons in the posterior pituitary.

Anterior pituitary

Posterior pituitary

Anterior Pituitary Posterior Pituitary

Supraoptic nucleus

Paraventricular nucleus

FIGURE 13.4 Control of the anterior and posterior pituitary by the hypothalamus.

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Regulation by Hormonal Signals The hormones themselves also influence hormone release. You have already learned, for example, that the tropic hormones of

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the anterior pituitary influence the release of hormones from their respective target glands. However, the regula- tion of endocrine function by the anterior pituitary is not a one-way street. Circulating hormones often provide feedback to the very structures that influence their re- lease: the pituitary gland, the hypothalamus, and other sites in the brain. The function of most hormonal feed- back is the maintenance of stable blood levels of the hor- mones. Thus, high gonadal hormone levels usually have effects on the hypothalamus and pituitary that decrease subsequent gonadal hormone release, and low levels usu- ally have effects that increase hormone release.

Regulation by Nonhormonal Chemicals Circulating chemicals other than hormones can play a role in regulat- ing hormone levels. Glucose, calcium, and sodium levels in the blood all influence the release of particular hor- mones. For example, you learned in Chapter 12 that in- creases in blood glucose increase the release of insulin from the pancreas, and insulin, in turn, reduces blood glu- cose levels.

Pulsatile Hormone Release Hormones tend to be released in pulses (see Armstrong et al., 2009; Khadra & Li, 2006); they are discharged several times per day in large surges, which typically last no more than a few minutes. Hormone levels in the blood are regulated by changes in the frequency and duration of the hormone pulses. One conse- quence of pulsatile hormone release is that there are often large minute-to-minute fluctuations in the levels of circulating hormones (e.g., Koolhaas, Schuurman, & Wierpkema, 1980). Accordingly, when the pattern of human male gonadal hormone release is referred to as “steady,” it means that there are no major systematic changes in circulating gonadal hormone levels from day to day, not that the levels never vary.

Summary Model of Gonadal Endocrine Regulation Figure 13.5 is a summary model of the regulation of gonadal hormones. According to this model, the brain controls the release of gonadotropin-releasing hor- mone from the hypothalamus into the hypothalamo- pituitary portal system, which carries it to the anterior pituitary. In the anterior pituitary, the gonadotropin- releasing hormone stimulates the release of go- nadotropin, which is carried by the circulatory system to the gonads. In response to the gonadotropin, the

gonads release androgens, estrogens, and progestins, which feed back into the pituitary and hypothalamus to regulate subsequent gonadal hormone release.

Armed with this general perspective of neuroen- docrine function, you are ready to consider how gonadal hormones direct sexual development and activate adult sexual behavior.

13.2 Hormones and Sexual Development of the Body

You have undoubtedly noticed that humans are dimorphic—that is, they come in two standard models: fe- male and male. This section describes how the develop- ment of female and male bodily characteristics is directed by hormones.

33313.2 ■ Hormones and Sexual Development of the Body

Positive or negative feedback influences the subsequent release of hormones.

Behavior is influenced by gonadal hormones acting on the brain.

HYPOTHALAMIC PORTAL SYSTEM

GENERAL CIRCULATION

BODY TISSUES

GONADS release estrogens,

androgens, and progestins

ANTERIOR PITUITARY releases gonadotropin

BRAIN neural signals

HYPOTHALAMUS releases gonadotropin-

releasing hormone

FIGURE 13.5 A summary model of the regulation of gonadal hormones.

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Sexual differentiation in mammals begins at fertiliza- tion with the production of one of two different kinds of zygotes: either one with an XX (female) pair of sex chro- mosomes or one with an XY (male) pair. It is the genetic information on the sex chromosomes that normally deter- mines whether development will occur along female or male lines. But be cautious here: Do not fall into the seduc- tive embrace of the men-are-men-and-women-are-women assumption. Do not begin by assuming that there are two

parallel but opposite genetic pro- grams for sexual development, one for female development and one for

male development. As you are about to learn, sexual devel- opment unfolds according to an entirely different princi- ple, one that males who still stubbornly cling to notions of male preeminence find unsettling. This principle is that we are all genetically programmed to develop female bodies; genetic males develop male bodies only because their fun- damentally female program of development is overruled.

Fetal Hormones and Development of Reproductive Organs Gonads Figure 13.6 illustrates the structure of the go- nads as they appear 6 weeks after fertilization. Notice

that at this stage of development, each fetus, regardless of its genetic sex, has the same pair of gonadal structures, called primordial gonads (primordial means “existing at the beginning”). Each primordial gonad has an outer cov- ering, or cortex, which has the potential to develop into an ovary; and each has an internal core, or medulla, which has the potential to develop into a testis.

Six weeks after conception, the Sry gene on the Y chro- mosome of the male triggers the synthesis of Sry protein (see Arnold, 2004; Wu et al., 2009), and this protein causes the medulla of each primordial gonad to grow and to develop into a testis. There is no female counterpart of Sry protein; in the absence of Sry protein, the cortical cells of the primordial gonads automatically develop into ovaries. Accordingly, if Sry protein is injected into a ge- netic female fetus 6 weeks after conception, the result is a genetic female with testes; or if drugs that block the ef- fects of Sry protein are injected into a male fetus, the re- sult is a genetic male with ovaries. Such “mixed-sex” individuals expose in a dramatic fashion the weakness of mamawawa thinking (thinking of “male” and “female” as mutually exclusive, opposite categories).

Internal Reproductive Ducts Six weeks after fertiliza- tion, both males and females have two complete sets of reproductive ducts. They have a male Wolffian system, which has the capacity to develop into the male reproduc- tive ducts (e.g., the seminal vesicles, which hold the fluid in which sperm cells are ejaculated; and the vas deferens, through which the sperm cells travel to the seminal vesi- cles). And they have a female Müllerian system, which has the capacity to develop into the female ducts (e.g., the uterus; the upper part of the vagina; and the fallopian tubes, through which ova travel from the ovaries to the uterus, where they can be fertilized).

In the third month of male fetal development, the testes secrete testosterone and Müllerian-inhibiting sub- stance. As Figure 13.7 illustrates, the testosterone stimu- lates the development of the Wolffian system, and the Müllerian-inhibiting substance causes the Müllerian sys- tem to degenerate and the testes to descend into the scrotum—the sac that holds the testes outside the body cavity. Because it is testosterone—not the sex chromo- somes—that triggers Wolffian development, genetic fe- males who are injected with testosterone during the appropriate fetal period develop male reproductive ducts along with their female ones.

The differentiation of the internal ducts of the female re- productive system (see Figure 13.7) is not under the control of ovarian hormones; the ovaries are almost completely in- active during fetal development. The development of the Müllerian system occurs in any fetus that is not exposed to testicular hormones during the critical fetal period. Accord- ingly, normal female fetuses, ovariectomized female fetuses, and orchidectomized male fetuses all develop female repro- ductive ducts (Jost, 1972). Ovariectomy is the removal of the ovaries, and orchidectomy is the removal of the testes

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At 6 weeks after conception, the primordial gonads of XX and XY individuals are identical.

Medulla of the

primordial gonad Cortex of the

primordial gonad

Female (XX) Male (XY)

If no Y chromosome is present, the cortex of the primordial gonad develops into an ovary.

Under the influence of the Y chromosome, the medulla of the primordial gonad develops into a testis.

FIGURE 13.6 The development of an ovary and a testis from the cortex and the medulla, respectively, of the primordial gonadal structure that is present 6 weeks after conception.

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(the Greek word orchis means “testicle”). Gonadectomy, or castration, is the surgical removal of gonads—either ovaries or testes.

External Reproductive Organs There is a basic differ- ence between the differentiation of the external reproduc- tive organs and the differentiation of the internal reproductive organs (i.e., the gonads and reproductive ducts). As you have just read, every normal fetus develops separate precursors for the male (medulla) and female (cor- tex) gonads and for the male (Wolffian system) and female (Müllerian system) reproductive ducts; then, only one set,

male or female, develops. In contrast, both male and fe- male genitals—external re- productive organs—develop from the same precursor. This

bipotential precursor and its subsequent differentiation are illustrated in Figure 13.8 on page 336.

In the second month of pregnancy, the bipotential pre- cursor of the external reproductive organs consists of four parts: the glans, the urethral folds, the lateral bodies, and the labioscrotal swellings. Then it begins to differentiate. The glans grows into the head of the penis in the male or the clitoris in the female; the urethral folds fuse in the male or enlarge to become the labia minora in the female; the lateral bodies form the shaft of the penis in the male or the hood of the clitoris in the female; and the labioscrotal swellings form the scrotum in the male or the labia majora in the female.

Like the development of the internal reproductive ducts, the development of the external genitals is controlled by the presence or absence of testosterone. If testosterone is present at the appropriate stage of fetal development, male external genitals develop from the bipotential precursor; if testosterone is not present, development of the external genitals proceeds along female lines.

Puberty: Hormones and Development of Secondary Sex Characteristics During childhood, levels of circulating gonadal hor- mones are low, reproductive organs are immature, and males and females differ little in general appearance. This period of developmental quiescence ends abruptly with the onset of puberty—the transitional period between childhood and adulthood during which fertility is achieved, the adolescent growth spurt occurs, and the sec- ondary sex characteristics develop. Secondary sex char- acteristics are those features other than the reproductive organs that distinguish sexually mature men and women. The body changes that occur during puberty are illus- trated in Figure 13.9 on page 337.

Puberty is associated with an increase in the release of hormones by the anterior pituitary (see Grumbach, 2002). The increase in the release of growth hormone—the only anterior pituitary hormone that does not have a gland as its primary target—acts directly on bone and muscle tissue to produce the pubertal growth spurt. Increases in the release of gonadotropic hormone and adrenocorticotropic hor- mone cause the gonads and adrenal cortex to increase their release of gonadal and adrenal hormones, which in turn initiate the maturation of the genitals and the development of secondary sex characteristics.

The general principle guiding normal pubertal sexual maturation is a simple one: In pubertal males, androgen levels are higher than estrogen levels, and masculinization is the result; in pubertal females, the estrogens predominate, and the result is feminization. Individuals castrated prior to puberty do not become sexually mature unless they receive replacement injections of androgens or estrogens.

But even during puberty, its only period of relevance, the men-are-men-and-women-are-women assumption stumbles badly. You see, androstenedione, an androgen

33513.2 ■ Hormones and Sexual Development of the Body

At 6 weeks, all human fetuses have the antecedents of both male (Wolffian) and female (Müllerian) reproductive ducts.

Developing gonad

Wolffian System

Müllerian System

Male (XY) Female (XX)

Seminal vesicle

Vas deferens

Testis

Uterus

Upper part of vagina

Ovary

Fallopian tube

Scrotum

Under the influence of testicular testosterone, the Wolffian system develops, and Müllerian-inhibiting substance causes the Müllerian system to degenerate.

In the absence of testosterone, the Müllerian system develops into female reproductive ducts, and the Wolffian system fails to develop.

FIGURE 13.7 The development of the internal ducts of the male and female reproductive systems from the Wolffian and Müllerian systems, respectively.

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that is released primarily by the adrenal cortex, is normally responsible for the growth of pubic hair and axillary hair (underarm hair) in females. It is hard to take seriously the practice of referring to androgens as “male hormones” when one of them is responsible for the develop- ment of the female pattern of pubic hair growth. The male pattern is a pyramid, and the female pattern is an inverted pyramid (see Figure 13.9).

Do you remember how old you were when you started to go through puberty? In most North American and European coun- tries, puberty begins at about 10.5 years of age for girls and 11.5 years for boys. I am sure you would have been unhappy if you had not started puberty until you were 15 or 16, but this was the norm in North America and Europe just a century and a half ago. Presumably, this acceleration of puberty has resulted from improvements in dietary, medical, and socioeconomic conditions.

13.3 Hormones and Sexual Development of Brain and Behavior

Biopsychologists have been particularly interested in the effects of hormones on the sexual differentiation of the brain and the effects of brain differences on behavior. This section reveals how seminal studies conducted in the 1930s generated theories that have gradually morphed, under the influence of subsequent research, into our cur- rent views. But first, let’s take a quick look at the differ- ences between male and female brains.

Sex Differences in the Brain The brains of men and women may look the same on casual inspection, and it may be politically correct to believe that they are—but they are not. The brains of men tend to be about 15% larger than those of women, and many other anatomical differences between average male and female brains have been documented. There are statistically

significant sex differences in the volumes of various nuclei and fiber tracts, in the numbers and types of neural and glial cells that compose various structures, and in the numbers and types of synapses that connect the cells in various struc- tures. Sexual dimorphisms (male–female structural differ- ences) of the brain are typically studied in nonhuman mammals, but many have also been documented in hu- mans (see Arnold, 2003; Cahill, 2005, 2006; de Vries & Södersten, 2009).

Let’s begin with the first functional sex difference to be identified in mammalian brains. It set the stage for every- thing that followed.

First Discovery of a Sex Difference in Mammalian Brain Function The first attempts to discover sex differ- ences in the mammalian brain focused on the factors that control the development of the steady and cyclic patterns

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Partially Developed

Male

Male and female

Female

Male Female

Fully Developed

Labia majora

Anus

Labia minora

Clitoral hood

Glans

Urethral fold

Lateral body

Labioscrotal swelling

Clitoris

Scrotum

Head of penis

Six Weeks After Conception

Shaft of penis

Anus

FIGURE 13.8 The development of male and female external reproductive organs from the same bipotential precursor.

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of gonadotropin release in males and females, respectively. The seminal experi- ments were conducted by Pfeiffer in 1936.

In his experiments, some neonatal rats (males and females) were gonadectomized and some were not, and some received gonad transplants (ovaries or testes) and some did not.

Remarkably, Pfeiffer found that gonadectomizing neonatal rats of either genetic sex caused them to develop into adults with the female cyclic pattern of gonadotropin release. In contrast, transplantation of testes into gonad-

ectomized or intact female neonatal rats caused them to develop into adults with the steady male pattern of go- nadotropin release. Transplantation of ovaries had no ef- fect on the pattern of hormone release. Pfeiffer concluded that the female cyclic pattern of gonadotropin release de- velops unless the preprogrammed female cyclicity is over- ridden by testosterone during perinatal development (see Harris & Levine, 1965).

Pfeiffer incorrectly concluded that the presence or ab- sence of testicular hormones in neonatal rats influenced the development of the pituitary because he was not

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Hair line recession begins

Larynx enlarges

Musculature develops

Axillary hair appears

Axillary hair appears

Menstruation begins

Uterus grows

Acne appears

Facial and body hair appears

Acne appears

Breasts develop

Body contours become roundedPubic hair

appears

Pubic hair appears

Reproductive organs grow

Growth spurt occurs

Growth spurt occurs

FIGURE 13.9 The changes that normally occur in males and females during puberty.

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aware of something we know today: The release of gonadotropins from the ante- rior pituitary is controlled by the hypo-

thalamus. Once this was discovered, it became apparent that Pfeiffer’s experiments had provided the first evidence of the role of perinatal (around the time of birth) andro- gens in overriding the preprogrammed cyclic female pat- tern of gonadotropin release from the hypothalamus and initiating the development of the steady male pattern. This 1960s modification of Pfeiffer’s theory of brain dif- ferentiation to include the hypothalamus was consistent with the facts of brain differentiation as understood at that time, but subsequent research necessitated major revisions. The first of these major revisions became known as the aromatization hypothesis.

Aromatization Hypothesis What is aromatization? All gonadal and adrenal sex hormones are steroid hor- mones, and because all steroid hormones are derived from cholesterol, they have similar structures and are readily converted from one to the other. For example, a slight change to the testosterone molecule that occurs under the influence of the enzyme (a protein that influ- ences a biochemical reaction without participating in it) aromatase converts testosterone to estradiol. This process is called aromatization (see Balthazart & Ball, 1998).

According to the aromatization hypothesis, perina- tal testosterone does not directly masculinize the brain; the brain is masculinized by estradiol that has been aromatized from perinatal testosterone. Although the idea that estradiol—the alleged female hormone— masculinizes the brain may seem counterintuitive, there is strong evidence for it. Most of the evidence is of two types, both coming from experiments on rats and mice: (1) findings demonstrating masculinizing effects on the brain of early estradiol injections, and (2) findings showing that masculinization of the brain does not occur in response to testosterone that is ad- ministered with agents that block aromatization or in response to androgens that cannot be aromatized (e.g., dihydrotestosterone).

How do genetic females of species whose brains are masculinized by estradiol keep from being masculinized by their mothers’ estradiol, which circulates through the fetal blood supply? Alpha fetoprotein is the answer. Alpha fetoprotein is present in the blood of rats during the peri- natal period, and it deactivates circulating estradiol by binding to it (Bakker et al., 2006; Bakker & Baum, 2007; De Mees et al., 2006). How, then, does estradiol masculin- ize the brain of the male fetus in the presence of the deac- tivating effects of alpha fetoprotein? Because testosterone is immune to alpha fetoprotein, it can travel unaffected from the testes to the brain cells where it is converted to estradiol. Estradiol is not broken down in the brain be- cause alpha fetoprotein does not readily penetrate the blood–brain barrier.

Modern Perspectives on Sexual Differentiation of Mammalian Brains The view that the female program is the default program of brain development and is nor- mally overridden in genetic males by perinatal exposure to testosterone aromatized to estradiol remained the pre- eminent theory of the sexual differentiation of the brain as long as research focused on the rat hypothalamus. Once studies of brain differentiation began to include other parts of the brain and other species, it became ap- parent that no single mechanism can account for the de- velopment of sexual dimorphisms of mammalian brains. The following findings have been particularly influential in shaping current views:

● Various sexual differences in brain structure and function have been found to develop by different mechanisms; for example, aromatase is found in only a few areas of the rat brain (e.g., the hypothalamus), and it is only in these areas that aromatization is crit- ical for testosterone’s masculinizing effects (see Ball & Balthazart, 2006; Balthazart & Ball, 2006).

● Sexual differences in the brain have been found to develop by different mechanisms in different mam- malian species (see McCarthy, Wright, & Schwartz, 2009); for example, arom- atization plays a less prominent role in primates than in rats and mice (see Zuloaga et al., 2008).

● Various sex differences in the brain have been found to develop at different stages of development (Bakker & Baum, 2007); for example, many differences do not develop until puberty (Ahmed et al., 2008; Sisk & Zehr, 2005), a possibility ignored by early theories.

● Sex chromosomes have been found to influence brain development independent of their effect on hor- mones (Arnold, 2009; Jazon & Cahill, 2010); for ex- ample, different patterns of gene expression exist in the brains of male and female mice before the gonads become functional (Dewing et al., 2003).

● Although the female program of brain development had been thought to proceed normally in the absence of gonadal steroids, recent evidence suggests that estra- diol plays an active role; knockout mice without the gene that forms estradiol receptors do not display a normal female pattern of brain development (see Bakker & Baum, 2007).

In short, there is overwhelming evidence that various sex- ual differences in mammalian brains emerge at different stages of development under different genetic and hor- monal influences (see Wagner, 2006). Although the con- ventional view that a female program of development is the default does an excellent job of explaining differenti- ation of the reproductive organs, it falters badly when it comes to differentiation of the brain.

In studying the many sexual differences of mammalian brains, it is easy to lose sight of the main point: We still do

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not understand how any of the anatomical differences that have been identified influence behavior.

Perinatal Hormones and Behavioral Development In view of the fact that perinatal hormones influence the development of the brain, it should come as no surprise that they also influence the development of behavior. Much of the research on perinatal hormones and behav- ioral development was conducted before the discoveries about brain development that we have just considered. Consequently, most of the studies have been based on the idea of a female default program that can be overridden by testosterone and have assessed the effects of perinatal testosterone exposure on reproductive behaviors in labo- ratory animals.

Phoenix and colleagues (1959) were among the first to demonstrate that the perinatal injection of testosterone masculinizes and defeminizes a genetic female’s adult copulatory behavior. First, they injected pregnant guinea pigs with testosterone. Then, when the litters were born,

the researchers ovariectomized the female offspring. Finally, when these ovariec- tomized female guinea pigs reached matu-

rity, the researchers injected them with testosterone and assessed their copulatory behavior. Phoenix and his col- leagues found that the females that had been exposed to perinatal testosterone displayed more male-like mount- ing behavior in response to testosterone injections in adulthood than did adult females that had not been ex- posed to perinatal testosterone. And when, as adults, the female guinea pigs were injected with progesterone and estradiol and mounted by males, they displayed less lordosis—the intromission-facilitating arched-back pos- ture that signals female rodent receptivity.

In a study complementary to that of Phoenix and col- leagues, Grady, Phoenix, and Young (1965) found that the lack of early exposure of male rats to testosterone both feminizes and demasculinizes their copulatory behavior as adults. Male rats castrated shortly after birth failed to display the normal male copulatory pattern of mounting, intromission (penis insertion), and ejaculation (ejection of sperm) when they were treated with testosterone and given access to a sexually receptive female; and when they were injected with estrogen and progesterone as adults, they exhibited more lordosis than did uncastrated controls.

The aromatization of perinatal testosterone to estra- diol seems to be important for both the defeminization and the masculinization of rodent copulatory behavior (Goy & McEwen, 1980; Shapiro, Levine, & Adler, 1980). In contrast, that aromatization does not seem to be critical for these effects in monkeys (Wallen, 2005).

When it comes to the effects of perinatal testosterone on behavioral development, timing is critical. The ability of single injections of testosterone to masculinize and

defeminize the rat brain seems to be restricted to the first 11 days after birth.

Because much of the research on hormones and be- havioral development has focused on the copulatory act, we know less about the role of hormones in the develop- ment of proceptive behaviors (solicitation behaviors) and in the development of gender-related behaviors that are not directly related to reproduction. However, perina- tal testosterone has been reported to disrupt the procep- tive hopping, darting, and ear wiggling of receptive female rats; to increase the aggressiveness of female mice; to disrupt the maternal behavior of female rats; and to in- crease rough social play in female monkeys and rats.

Ethical considerations prohibit experimental studies of the developmental effects of hormones on human devel- opment. However, there have been many correlational studies of clinical cases and of ostensibly healthy individ- uals who received abnormal prenatal exposure to andro- gens (due to their own pathology or to drugs taken by their mothers). The results have been far from impressive. Cohen-Bendahan, van de Beek, and Berenbaum (2005) reviewed the extensive research literature and concluded that, despite many inconsistencies, the weight of evidence indicated that prenatal androgen exposure contributes to the differences in interests, spatial ability, and aggressive- ness typically observed between men and women. How- ever, there was no convincing evidence that