Genitals and Gender: What Makes Us Male and Female?
No aspects of biology are more impressive
the child as a boy without a penis, despite
or humbling than the making of a baby; it is the emotional costs of the deformity? Or is it
a developmental ballet of staggering com-
better to assign the child to the female gen-
plexity and critical timing. Given the countless der, surgically remove the testes and fashion
processes that must unfold perfectly and in
female-looking genitals, and then raise the
precisely the right order, it is a marvel that, in child as a girl? Which would you choose?
a hitch. Inevitably, though, there are times
down to different opinions about the extent to
when a crucial part of the program is derailed which our gender is shaped through nurtur-
ing and socialization, rather than biological
factors. In other words, we need to consider
Such is the case with cloacal exstrophy, the larger question of why men and women
which occurs in about one in 400,000 human behave differently. Is it because as boys and
births, characterized by an incomplete clos- girls they were treated differently and trained
ing of the abdomen that leaves the bladder to grow into their gender roles, or do the forc-
and intestines exposed. A genetic male with es that provide a fetus with testes or ovaries
this condition is typically born with normal
also induce the developing brain to take on a
testes but a very short, split penis or no pe- masculine or feminine form? In an age where
nis at all. Surgery is required to close up the many people reject the notion of only two
abdomen, but it isn't really possible to surgi- genders, do biological factors have any say
cally fashion a normal penis, so the parents in gender identity?
are faced with a dilemma. Is it better to raise
In this chapter we'll discuss research that informs us about this long-standing question: How do biological and social forces combine to direct development in male-typical and female-typical ways? First, we'll learn how hormones can affect the brain to influence behavior. Then we will explore how hormones act on different parts of the brain to influence sexual behavior and parental behavior in particular. That will take us to the question of how the fetus normally develops into either a male or a female form, not just in terms of the body, but also in terms of the brain and behavior. We'll see that not everyone fits neatly into the binary categories in terms of either body structures or behavior. In animals, prenatal hormones have a tremendous influence on the brain and sexual behaviors. We'll close by reviewing growing evidence that those same prenatal hormones also affect our development into men, women, or other, as well as our sexual orientation.
FIGURE 8.1 Major Endocrine Glands and Their Functions
Major endocrine structures Hypothalamus Pineal gland Pituitary gland: Anterior pituitary Posterior pituitary Thyroid Adrenal glands: Adrenal cortex (outer bark) Adrenal medulla (inner core) Pancreas Gut Gonads (testes/ovaries)
Some main functions regulated by secretion Control of hormone secretions Reproductive maturation; body rhythms Hormone secretion by thyroid, adrenal cortex, and gonads; growth Water balance; salt balance Growth and development; metabolic rate Salt and carbohydrate metabolism; in ammatory reactions Emotional arousal (epinephrine) Sugar metabolism Digestion and appetite control Body development; maintenance of reproductive organs in adults
8.1Hormones Act in a Great Variety of Ways throughout the Body
View Activity 8.1: Major Endocrine Glands cloacal exstrophy A rare medical condition in which individuals are born with an incompletely sealed lower abdomen. hormone A chemical, usually secreted by an endocrine gland, that is conveyed by the bloodstream and regulates target organs or tissues. endocrine gland A gland that secretes hWoramtsoonn/eBsrienetodltohvee bloodstream to act on dTihsteaMntintadr'gs eMtsa.chine Foundations of Brain and Behavior 4e castration Removal of the gonads, uMsuMa4lley_t0h8e.0t1este0s4./07/20
The chapter begins by considering the way the chemical signals called hormones coordinate action in different parts of the body. After reading this material, you should be able to: 8.1.1 Distinguish the different classes of chemical signaling, from neurotransmitters to hormones and pheromones. 8.1.2 Contrast the mechanisms of action of peptide and amine hormones versus steroid hormones. 8.1.3 Contrast the modes of hormone release from the posterior pituitary versus the anterior pituitary. 8.1.4 Explain how the brain regulates circulating levels of hormone. 8.1.5 Give examples of the interaction of hormonal and neuronal communication in controlling behavior. Hormones are chemicals secreted by one group of cells and carried through the bloodstream to other parts of the body, where they act on specific target tissues to produce physiological effects. Most hormones are produced by endocrine glands (from the Greek endon, "within," and krinein, "to secrete"), so called because they release their hormones within the body (FIGURE 8.1). Endocrine glands are sometimes contrasted with exocrine glands (tear glands, salivary glands, sweat glands), which use ducts to secrete fluid outside the body.
Our current understanding of hormones developed in stages
Without knowing that hormones exist, ancient civilizations nevertheless noted their consequences. In the fourth century bce, Aristotle described the effects of castration (removal of the testes) in chickens and compared them with the effects in eunuchs (castrated men). But learning that these effects were due to the loss of chemical signals coming from the testes would not happen until 1849, when German physician Arnold Berthold (1803-1861) conducted the first endocrinology experiment. Aristotle had reported that when roosters are castrated as juveniles, they fail to develop normal reproductive behavior and secondary
sexual characteristics, such as the rooster's comb, in adulthood. Berthold observed, however, that returning one testis back into the body cavity of the young birds allowed them to develop normal male anatomy and behavior. In adulthood, these animals showed the usual male sexual behaviors--mounting hens, fighting, and crowing (FIGURE 8.2). Because no nerves had reestablished contact with the transplanted testis, the organ could not be communicating to the brain through nerves. Berthold (1849) concluded that the testes release a chemical into the blood that affects both male behavior and male body structures.
Today we know that the testes make and release the hormone testosterone to exert these effects. Although Berthold didn't know it, experiments like this also illustrate another principle of hormone action. If he had waited until the castrated chicks were adults before returning their testes, Berthold would have seen little effect. The testosterone must be present early in life to have such dramatic effects on the body and behavior. We'll return to this point later in this chapter. For now, let's see how hormones fit into the grand scheme of chemical signaling by the body.
FIGURE 8.2 Berthold's (1849) Experiment Demonstrated the Importance of Hormones for Behavior
Question Male chicks that are castrated grow up to have small wattles and combs, and they show little interest in mounting hens, fighting, or crowing. What causes these changes--the loss of a nerve connection between the testes and the body, or the loss of a chemical signal released from the testes?
Experiment Berthold removed the testes from their normal position but then reimplanted them elsewhere in the abdomen, disconnected from normal innervation.
Left undisturbed, young roosters grow up to have large red wattles and combs, to mount and mate with hens readily, and to fight one another and crow loudly.
Males whose testes were removed during development displayed neither the appearance nor the behavior of normal roosters as adults.
However, if one of the testes was reimplanted into the abdominal cavity immediately after its removal, the rooster developed normal wattles and normal behavior.
Comb and wattles: Mount hens? Aggressive? Crowing?
Outcome The animals with the reimplanted testes grew up to look and act like normal males. Berthold reasoned that the testes must have secreted a signal, which today we would call a hormone, that has widespread effects on the body and brain. Today we know that the hormone is testosterone.
248CHAPTER8 (A) Neural function (synaptic transmission) Action potential Neuron FIGURE 8.3 Chemical Communication Systems
View Animation 8.2: Brain Explorer View Animation 8.3: Chemical Communication Systems synapse The cellular location at which information is transmitted from a neuron to another cell. eWnadtosocnr/inBereedRloevfeerring to glands that rTehleeaMseincdh'semMiaccahlisneto the interior of the bFooudny.daTthioensseofgBlarnaidnsansdecBreehtaevitohre4eprincipal hMorMm4oen_e0s8.0u3sed0b6/y0t5h/e2b0 ody. pheromone A chemical signal that is released outside the body of an animal and affects other members of the same species. allomone A chemical signal that is released outside the body by one species and affects the behavior of other species.
Hormones are one of several types of chemical communication People had long suspected that special substances circulate to carry messages through the body, but as we discussed above, it wasn't until the nineteenth century that details of chemical communication began to emerge. We can compare hormonal communication with other methods of chemical signaling: · Synaptic communication Communication via synapses was described in Chapter 2 and Chapter 3. In typical synaptic transmission, the released chemical signal diffuses a tiny distance across the synaptic cleft and causes a change in the postsynaptic membrane (FIGURE 8.3A). · Endocrine communicationIn endocrine communication, our topic for this chapter, the chemical signal is a hormone released into the bloodstream to selectively affect distant target organs (FIGURE 8.3B). · Pheromone communication Chemicals can be used for communication not only within an individual, but also between individuals. Pheromones are chemicals that are released outside the body to affect other individuals of the same species (FIGURE 8.3C). For example, ants produce pheromones that identify the route to a rich food source (to the annoyance of picnickers). Dogs and wolves urinate on landmarks to designate their territory. In Chapter 6 we discussed pheromones in more detail (see Figure 6.23). · Allomone communication Some chemical signals are released by members of one species to affect the behavior of individuals of another species. These substances are called allomones (FIGURE 8.3D). Flowers exude scented allomones to attract insects and birds in order to distribute pollen. And the bolas spider--nature's femme fatale--releases a moth sex pheromone to lure male moths to their doom (Haynes et al., 2002). Let's review the basic types of hormones and how they influence cells. Hormones can be classified by chemical structure Most hormones fall into one of three categories: peptide hormones, amine hormones, or steroid hormones. Peptides are simply small protein molecules, so, like any other
FIGURE 8.4 Chemical Structures of the Three Main Hormone Types
Protein hormones consist of strings of amino acids. A short string, as here, may be referred to as a peptide hormone.
I I NH2 HO Thyroxine (tetraiodothyronine)
Steroid hormones are derived from cholesterol and consist of four interconnected rings of carbon atoms, with various chemical attachments. OH CH3 Estradiol
peptide hormone Also called protein hormone. A hormone that consists of a string of amino acids. amine hormone Also called monoamine hormone. A hormone composed of a single amino acid that has been modified into a related molecule, such as melatonin or epinephrine. steroid hormone Any of a class of hormones, each of which is composed of four interconnected rings of carbon atoms.
protein, a molecule of peptide hormone is made up of a short string of amino acids (FIGURE 8.4A). Different peptide hormones consist of different combinations of amino acids. Amine hormones are smaller and simpler, consisting of a modified version of a single amino acid (hence their alias, monoamine hormones) (FIGURE 8.4B). The amine hormone melatonin is discussed in A STEP FURTHER 8.1, on the website. Steroid hormones are derived from cholesterol and thus share its structure of four rings of carbon atoms (FIGURE 8.4C). Different steroid hormones vary in the number and kinds of atoms attached to the rings. BeWatson/Breedlocvaeuse steroids dissolve readily in lipids, they can pass The Mind's Macthhinroe ugh membranes easily (recall from Chapter 1 that Foundations of BrcaeinllamndeBmehbavriaorn4ees consist of a lipid bilayer). TABLE 8.1 MM4e_08.04 0g4i/v0e7s/e2x0amples of each class of hormones. The distinction between peptide or amine hormones and steroid hormones is important because the different types of hormones interact with different types of receptors, as we discuss next. Hormones act on a wide variety of cellular mechanisms Let's look briefly at two aspects of hormone activity: first the mechanisms of hormone action, then the types of changes that hormones cause in target cells, including neurons. The three classes of hormones exert their influences on target organs in two different ways. PEPTIDE AND AMINE HORMONES Peptide and amine hormones bind to specific receptor proteins on the surface of the target cell and activate chemical signals inside the
TABLE 8.1 Examples of Major Classes of Hormones
Adrenocorticotropic hormone (ACTH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Thyroid-stimulating hormone (TSH) Growth hormone (GH) Prolactin Insulin Glucagon Oxytocin Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, ADH) Releasing hormones, such as: Corticotropin-releasing hormone (CRH) Gonadotropin-releasing hormone (GnRH)
Epinephrine (adrenaline) Norepinephrine (NE) Thyroid hormones (e.g., thyroxine) Melatonin
Estrogens (e.g., estradiol) Progestins (e.g., progesterone) Androgens (e.g., testosterone, dihydrotestosterone) Glucocorticoids (e.g., cortisol) Mineralocorticoids (e.g., aldosterone)
FIGURE 8.5 Two Main Mechanisms of Hormone Action
(B) Steroid hormone action Steroid hormone
Peptide hormone receptors embedded in the cell membrane bind to the hormone, activating a second-messenger system that affects various processes inside the target cell.
New protein production and multiple biological effects DNA Steroid hormones diffuse passively in, binding to large receptor molecules inside target cells. The steroid-receptor complex then binds to DNA, altering the expression of certain genes--a so-called genomic effect.
second messenger A slow-acting substance in a target cell that amplifies the effects of synaptic or hormonal activity and regulates activity within the target cell. knockout organism An individual in which a particular gene has been disabled by an experimenter. autoradiography A technique that shows the distribution of radioactive chemicals in tissues.
cell that are called second messengers (see Chapter 3) (FIGURE 8.5A). What determines whether a cell responds to a particular peptide hormone? Receptors are highly specific, so only those cells that produce the appropriate receptor proteins for a hormone can respond to that hormone. As we saw with neurotransmitter receptors in Chapter 2 and Chapter 3, the receptor protein spans the cellular membrane. The specific effect of the hormone depends in large part on the receptor it activates. Peptide and amine hormones usually act relatively rapidly, within seconds to minutes. (Although rapid for a hormone, this action is much slower than neural activity.) STEROID HORMONES We mentioned earlier that steroid hormones easily pass through cell membranes, so their receptors are generally located inside the target cell. Different classes of steroids have their own specific receptors; for example, estrogens selectively interact with estrogen receptors, and androgens like testosterone bind to androgen receptors. When a steroid molecule and a receptor molecule combine, the steroid-receptor complex enters the nucleus of the cell and binds to the DNA, controlling the expression of specific genes (FIGURE 8.5B), increasing or decreasing the rate of protein production (see the Appendix). Because they involve multiple steps and the synthesis of large new molecules, steroid hormones are typically slower acting than peptide or amine hormones. Steroid effects may take hours, days, or even years to fully unfold. We can study where a steroid hormone is active by injecting radioactively tagged molecules of the steroid and observing where they accumulate. For example, tagged estrogens accumulate not only in the uterus (as you might expect), but also in the nuclei of some neurons throughout the hypothalamus. Because neurons that produce Whaotsromn/oBnreerdelocveeptors are found in only a limited number of brain regions, we can begin Thtoe Mleianrdn'shMoawchihnoermones affect behavior by finding those brain sites and asking what Foundations of Brain and Behavior 4e happens when the hormone arrives there. This strategy for learning about hormones MaMn4de_b0e8h.0a5vio0r7i/s0d1/is2c0ussed in BOX 8.1. Hormones can have different effects on different target organs Virtually all hormones, whether peptide or steroid, act on more than one target organ. What's more, a given hormone may have one type of effect on one organ, and a quite different effect on another organ. This means hormones often act to coordinate
Box 8.1 Techniques of Behavioral Endocrinology
To establish that a particular hormone affects behavior, investigators usually begin with an experiment like that of Arnold Berthold (see Figure 8.2): observing the behavior of the intact animal and then removing the endocrine gland and looking for a change in behavior. Modern scientists have many options to understand that basic finding. Let's imagine that we're investigating a particular effect of hormones on behavior to see how we might proceed. First we carefully observe the behavior of several individuals, to classify and quantify the different types of behavior and to place them in the context of other individuals. For example, most adult male rats will try to mount and copulate with females placed in their cages. If its testes are removed, the male rat will eventually stop copulating with females. We know that one of the hormones produced by the testes is testosterone. Is it the loss of testosterone that causes the loss of male copulatory behavior? To explore this question, we inject some testosterone into castrated males and observe whether the copulatory behavior returns. (It does.) Another way to ask whether a steroid hormone is affecting a particular behavior is to examine the behavior of animals that lack the receptors for that steroid. We can delete the gene for a given hormone receptor, making a knockout organism (so called because the targeted gene has been "knocked out"), and ask which behaviors are different in the receptor knockouts versus normal animals. What does testosterone do to facilitate sexual behavior? One step toward answering this question is to determine which parts of the brain are normally affected by this hormone. First we might inject a castrated animal with radioactively labeled testosterone and wait for the hormone to accumulate in the brain regions that have receptors
Exposure for the hoWrmatosonne/.BTrheeednlowvee could sacrifice the animTahl,erMeminodv'seMthaechbinraein, freeze it, Foundations of Brain and Behavior 4e cut thin sections from it, and place the thin sectionsMonMp4he_oBtoogxr8a.p1Ahic 0fi5lm/1.8R/2a0dioactive emissions from the tissue would expose the film, revealing which brain regions accumulated the labeled testosterone. This method is known as autoradiography
1 A rat is injected with molecules of testosterone (an androgen) that have been radioactively labeled. 2 The testosterone molecules enter the bloodstream and accumulate in those cells that have androgen receptors. 3 The brain is removed and frozen to keep the testosterone molecules inside the target cells. Film 4 The brain is thinly sliced and lm is placed on top in the dark. The radioactive molecules release particles that "expose" the film just as light would. 5 When the lm is developed, small black dots form on the lm where the androgen has accumulated in target cells. (A) Steps in steroid autoradiography. because the tissue "takes its own picture" with radioactivity (FIGURE A). When the labeled hormone is a steroid like testosterone, the radioactivity accumulates in the nuclei of neurons and leaves small black specks on the overlying (Continued )
Box 8.1 (continued)
film (FIGURE B). When the radiolabeled hormone is a peptide hormone such as oxytocin, the radioactivity accumulates in the membranes of cells and appears in particular layers of the brain. Computers can generate color maps that highlight regions with high densities of receptors (FIGURE C). Another method for detecting hormone receptors is immunocytochemistry (ICC) (described in more detail in Box 1.1). ICC enables us to map the distribution of hormone receptors in the brain. We allow specific antibodies to seek out and bind to receptors on slices of brain tissue, then we use chemical methods to make the
antibodies visible, leaving a dark color in the spherical nuclei of target brain cells (FIGURE D). We can also use in situ hybridization (see Box 1.1, Appendix Figure A.4) to look for the neurons that make the mRNA for the steroid receptor. Because these cells make the transcript for the receptor, they are likely to possess the receptor protein itself. Once we've used autoradiography, immunocytochemistry, or in situ hybridization to identify brain regions that have receptors for the hormone, those regions become candidates for the places at which the hormone works to change behavior. Now we can take castrated males, implant tiny pellets of
testosterone into one of those brain regions, and see whether the behavior is restored. It turns out that such implants can restore male sexual behavior in rats only if they are placed in the medial preoptic area (mPOA) of the hypothalamus. So far, we've found that testosterone does something to the mPOA to permit individual males to display sexual behavior. Now we can examine the mPOA in detail to learn which changes in the anatomy, physiology, or protein production of this region are caused by testosterone. And with that, we have more or less caught up to present-day scientists who work on this very question.
Courtesy of Cynthia L. Jordan (Michigan State University) Courtesy of Bruce S. McEwen
(B) An autoradiogram showing that spinal motor neurons (purple cell profiles) accumulate radioactive testosterWatsoonne/B(sremedallol vdeots). The Mind's Machine Foundations of Brain and Behavior 4e MM4e_Box 8.1 B-D 04/08/20
A single hormone may affect multiple target tissues throughout the body.
Similarly, a single process or body organ may be affected by several hormones.
(C) An autoradiogram showing the concentration of oxytocin receptors (orange) in the ventromedial hypothalamus (oval outlines).
(D) Immunocytochemistry revealing cells with nuclei that contain androgen receptors (dark circles), to which testosterone can bind. The cell bodies of these neurons have been labeled with two different tracers, one white and the other red.
different parts of the body, causing diverse changes to several different parts of the body, all of which prepare the animal for a particular activity. For example, the testes secrete testosterone, which acts in the testes themselves to drive sperm production but also acts to masculinize the body in diverse ways, favoring muscle development and, in humans, beard growth (FIGURE 8.6). In this and numerous other cases we'll discuss, the same hormone also acts on the brain--in the case of testosterone, to promote sexual behavior and aggression in many animal species. How can the same hormone cause many different responses in different organs? First, often more than one receptor responds to a given hormone. For example, there are at least two different subtypes of receptors for estrogens, and for other hormones there may be four or more. In addition, sometimes the same receptor, in response to the same hormone, will have a different effect because the target cell uses different second messengers to respond differently.
FIGURE 8.6 The Multiplicity of Hormone Action
As we'll see later, the brain maintains strict control over most hormone secretions, which means, among other things, that the brain has receptors to detect almost all hormones, in order to monitor their release.
1. What are hormones, and how do they act? 2. Describe Berthold's experiment with young roosters, and explain how it indicated hormonal effects. 3. Compare and contrast the mechanisms by which peptide/amine hormones versus steroid hormones act on cells. 4. Why are hormones effective for coordinating different changes in different parts of the body? Each endocrine gland secretes specific hormones Now we'll discuss the specific hormones that endocrine glands secrete. To cover all the hormones would require an entire book, so we will consider only some of the main endocrine glands. A STEP FURTHER 8.2, on the website, gives a fuller (though far from complete) listing of hormones and their functions. Hormones involved in thirst and hunger are discussed in Chapter 9. We begin with the pituitary because it regulates so many other endocrine glands. Resting in a socket in the base of the skull, the pituitary gland is about the size of a garden pea, weighing about 1 gram (see Figure 8.1). The hypothalamus sits just above the pituitary and is connected to the gland by a slender thread called the pituitary stalk. The term pituitary comes from the Latin pituita, "mucus," reflecting the outmoded belief that waste products dripped down from the brain into the pituitary, which then secreted them out through the nose. (If this were true, you could literally sneeze some of your brains out!) Because the pituitary regulates most other endocrine glands, it is sometimes referred to as the master gland. But the pituitary is itself enslaved by the hypothalamus above it, as we'll see. To understand how the pituitary works, we need to consider a special category of cells that are something of a blend of neuronal cells and endocrine cells, called neuroendocrine cells. On the one hand, neuroendocrine cells receive synaptic input from other neurons and, if they are excited past threshold, produce action potentials. But unlike regular neurons, which release a neurotransmitter into a synapse when they fire, neuroendocrine cells release a hormone into the bloodstream (FIGURE 8.7). To understand the pivotal role of such neuroendocrine cells in hormone release from the pituitary, we need to consider separately the two parts of the pituitary: the anterior pituitary and the posterior pituitary. The mechanism of hormone release is simpler in the posterior pituitary, so let's discuss that first.
Neuroendocrine cells receive synaptic signals from other neurons and produce action potentials...
...yet secrete a hormone into the bloodstream.
immunocytochemistry (ICC) A method for detecting a particular protein in tissues in which an antibody recognizes and binds to the protein and then chemical methods are used to leave a visible reaction product around each antibody. in situ hybridization A method for detecting particular RNA transcripts in tissue sections by providing a nucleotide probe that is complementary to, and will therefore hybridize with, the transcript of interest. pituitary gland A small, complex endocrine gland located in a socket at the base of the skull. pituitary stalk A thin piece of tissue that connects the pituitary gland to the hypothalamus. neuroendocrine cell A neuron that releases hormones into local or general circulation. View Animation 8.4: Mechanisms of Hormone Action
Action Hormones potential Thus electrical signals are converted into hormonal signals.
FIGURE 8.7 Neuroendocrine Cells Are the Interface between Neurons and Endocrine Glands
posterior pituitary The rear division of the pituitary gland. oxytocin A peptide hormone, released from the posterior pituitary, that triggers milk letdown in the nursing female and is also associated with a variety of complex behaviors. vasopressin Also called arginine vasopressin or antidiuretic hormone. A peptide hormone from the posterior pituitary that promotes water conservation and increases blood pressure. milk letdown reflex The reflexive release of milk by the mammary glands of a nursing female in response to suckling or to stimuli associated with suckling. Optic chiasm Direction of blood ow Posterior pituitary hormones: Oxytocin Vasopressin
The posterior pituitary releases two hormones directly into the bloodstream
While the posterior pituitary releases hormones, the organ itself does not make them.
Rather, the hormones are manufactured by neuroendocrine cells in two hypothalamic
regions: the supraoptic and paraventricular nuclei. These neuroendocrine cells transport
hormones down their axons, which extend through the pituitary stalk to terminate in
the posterior pituitary. When the hypothalamic neuroendocrine cells are excited by
synaptic input, they produce action potentials that travel down the axons and release
hormone directly onto capillaries (small blood vessels) in the posterior pituitary, send-
ing the hormone into circulation immediately (FIGURE 8.8).
In this fashion, the neuroendocrine cells in the hypothalamus produce and release
two peptide hormones from the posterior pituitary: oxytocin and vasopressin. Some
of the signals that activate the nerve cells of the supraoptic and paraventricular nuclei
are related to thirst and water regulation; vasopressin is involved in these interactions,
which will be discussed in Chapter 9. Oxytocin is involved in many aspects of repro-
ductive and parental behavior. One of its functions is to stimulate contractions of the
uterus in childbirth. Injections of oxytocin (or a synthetic version) are frequently used
in hospitals to induce or accelerate labor and delivery.
Oxytocin also triggers the milk letdown reflex, the contraction of mammary gland
cells that ejects milk into the breast ducts. This reflex exemplifies the reciprocal re-
lationship between behavior and hormone release. When an infant first begins to
suckle, the arrival of milk at the nipple is delayed
by 30-60 seconds. This delay is caused by the se-
quence of steps that precedes letdown. Stimula-
tion of the nipple activates receptors in the skin, which transmit this information through a chain
of neurons and synapses to hypothalamic cells that contain oxytocin. Once these neuroendo-
Neuroendocrine cell bodies in the hypothalamus produce
crine cells have been sufficiently stimulated, they produce action potentials that travel down their axons to the posterior pituitary, where they re-
lease oxytocin into the bloodstream. The oxytocin
reaches muscle tissue in the mammary glands, and the muscle contracts to make milk available at the nipple (FIGURE 8.9).
For mothers, this reflex response to suckling
frequently becomes conditioned to baby cries,
Axons from these neurons pass through the pituitary stalk...
so milk appears promptly at the start of nursing. Because the mother is conditioned to release oxytocin before the suckling begins, sometimes the
cries of someone else's baby in public may trigger
capillaries of the posterior pituitary. When an action potential arrives at a
Posterior pituitary hormones can affect social behavior
terminal, oxytocin or vasopressin is released from the terminal directly
We've already seen the role of oxytocin in the interaction of nursing babies and their mothers (see
Figure 8.9). It turns out that this hormone is in-
volved in several other social behaviors too. For
one thing, a pulse of oxytocin is released during
orgasm in both men and women (Caruso et al.,
2017), adding to the pleasurable feelings accom-
FIGURE 8.8 Hormone Secretion by the Posterior Pituitary
1 Stimulation of the mother's nipple by the infant's suckling response produces brain activity in the mother.
2 The brain activity stimulates hypothalamic cells to release oxytocin from the posterior pituitary.
Hormones and Sex 255 FIGURE 8.9 The Milk Letdown Reflex
4 The baby, rewarded with milk, continues suckling until sated.
Nerve impulses to hypothalamus Oxytocin from pituitary gland 3 The oxytocin causes the cells of the mammary glands to contract, thereby releasing milk.
In nonhuman animals, oxytocin and vasopressin facilitate many social processes (Lim and Young, 2006). Rodents given supplementary doses of oxytocin spend more time in physical contact with one another (Carter, 2017). Male mice that have the oxytocin gene knocked out and are therefore unable to produce the hormone display social amnesia: they seem unable to recognize the scents of female mice that they have met before (Ferguson et al., 2000). These oxytocin knockout males can be cured of their social amnesia with brain infusions of oxytocin (Winslow and Insel, 2002). In prairie voles (Microtus ochrogaster), couples form stable pair-bonds, and oxytocin infusions in the brains of females help them bond to their mates. In male prairie voles, it is vasopressin rather than oxytocin that facilitates the formation of a preference for a specific female partner. In fact, the distribution of vasopressin receptors in the brains of male prairie voles may be what makes them monogamous. Supporting this idea is the finding that the closely related meadow voles (Microtus pennsylvanicus), which do not form pair-bonds and instead have multiple mating partners, have far fewer vasopressin receptors in certain brain regions than prairie voles have (Lim et al., 2004). Thus, oxytocin and vasopressin regulate a range of social behaviors, and natural selection appears to alter the social behaviors of a species by changing the brain distribution of receptors for the peptides (Donaldson and Young, 2008) (FIGURE 8.10). Feedback control mechanisms regulate the secretion of hormones Watson/Breedlove The Mind's MAalclhhinoermone release is carefully controlled by the brain, which monitors internal and Foundations oefxBtrearinnaanldcBueehasvtioor 4deecide whether and how much hormone should be released. Brain regulation of posterior pituitary hormone release is readily understood because the MM4e_08.09 04/07/20 neuroendocrine cells secrete hormone only when they are excited synaptically. For example, sensory information from a child's suckling at the breast reaches the brain and excites hypothalamic neuroendocrine cells, which fire action potentials and release oxytocin. Once the baby is satisfied, the suckling stops, so the brain stops exciting the neuroendocrine cells and oxytocin release ceases.
pair-bond A durable and exclusive relationship between two individuals. Peptide Hormones in the Hypothalamus This section of the paraventricular nucleus reveals cells that make oxytocin (red) or vasopressin (green), hormones that are released from the posterior pituitary.
Image by Vicky Tobin and Mike Ludwig, Center for Integrative Physiology, University of Edinburgh
(B) Monogamy in male prairie voles seems to be due to the dense concentration of vasopressin receptors in the ventral pallidum (VP).
(C) Males of the closely related meadow vole species have fewer vasopressin receptors in the VP, which may explain why they are not monogamous.
B and C courtesy of Miranda Lim and Larry Young © Yva Momatiuk and John Eastcott/ Minden Pictures
FIGURE 8.10 Vasopressin and the Monogamous Brain
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_08.10 04/08/20 negative feedback The property by which some of the output of a system feeds back to reduce the effect of input signals. anterior pituitary The front division of the pituitary gland. It secretes tropic hormones. tropic hormone Any of a class of anterior pituitary hormones that affect the secretion of hormones by other endocrine glands.
This is an example of the basic mechanism that regulates all hormone secretion, called negative feedback: output of the hormone feeds back to inhibit the drive for more of that same hormone (FIGURE 8.11A). This negative feedback action of a hormonal system is like that of a thermostat, and just as the thermostat can be set to different temperatures at different times, the set points of a person's endocrine feedback systems can change to meet varying circumstances. We'll discuss negative feedback regulation of other processes in Chapter 9 (see Figure 9.1). Hormone secretion from the anterior pituitary is also regulated by negative feedback, but the mechanism is a bit more complicated, as we'll see next. Hypothalamic releasing hormones govern the anterior pituitary The anterior pituitary consists of many different endocrine cells, each secreting a different peptide hormone. So, unlike the posterior half of the pituitary, the anterior pituitary actually synthesizes the hormones it releases. The anterior pituitary hormones are called tropic hormones. (The o in tropic is pronounced "oh"; there is nothing
(A) Brain regulation Hypothalamus - + Endocrine cells
View Animation 8.5: The Hypothalamus and Endocrine Function
FIGURE 8.11 Endocrine Feedback Loops
Sometimes negative feedback is simple: the biological response is detected by the brain, which halts further hormone release.
For the anterior pituitary, hormones from the endocrine gland have a negative feedback effect on both the hypothalamus and pituitary.
"tropical" about these hormones.) The term tropic means "directed toward," and each tropic hormone acts on a different endocrine gland, such as the thyroid or ovaries, as if the tropic hormone were directed toward that gland. Actually, the tropic hormone travels throughout the bloodstream, reaching all glands, but only the target glands have the appropriate receptors to respond to it. Once the tropic hormone reaches a target gland, it drives the gland to produce its own hormone. For example, one anterior pituitary tropic hormone acts on the thyroid gland to make it secrete thyroid hormones. To regulate secretions of tropic hormones from the anterior pituitary, the hypothalamus uses another whole set of peptide hormones, called releasing hormones. The cells that synthesize the different releasing hormones are neuroendocrine cells residing in various regions of the hypothalamus (FIGURE 8.11B). The axons of these neuroendocrine cells converge on the median eminence, just above the pituitary stalk. This region contains a profusion of blood vessels that form the hypothalamic-pituitary portal system. Here, in response to inputs from the rest of the brain, the axon terminals of the hypothalamic neuroendocrine cells secrete their releasing hormones into the local bloodstream (FIGURE 8.12). Blood carries the various releasing hormones only a very short distance, into the anterior pituitary. The rate at which releasing hormones arrive at the anterior pituitary controls the rate at which the anterior pituitary cells, in turn, release their tropic hormones into the general circulation. These tropic hormones then regulate the activity of major endocrine organs throughout the body. Thus, the brain's releasing hormones affect the anterior pituitary's tropic hormones, which affect the release of hormones from endocrine glands.
releasing hormone Any of a class of hormones, produced in the hypothalamus, that traverse the hypothalamic-pituitary portal system to control the pituitary's release of tropic hormones. median eminence A midline feature on the base of the brain that marks the point at which the pituitary stalk exits the hypothalamus to connect to the pituitary. The median eminence contains one end of the hypothalamic-pituitary portal system. hypothalamic-pituitary portal system An elaborate bed of blood vessels leading from the hypothalamus to the anterior pituitary.
Neuroendocrine cell bodies in the hypothalamus produce releasing hormones...
Median eminence Hypothalamicpituitary portal veins
Posterior pituitary Cells that produce anterior pituitary hormones
Tropic hormones: Prolactin Gonadotropic hormones (FSH and LH) Thyroid-stimulating hormone ACTH Growth hormone
... which are released from axons that terminate on the portal system. The hormones travel via the portal veins to the anterior pituitary. Cells in the anterior pituitary respond to the hypothalamic releasing hormones by secreting tropic hormones. Tropic hormones travel through the bloodstream and regulate endocrine glands throughout the body.
FIGURE 8.12 Hormone Release by the Anterior Pituitary
The hypothalamic neuroendocrine cells that synthesize the releasing hormones are themselves subject to two kinds of influences. First, they are directly affected by circulating messages, such as other hormones, especially hormones that were secreted in response to tropic hormones (see Figure 8.11B). This hormone sensitivity of the hypothalamic neurons is an important part of the negative feedback we mentioned earlier, because typically the hormones secreted from an endocrine gland feed back to inhibit the secretion of releasing hormones and tropic hormones. Negative feedback in this case goes from the hormone of the endocrine gland to both the hypothalamus and the anterior pituitary. Second, the hypothalamic neuroendocrine cells that provide releasing hormones also receive synaptic inputs (either excitatory or inhibitory) from many other brain regions. As a result, the release of hormones by the anterior pituitary is coordinated with ongoing events, such as time of day, time of the year, safety of the individual, and so on. For example, if a child is living in stressful, abusive conditions, the brain monitors these conditions and reduces the production of releasing hormones that stimulate the anterior pituitary secretion of growth hormone (GH), as we discuss in A STEP FURTHER 8.3, on the website. Thus, the hypothalamic-releasing-hormone system exerts high-level control over endocrine organs throughout the body, translating brain activity into hormonal action. Cutting the pituitary stalk interrupts the portal blood vessels and the flow of releasing hormones, leading to profound atrophy of the pituitary, as well as major hormonal disruptions.
growth hormone (GH) Also called somatotropin or somatotropic hormone. A tropic hormone, secreted by the anterior pituitary, that promotes the growth of cells and tissues. gonad Any of the sexual organs (ovaries in females, testes in males) that produce gametes for reproduction. gonadotropin-releasing hormone (GnRH) A hypothalamic hormone that controls the release of luteinizing hormone and follicle-stimulating hormone from the pituitary. gonadotropin An anterior pituitary tropic hormone that stimulates the cells of the gonads to produce sex steroids and gametes. follicle-stimulating hormone (FSH) A gonadotropin, named for its actions on ovarian follicles. follicle The structure of the ovary that contains an immature ovum (egg). luteinizing hormone (LH) A gonadotropin, named for its stimulatory effects on the ovarian corpora lutea. corpus luteum The structure that forms from the collapsed ovarian follicle after ovulation. The corpora lutea are a major source of progesterone.
1. How do hormones and behaviors interact in the milk letdown reflex? 2. How are hormones released from the posterior pituitary? 3. Describe the system regulating hormone release from the anterior pituitary, and explain how that system controls other endocrine glands. Two anterior pituitary tropic hormones act on the gonads Driven by various releasing hormones from the hypothalamus, the anterior pituitary gland secretes at least six different tropic hormones. We don't really need to go into all these hormones and the glands they control right now, but you can learn more about them in A STEP FURTHER 8.4, on the website. Here we will concentrate on the tropic hormones that affect male and female gonads (the testes and ovaries, respectively), because the hormones produced by gonads play a role in the rest of this chapter. In the hypothalamus, neuroendocrine cells produce gonadotropin-releasing hormone (GnRH), which is secreted into the capillaries of the median eminence, traveling via the hypothalamic-pituitary portal system to arrive at the anterior pituitary. In response to this GnRH, anterior pituitary cells release one or both of the tropic hormones that act on the gonads, which are thus collectively known as gonadotropins: 1. Follicle-stimulating hormone (FSH) gets its name from its actions in the ovary, where it stimulates the growth and maturation of egg-containing follicles and the secretion of estrogens from the follicles. In males, FSH governs sperm production. 2. Luteinizing hormone (LH) stimulates the follicles of the ovary to rupture, release their eggs, and form into structures called corpora lutea (singular corpus luteum) that secrete the sex steroid hormone progesterone. In males, LH stimulates the testes to produce testosterone. Since both of the gonadotropins drive the release of gonadal steroids, we'll turn our attention to those hormones next. The gonads produce steroid hormones, regulating reproduction Almost all aspects of reproductive behavior, including mating and parental behaviors, depend on hormones, as we'll see later in this chapter. Each ovary or testis consists of
FIGURE 8.13 Gonadal Hormone Regulation in Males
Testosterone and other androgens + Target cells Androgens promote: · Development and maintenance of male reproductive organs · Development of male secondary sex characteristics (body form, larynx, beard, etc.) two different subcompartments--one to produce hormones (the sex steroids we mentioned earlier) and another to produce gametes (eggs or sperm). The gonadal hormones are critical for triggering both reproductive behavior controlled by the brain, and gamete production. THE TESTES Within the testes (singular testis) are Sertoli cells, which produce sperm, and Leydig cells, which produce and secrete the steroid testosterone. Testosterone and other male hormones are called androgens (from the Greek andro, "man," and gennan, "to produce"). Testosterone controls a wide range of bodily changes that become visible at puberty, including cWhaatnsogne/sBirneevdoloicvee, hair growth, and genital size. In species that breed only in certain seasTohnesMoifndth'seMyaecahri,nteestosterone has especially marked effects on appearance Foundations of Brain and Behavior 4e and behavior--for example, the antlers and fighting between males that are displayed by many species oMfMde4ee_r.0F8.I1G3UR0E7/80.11/32s0ummarizes the regulation of testosterone secretion. THE OVARIES The paired female gonads, the ovaries, also produce both the mature gametes--called ova (singular ovum) or eggs--and sex steroid hormones. However, hormone secretion is more complicated in ovaries than in testes. Ovarian hormones are produced in cycles, the duration of which varies with the species. Human ovarian cycles last about 4 weeks; rat cycles last only 4 days. The ovary produces two major classes of steroid hormones: progestins (from the Latin pro, "favoring," and gestare, "to bear," because these hormones help to maintain pregnancy) and estrogens (from the Latin oestrus, "frenzy"--estrus is the scientific term for the periodic sexual receptivity of females in many species). The most important naturally occurring estrogen is estradiol (specifically, 17-beta-estradiol). The primary progestin is progesterone.
testes The male gonads, which produce sperm and androgenic steroid hormones. testosterone A hormone, produced by male gonads, that controls a variety of bodily changes that become visible at puberty. It is one of a class of hormones called androgens. androgen Any of a class of hormones that includes testosterone and similar steroids. ovaries The female gonads, which produce eggs (ova) for reproduction. progestin Any of a major class of steroid hormones that are produced by the ovary, including progesterone. estrogen Any of a class of steroid hormones, including estradiol, produced by female gonads. estradiol Formally called 17-betaestradiol. The primary type of estrogen secreted by the ovary. progesterone The primary type of progestin secreted by the ovary.
The ovulatory cycle begins when FSH stimulates ovarian follicles to grow and secrete es-
trogens (FIGURE 8.14). The estrogens induce
the hypothalamus and pituitary to release LH, which triggers the release of an egg from a follicle (ovulation) and causes the follicle to develop as a
- corpus luteum. The corpus luteum then secretes progesterone for a limited time to maintain the
uterus for pregnancy. If the female does not become pregnant, the cycle starts over again.
Estrogens may improve aspects of cognitive
functioning (Ycaza Herrera and Mather, 2015), although this topic is still debated (Dohanich, 2003;
Sherwin, 2009; Korol and Pisani, 2015). Estrogens
may also protect the brain from some of the ef-
fects of stress and stroke (S. Suzuki et al., 2009;
FSH stimulates follicle development; follicles secrete estrogens. LH stimulates ovulation and formation of a corpus luteum, which secretes progesterone.
Petrone et al., 2014). For these reasons and others, estrogen replacement therapy has been a popular postmenopausal treatment, but the possibility that these treatments increase the risk of serious diseases like cancer and heart disease (Turgeon et al., 2004; Prentice, 2014) makes the decision of whether to take the hormones difficult for postmenopausal women.
Estrogens promote development, maintenance of:
· Female reproductive organs · Female secondary sex characteristics
RELATIONS AMONG GONADAL HORMONES All steroid hormones--including androgens,
Progesterone prepares: · Uterus for implantation of fertilized egg · Breasts for milk secretion
estrogens, and progestins--are based on the chemical structure of cholesterol (see Figure 8.4C). Glands manufacture steroid hormones
by using enzymes to modify cholesterol, step by
FIGURE 8.14 Gonadal Hormone Regulation in Females
step, into different steroids. For example, ovaries
first convert cholesterol into progestins, and then
they convert those progestins into androgens,
ovulatory cycle The periodic occurrence of ovulation in females.
Different organs--and the two sexes--differ in the relative amounts of gonadal steroids that they produce. For example, whereas the testes convert only a relatively
small proportion of testosterone into estradiol, the ovaries convert most of the testos-
terone they make into estradiol. What's important to understand is that no steroid is
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e
found exclusively in either males or females. Hormonal and neural systems interact to produce integrated responses
The endocrine system and the nervous system work together, each affecting the other,
seamlessly integrating various body systems to produce adaptive responses to the en-
vironment. So, for example, if our sensory system tells us that a stimulus calls for ac-
tion--perhaps that faint buzzing sound you're hearing turns out to be coming from a
nest of angry wasps--hormones can be released to provide energy to fuel appropriate
behaviors (sprinting away, yelling, cursing maybe).
Four kinds of signals are possible between neurons and endocrine cells: neu-
ral-to-neural, neural-to-endocrine, endocrine-to-endocrine, and endocrine-to-neu-
ral. All four types are illustrated in the courtship behavior of the ringdove. The
visual processing that occurs when a male dove sees an attractive female involves neu-
ral-to-neural transmission (FIGURE 8.15, step 1). The details of the particular visual
stimulus--namely, an opportunity to mate--activate a neural-to-endocrine link (step
2), which causes neuroendocrine cells in the male's hypothalamus to secrete GnRH.
1 The male ringdove sees an attractive female. The stimulation of his retina sets off a chain of neural-to-neural transmission of information. Glass barrier
Hormones and Sex 261 2 The male's perception of an available mate activates a neural-to-endocrine link, as neuroendocrine cells in his hypothalamus secrete GnRH into the hypothalamic-pituitary portal system.
3 The pituitary mediates an endocrine-toendocrine signal, releasing gonadotropins (LH and FSH). These hormones provide an endocrine-to-endocrine signal, inducing the testes to increase release of the hormone testosterone.
5 The female dove responds to his display, thus providing new visual stimulation to the male and further neural-to-neural signals within his brain. Then the cycle begins again.
4 Testosterone, in turn, uses an endocrine-toneural link, altering the excitability of some brain neurons and thus causing the male to display courtship behavior ("bowing coos").
FIGURE 8.15 Four Kinds of Signals between the Nervous System and the Endocrine System
The GnRH provides an endocrine-to-endocrine signal (step 3), stimulating the pituitary to release gonadotropins, which induce the testes to release more testosterone. Testosterone in turn alters the excitability of neurons in the male's brain through an endocrine-to-neural link (step 4), causing the male to display courtship behavior. The female dove responds to this display (step 5), thus providing new visual stimulation to the male, which triggers another cycle of signaling in him. The interactions between endocrine activity and behavior are cyclical, as depicted by the circle schema in FIGURE 8.16. The levels of circulating hormones can be altered by experience, which in turn can affect future behavior and future experience. For example, men supporting a candidate in a presidential election will produce more testosterone if their candidate wins, and less if their preferred candidate loses (Stanton et al., 20W0a9t)s,own/hBircehedmlovaey in turn affect their future behavior and future experience. Physical stTrheessMesin,dp'as iMna, cahnindeunpleasant emotional situations trigger the release of steroids from thFeouanddraetinonaslogf lBarnaidn (asnedeBCehhavaioprte4er 11). MMCo4en_v0e8.r1s5ely,06e/a1c7h/2o0f these hormonal events will affect the brain, shaping behavior, which will once more affect the person's future hormone production, and so on. It will be important to keep in mind these interactions between hormones and behavior as we consider reproductive behavior in the next section. 1. Describe the role of the hypothalamus and the anterior pituitary in regulating gonadal hormones. 2. What hormones are found in birth control pills, and how do they prevent pregnancy? 3. Describe the interplay of neural and hormonal signaling in the human milk letdown reflex and the male ringdove's courtship behavior.
FIGURE 8.16 The Reciprocal Relations between Hormones and Behavior
8.2Reproductive Behavior Is Regulated by the Brain
sexual attraction The first step in the mating behavior of many animals, in which animals emit stimuli that attract members of the opposite sex. proceptive Referring to a state in which a female advertises her readiness to mate through species-typical behaviors.
Now we consider the role of hormones in regulating reproductive behavior, including maternal behavior. Integrating this material should allow you to: 8.2.1 Discuss the sequence of mating behaviors in animals and the role of hormones in regulating those behaviors. 8.2.2 Outline the brain regions that control sexual behavior in male and female rats. 8.2.3 Describe the maternal behaviors of rats and the roles of experience versus hormones in facilitating them. 8.2.4 Describe the typical sequence of sexual arousal in women and men, and offer a critical appraisal of whether hormones influence human sexual behavior. Sexual attraction is the first stage in bringing males and females together. In many species, sexual attraction is closely synchronized with physiological readiness to reproduce. Most male mammals are attracted by particular female odors, which tend to reflect estrogen levels. Because estrogen secretion is associated with the release of eggs, this means female sexual attractiveness peaks alongside fertility. Of course, the female may find a particular male unattractive and refuse to mate with him. Although apparent rape has been described in some nonhuman species (Thornhill and Palmer, 2000; Maggioncalda and Sapolsky, 2002), for most species copulation is not possible without the female's active cooperation. If the animals are mutually attracted, they may progress to the species-specific behaviors that establish, maintain, or promote sexual interaction. A female displaying these behaviors is said to be proceptive: she may approach males, remain close to them, or show alternating approach and retreat behaviors. Proceptive female rats typically exhibit "ear wiggling" and a hopping and darting gait to induce a male to mount. Male behaviors usually consist of staying near the females. In many mammals, the male may sniff around the female's face and vagina. Male birds may engage in elaborate songs or nest-building behaviors, as illustrated for the ringdove in Figure 8.14.
Enough Already! By reducing the refractory phase, when a sexually exhausted male encounters an unfamiliar female, the Coolidge effect permits him to take advantage of a new reproductive opportunity and sire more offspring. (Of course, encountering 24 lovelorn females at once is a situation few males--guinea pig or otherwise--could even dream of.)
Sooty enjoyed two nights of passion among 24 females.
Guinea pig Don Juan sires 43 offspring in 2 nights PONTYPRIDD, WALES, 1 DECEMBER 2000 HAVING ESCAPED from captivity at Little Friend's Farm earlier this year, a male guinea pig named Sooty chose to re-enter captivity immediately--in the nearby cage housing 24 females. Two months later he is now the father of 43 offspring. According to his owner, Carol Feehan, Sooty was missing for two whole days before the staff checked the females' pen. "We did a head count and found 25 guinea pigs," she told the press. "Sooty was fast asleep in the corner. "He was absolutely shattered. We put him back in his cage and he slept for two days."
The pair may then progress to copulation, also known as coitus. In many vertebrates, including all mammals, copulation involves one or more intromissions, in which the male inserts his penis into the female's vagina, followed by a variable amount of stimulation, usually through pelvic thrusting. When stimulation reaches a threshold level, the male ejaculates sperm-bearing semen into the female; the length of time required for ejaculation varies greatly between species. After one bout of copulation, the animals will not mate again for a period of time, which is called the refractory phase. The refractory phase varies from minutes to months, depending on the species and circumstances. Many animals will resume mating sooner if they are provided with a new partner--a phenomenon known as the Coolidge effect (named after an old joke about U.S. President Calvin Coolidge [Google it]). The female is often the one to choose whether copulation will take place; when she is willing to copulate, she is said to be sexually receptive, in heat, or in estrus. In some species, the female may show proceptive behaviors days before she will participate in copulation itself. In most (but not all) species, females are receptive only when mating is likely to produce offspring. Most species are seasonal breeders, with females that are receptive only during the breeding season; some--such as Pacific salmon, octopuses, and cicadas--reproduce only once, at the end of life. Finally, reproductive behavior includes postcopulatory behaviors. These behaviors are especially varied, having been strongly shaped by diverse evolutionary pressures related to the different species' mating systems. For example, in some mammals, including dogs and southern grasshopper mice, the male's penis swells so much after ejaculation that he can't remove it from the female for a while. In species like these, where several males may copulate with an ovulating female in quick succession, this phenomenon, called copulatory lock, prevents other males from mating, at least for a while. Despite wild stories you may have heard or read, humans never experience copulatory lock; that urban myth started in 1884 when a physician submitted a fake report as a practical joke (Nation, 1973). For mammals and birds, postcopulatory behavior includes extensive parental behaviors to nurture the offspring, as we describe later in this chapter. Copulation brings gametes together All mammals, birds, and reptiles employ internal fertilization: the fusion of their gametes--sperm and ovum--within the female's body to form a zygote. Most of what we know about the copulatory behavior of mammals comes from studies of lab animals, especially rats. Like most other rodents, rats do not engage in lengthy courtship, nor do the partners tend to remain together after copulation. Rats are attracted to each other largely through odors. Female rats, like humans, are spontaneous ovulators; that is, even when left alone, they ovulate (release eggs from the ovary). For a few hours around the time of ovulation, the female rat seeks out a male and displays proceptive behaviors, including vocalizations at frequencies too high for humans to detect but audible to other rats. These behaviors prompt the male to mount the female from the rear, grasp her flanks with his forelegs, and rhythmically thrust his hips against her rump. If she is receptive, the female adopts a stereotyped posture called lordosis (FIGURE 8.17), elevating her rump and moving her tail to one side to allow intromission. Once intromission has been achieved, the male rat makes a single deep thrust and then springs back off the female. During the next 6-7 minutes the male and female orchestrate seven to nine such intromissions; then, instead of springing away, the male raises the front half of his body up for a second or two while he ejaculates, then falls backward off the female.
FIGURE 8.17 Copulation in Rats (After S. A. Barnett, 1975. The rat: A study in behavior. University of Chicago Press. Chicago, IL.)
copulation Also called coitus. The transfer of sperm from a male to a female. intromission Insertion of the penis into the vagina during copulation. vagina The opening from the outside of the body to the cervix and uterus in females. ejaculation The forceful expulsion of semen from the penis. semen A mixture of fluid and sperm that is released during ejaculation. refractory phase A period following copulation during which an individual does not recommence copulation. Coolidge effect The propensity of an animal that appears sexually satisfied with a current partner to resume sexual activity when provided with a new partner. sexually receptive Referring to the state in which an individual (in mammals, typically the female) is willing to copulate. estrus The period during which female animals are sexually receptive. postcopulatory behavior The final stage in mating behavior. Species-specific postcopulatory behaviors include rolling (in the cat) and grooming (in the rat). gamete A sex cell (sperm or ovum) that contains only unpaired chromosomes and therefore has only half of the usual number of chromosomes. sperm The gamete produced by males for the fertilization of eggs (ova). ovum An egg, the female gamete. zygote The fertilized egg. ovulation The production and release of an egg (ovum). lordosis A female receptive posture in four-legged animals in which the hindquarters are raised and the tail is turned to one side, facilitating intromission by the male. The raised rump and de ected tail of the female (the lordosis posture) make intromission possible in rats.
264CHAPTER8 activational effect A temporary change in behavior resulting from the availability of a hormone to an adult animal.
After copulation, the male and female each groom their own genitalia, and the male pays little attention to the female for the next 5 minutes or so, until, often in response to the female's proceptive behaviors, the two engage in another bout of intromissions and ejaculation. The cycle may repeat five or six times in one mating session. Gonadal steroids activate sexual behavior Hormones play an important role in rat mating behaviors. Testosterone drives the male's interest in copulation: if he is castrated, he will stop ejaculating within a few weeks and will eventually stop mounting receptive females. Although testosterone disappears from the bloodstream within a few hours after castration, the hormone's effects on the nervous system take days or weeks to wane. Treating a castrated male with testosterone eventually restores mating behavior; if testosterone treatment is stopped, the mating behavior fades away again. This is an example of a hormone exerting an activational effect: the hormone transiently promotes certain behaviors. In normal development, the rise of androgen secretion at puberty activates masculine behavior in males. In female rats, estrogens secreted at the beginning of the ovulatory cycle facilitate proceptive behavior, and the subsequent production of progesterone increases proceptive behavior and activates receptivity (FIGURE 8.18). An adult female whose ovaries have been removed will show neither proceptive nor receptive behaviors. However, 2 days of estrogen treatment followed by a single injection of progesterone will, about 6 hours later, make the female rat proceptive and receptive for a few hours. Only the correct combination of estrogens and progesterone will fully activate copulatory behaviors in female rats. Because steroids activate sexual behavior, you might wonder if individual differences in hormone levels account for differences in mating vigor, the subject of Researchers at Work, next. Next we'll discuss how steroid hormones affect the brain to activate mating behavior.
1 Changes in hormone levels indicate when the female rat will display lordosis.
2 Behavioral receptivity, or estrus, occurs after the animal has been exposed rst to estrogens and then to progesterone.
FIGURE 8.18 The Ovulatory Cycle of Rats
3 In spontaneous ovulators, the cycle of hormone secretion repeats unless eggs are fertilized. In that case, embryos secrete hormones to interrupt the cycle, maintaining pregnancy.
RESEARCHERS AT WORK Individual differences in mating behavior Although individual male rats and guinea pigs differ considerably in how eagerly they will mate, blood levels of testosterone clearly are not responsible for these differences. For one thing, animals displaying different levels of sexual vigor do not show reliable differences in blood levels of testosterone. Furthermore, when these males are castrated and subsequently all treated with exactly the same dose of testosterone, their precastration differences in sexual activity persist (FIGURE 8.19).
FIGURE 8.19 Androgens Permit Male Copulatory Behavior (After J. A. Grunt & W. C. Young, 1953. J. Comp. Physiol. Psychol. 46: 138.)
Hypothesis Individual differences in the vigor with which male guinea pigs mate are caused by differences in testosterone secretion.
Test Classify individual males by mating vigor, then castrate and provide them all with the same dose of testosterone.
Result A few weeks after castration, all males stopped mating. But when provided the same dose of testosterone, males returned to their previous levels of mating vigor. Giving a higher dose of testosterone did not eliminate these differences.
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 Time (weeks) Conclusion Although androgens--especially testosterone--are important for activating normal male sexual function, individual differences in sexual activity are not determined by differences in androgen levels. Furthermore, it turns out that a very small amount of testosterone--one-tenth the amount normally produced by the animals--is enough to fully maintain the mating behavior of male rats (Damassa et al., 1977). Thus, since all male rats make more testosterone than is required to maintain their copulatory behavior, some other factor, which we can call drive, must differ across individual males. 1. What are the stages of reproductive behavior? 2. Describe a typical mating session of laboratory rats. 3. Describe the activational effects of gonadal steroids on mating behaviors in male and female rodents. 4. How do we know whether differences in testosterone secretion are responsible for individual differences in male mating vigor?
266CHAPTER8 ventromedial hypothalamus (VMH) A hypothalamic region involved in sexual behaviors, eating, and aggression. periaqueductal gray A midbrain region involved in pain perception. medial preoptic area (mPOA) A region of the anterior hypothalamus implicated in the control of many behaviors, including sexual behavior, gonadotropin secretion, and thermoregulation. vomeronasal organ (VNO) A collection of specialized receptor cells, near to but separate from the olfactory epithelium, that detects pheromones and sends electrical signals to the accessory olfactory bulb in the brain. medial amygdala A portion of the amygdala that receives olfactory and pheromonal information.
Estrogen and progesterone act on a lordosis circuit that spans from brain to muscle Although most of what we know about the neural circuitry of sexual behavior comes from studies of rats, steroid receptors are found in the same specific brain regions across a wide variety of vertebrate species. Steroid-sensitive regions include the cortex, brainstem nuclei, medial amygdala, hypothalamus, and many others. We'll see that the hypothalamus plays a particularly important role in regulating copulatory behavior. Scientists exploited the steroid sensitivity of the rat lordosis response to map the neural circuitry that controls this behavior (Pfaff et al., 2018). Using steroid autoradiography (see Box 8.1), investigators identified hypothalamic nuclei containing many estrogen- and progesterone-sensitive neurons. In particular, the ventromedial hypothalamus (VMH) is crucial for lordosis, because lesions there abolish the response. Furthermore, tiny quantities of estradiol implanted directly into the brain can induce receptivity in females, but only when the hormone is placed in the VMH (Sakuma, 2015). One action of estrogen treatment is to cause dendrites of VMH neurons to grow and become more complex (Ferri et al., 2014). Another important action of estrogens is to stimulate the production of progesterone receptors so that the animal will become more responsive to that hormone. Progesterone receptors in turn help mediate the lordosis reflex (Mani et al., 2000). The VMH sends axons to the periaqueductal gray region of the midbrain, where again, lesions greatly diminish lordosis. The intact periaqueductal gray neurons project to other brain regions and the spinal cord. In the spinal cord the sensory information provided by the mounting male will evoke the motor response of lordosis when the female's estrogen and progesterone levels are right. Thus, the role of the VMH is to monitor steroid hormone concentrations and, at the right time in the ovulatory cycle, enable a neural circuit that allows a lordosis response to a mounting male. FIGURE 8.20B schematically represents this neural pathway and its steroid-responsive components. Androgens act on a neural system for male reproductive behavior As with the lordosis circuit, mapping the sites of steroid action provided important clues about the neural circuitry controlling male copulatory behavior (FIGURE 8.20A). The hypothalamic medial preoptic area (mPOA) is chock-full of steroid-sensitive neurons, and lesions of the mPOA abolish male copulatory behavior in a wide variety of vertebrate species (Balthazart and Ball, 2007). Note that lesions of the mPOA do not interfere with males' motivation for females; males will still press a bar to gain access to a receptive female, but they seem unable to commence mounting. Furthermore, mating can be reinstated in castrated males by small implants of testosterone in the mPOA, but not in other brain regions. Thus, the mPOA seems to provide "higher-order" control of male copulatory behaviors. The mPOA coordinates copulatory behavior by sending axons to the ventral midbrain (which innervates several brain regions to coordinate mounting behaviors) and, via a multisynaptic pathway, to the spinal cord (Hamson and Watson, 2004), which mediates various genital reflexes, such as ejaculation. Brainstem projections of serotonergic fibers to the spinal cord normally hold the penile erection reflex in check (Hull et al., 2004). Antidepressant drugs that boost serotonergic activity in the brain--for example, selective serotonin reuptake inhibitors like Prozac (see Chapter 12)--can produce side effects that include difficulty achieving erection, ejaculation, and/or orgasm, probably by enhancing serotonergic inhibition of the spinal cord. (If you're wondering, the drug sildenafil, better known as Viagra, acts directly on tissue in the penis, not in the spinal cord or brain, to promote erection [Mitidieri et al., 2020].)
Androgens and other steroid hormones act on these two sites.
Pheromones from receptive females are detected by the vomeronasal organ.
Androgens act on spinal neurons to augment re exes.
Estrogens induce production of progesterone receptors to respond to that hormone.
Estrogens affect neurons at these two sites.
We can also learn about male copulatory mechanisms by tracing a sensory system that boosts male arousal in rodents: the vomeronasal system. The vomeronasal organ, or VNO (see Chapter 9), consists of specialized receptor cells near to, but separate from, the olfactory epithelium. These sensory cells detect chemicals called pheromones (see Figure 8.3C and Chapter 6) that are released by other individuals. For example, receptive female rats release pheromones that male rats find arousing, as evidenced by penile erections. (You can learn more about the role of pheromones in reproductive Watson/Breedlove TbheehMaviniodr'sinMaAchSinTeEP FURTHER 8.5, on the website.) FounVdaotmionesroofnBarasinalanredcBeephatvoirorn4eeurons send their axons to the brain's accessory olfactory bulb. The accessory olfactory bulb in turn projects to the medial amygdala, which MM4e_08.20 06/17/20 in rats depends on adult circulating levels of sex steroids to maintain a masculine form and function (Cooke et al., 2003). Lesions here will abolish the penile erections
FIGURE 8.20 Neural Circuits for Reproduction in Rodents (After D. W. Pfaff, 1980. Estrogens and brain function: Neural analysis of a hormonecontrolled mammalian reproductive behavior. Springer-Verlag. New York, NY.)
FIGURE 8.21 Maternal Behavior in Rats Rat dams clean their pups...
...crouch over them to allow them to nurse... ...and will retrieve them if they stray from the nest. maternal behavior Behavior of adult females that has the goal of enhancing the well-being of their own offspring, often at some cost to the parents. parabiotic Referring to a surgical preparation that joins two animals to share a single blood supply.
that normally occur around receptive females (Dominguez et al., 2001). The medial amygdala, in turn, sends axons to the mPOA. So the mPOA appears to integrate hormonal and sensory information, such as pheromones, and to coordinate the motor patterns of copulation. We will see later that testosterone activates sexual arousal in humans too. Maternal behaviors are governed by several sex-related hormones In many vertebrate species, copulation is not enough to ensure reproduction. Many young vertebrates, and all newborn mammals, need parental attention to survive. Earlier we discussed the milk letdown reflex, when the infant's suckling on the nipple triggers the secretion of oxytocin to promote the release of milk (see Figure 8.9). In rats, the pregnant female prepares for her pups by licking all of her nipples. Doing so probably helps clean the nipples before the pups arrive, but it also makes them more sensitive to touch. This self-grooming actually expands the amount of sensory cortex that responds to skin surrounding the nipples (Xerri et al., 1994), setting the stage for the letdown reflex. This is a wonderful example of an animal's behavior altering its own brain and therefore changing its future behavior. Rat mothers (called dams) show easily measured maternal behaviors: nest building, crouching over pups, cleaning pups, retrieving pups, and nursing (FIGURE 8.21). Neither virgin female rats nor male rats normally show these behaviors toward rat pups. In fact, a virgin female finds the smell of newborn pups aversive. Information about the odor from pups projects via the olfactory bulb to the medial amygdala and on to the VMH. Lesions anywhere along that path will cause a virgin rat to show maternal behavior right away (Holschbach et al., 2018) because she no longer detects the smell. However, if a virgin female is exposed to newborn pups a few hours a day for several days in a row, she (or almost any adult rat--male or female) will start building a nest, crouching over pups, and retrieving them. As the rat gradually habituates to the smell of the pups, it starts taking care of them. But the rat dam that gives birth to her first litter will instantly show these behaviors. It turns out that the rather complicated pattern of hormones during pregnancy shapes her brain to display maternal behaviors before she is exposed to the pups. The effect of pregnancy hormones on a rat's maternal behaviors was demonstrated by a parabiotic preparation in which two female rats were surgically joined, sharing a single blood supply, such that each was exposed to any hormones secreted by the other (FIGURE 8.22). When two female rats are connected in this way, if
A pregnant rat dam will instantly show maternal behavior when her pups arrive.
These animals are connected parabiotically, sharing all hormones in circulation.
A virgin female, which would normally avoid pups, will show maternal behavior if she has been exposed to the hormones circulating in a pregnant female.
FIGURE 8.22 Parabiotic Exchange Facilitates Maternal Behavior (After J. Terkel and J. S. Rosenblatt, 1972. J. Comp. Physiol. Psychol. 80: 365.)
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e
one is pregnant, then at the end of her pregnancy the other female, that was never pregnant but was exposed to the pregnant rat's hormones, will also immediately show maternal behavior (Bridges, 2015). Which hormone is responsible for promoting maternal behavior? No single hormone alone can do it; the combination of several hormones, including estrogens, progesterone, oxytocin, and prolactin, is required. There is a growing realization that parenting behaviors shape the brains of male and female rodents (Kinsley and Lambert, 2006; Franssen et al., 2011). There is ample evidence that the hormones of pregnancy also prepare human mothers to nurture their newborns (Fleming et al., 2002). Compared with other women, mothers who have recently given birth are better at distinguishing odors from different newborns, and they can even recognize odors from their own newborn. This increased ability to discriminate odors correlates with hormone levels after delivery (Almanza-Sepulveda et al., 2020). Pregnancy may also have long-lasting effects on brain structure and cognitive processing in women (Henry and Sherwin, 2012; Hoekzema et al., 2017). The hallmark of human sexual behavior is diversity How much of what we've described so far about sexual behavior in animals is relevant to human sexuality? Until the 1940s, when biology professor Alfred Kinsey began to ask friends and colleagues about their sexual histories, there was virtually no scientific study of human sexual behavior. Kinsey constructed a standardized set of questions and procedures to get information. Eventually, he and his collaborators published extensive surveys, based on tens of thousands of respondents, on the sexual behavior of American males (Kinsey et al., 1948) and females (Kinsey et al., 1953). Controversial in their time, these surveys indicated that nearly all men masturbated, that college-educated people were more likely to engage in oral sex than were non-college-educated people, that many people had at one time or another engaged in homosexual behaviors, and that a stable proportion of the population preferred samesex partners. Another way to investigate human sexual behavior is to make behavioral and physiological observations of people engaged in sexual intercourse or masturbation, but the squeamishness of the general public impeded such research for many years. Finally, after Kinsey's surveys were published, physician William Masters and psychologist Virginia Johnson began a large, famous project of this kind (Masters et al., 1994), documenting the impressively diverse sexuality of humans. Among most mammalian species, including most nonhuman primates, the male mounts the female from the rear; but among humans, face-to-face postures are most common. A great variety of coital positions have been described, and many couples vary their positions from session to session or even within a session. It is this variety in reproductive behaviors, rather than differences in reproductive anatomy, that distinguishes human sexuality from that of most other species. Unlike other animals, humans can report their subjective reactions to sexual behavior--specifically orgasm, the brief, extremely pleasurable sensations experienced by most men during ejaculation and by most women during copulation. In the original conceptual model of human sexuality, Masters and Johnson summarized the typical response patterns of both men and women as consisting of four phases: increasing excitement, plateau, orgasm, and resolution. During the excitement phase, the phallus--the penis in men, the clitoris in women--becomes engorged with blood, making it erect. In women, parasympathetic activity during the excitement phase causes changes in vaginal blood vessels, producing lubricating fluids that facilitate intromission. Stimulation of the penis, clitoris, and vagina during rhythmic thrusting accompanying intromission may lead to orgasm. In both men and women, orgasm is accompanied by waves of contractions
orgasm The climax of sexual behavior, marked by extremely pleasurable sensations. phallus The clitoris or penis. penis The male phallus. clitoris The female phallus. Masters of Sex Virginia E. Johnson and William H. Masters.
These diagrams are schematic and do not represent a particular physiological measure, although heart rate varies in roughly this manner. (A) Male Orgasm Plateau
The typical male pattern includes an absolute refractory phase after orgasm. Orgasm
These three patterns (A, B, C) are often observed in women, and they vary considerably from one individual to another.
Refractory phase Time FIGURE 8.23 Human Sexual Response Cycles (After W. H. Masters and V. E. Johnson, 1966. Human sexual response. Little, Brown. Boston, MA.) Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_08.23 08/21/20
of genital muscles (mediating ejaculation in men and contractions of the uterus and vaginal opening in women) (FIGURE 8.23A). In spite of some basic similarities, the sexual responses of men and women differ in important ways. For one thing, women show a much greater variety of commonly observed copulatory sequences. Whereas men have only one basic pattern, captured by the linear model of Masters and Johnson (see Figure 8.23A), women have at least three typical patterns (FIGURE 8.23B). Another important aspect of human sexuality is that most men, but not most women, have an absolute refractory phase following orgasm (also illustrated in Figure 8.23A). That is, most men cannot achieve full erection and another orgasm until some time has elapsed--the length of time varying from minutes to hours, depending on individual differences and other factors. Many women, on the other hand, can have multiple orgasms in rapid succession. Functional imaging of the brains of men and women during sexual activity suggests that, although the brain circuitry associated with orgasm itself is quite similar between the sexes, substantially different networks are active in men's and women's brains during sexual activity prior to orgasm (Georgiadis et al., 2009). Taking a broader perspective on sexuality reveals additional distinctions between men and women (Peplau, 2003). Basic sex drive seems to be greater in men, reflected in more frequent masturbation, sexual fantasies, and pursuit of sexual contacts. Emotional components and cognitive factors play a stronger role in women's sex lives than in men's. While Masters and Johnson simply adapted the linear model of male sexuality to women, the more modern perspective views women's sexuality as a cycle, governed in large measure by emotional factors (Basson, 2001, 2008). According to this model, emotional intimacy and desire (more than physiological arousal) are crucial in the initiation of sexual responses, and following a sexual encounter, a combination of both emotional and physical satisfaction affects the likelihood of subsequent sexual activity. Although male and female sexuality may bear the imprint of our evolutionary history, on an individual basis it is also shaped by sociocultural pressures and experience. Sexual therapy, for example, usually consists of helping the person to relax, to recognize the sensations associated with coitus, and to learn the behaviors that produce the desired effects in both partners. Masturbation during adolescence, rather than being harmful as suggested in previous times, may help avoid sexual problems in adulthood. As with other behaviors, practice, practice, practice helps. Of course, it is also important to one's health to take precautions (such as using condoms) to avoid contracting sexually transmitted infections.
Hormones play only a permissive role in human sexual behavior We have already seen that a little bit of testosterone must be in circulation to activate male-typical mating behavior in rodents. The same relation seems to hold for human males. For example, boys who fail to produce testosterone at puberty show little interest in dating unless they receive androgen treatments. These males, as well as men who have lost their testes as a result of cancer or accident, made it possible to conduct experiments showing that testosterone indeed stimulates sexual interest and activity in men, as well as a sense of heightened energy. Recall that, in rodents, additional testosterone has no effect on the vigor of mating. Consequently, there is no correlation between the amount of androgens produced by an individual male and his tendency to copulate. In humans, too, just a little testosterone is sufficient to restore behavior fully, and there is no correlation between circulating androgen levels and sexual activity among men who have at least some androgen. Some women experience sexual dysfunction after menopause, reporting decreased sexual desire and difficulty achieving comfortable coitus. There are many possible reasons for such a change, including several hormonal changes. Providing postmenopausal women with low doses of both estrogens and androgens can have beneficial effects on the genital experience of sex and also on women's sexual interest (Sherwin, 2002; Basson, 2008). Now that we've discussed some of the unique aspects of male and female sexuality, let's look at some of the developmental processes that cause the growing individual to take on male-typical or female-typical forms and functions in the first place. 1. What brain regions appear to be involved in male and female sexual behaviors? 2. Compare and contrast the maternal behavior of a female rat that has just been pregnant with that of a naive female. What factor is responsible for the differences? 3. Compare and contrast the patterns of sexual arousal in men and women. 4. What are the effects of gonadal steroids on human sexual behavior? 8.3Genetic and Hormonal Mechanisms Guide the Development of Masculine and Feminine Structures
Hormones and Sex 271 Testosterone Patches These patches can revive libido in men who have lost their testes through accident or disease.
Now we take up the question of how developing females and males come to differ. Reading this final section of the chapter should allow you to: 8.3.1 Describe the chain of molecular and hormonal events that sculpt the mammalian fetus into a male or female form. 8.3.2 Identify several differences of sexual development that affect that process. 8.3.3 Explain the organizational hypothesis of how sex differences in animal behavior arise. 8.3.4 Describe the role of hormones in the development of two prominent sexual dimorphisms in neuronal structure. 8.3.5 Critically discuss the extent to which prenatal hormones influence sex differences in human behavior, including sexual orientation. A persistent bias in biomedical science has resulted in males being studied exclusively in most cases, on the assumption that female ovulatory cycles would introduce more variability and that whatever was found in males would hold true for both sexes.
Mammalian Sex Chromosomes The Y chromosome (left) is much shorter than the X (right) because it carries far fewer genes. But one of those genes, SRY, is critical for masculine development. sexual differentiation The process by which individuals develop either male-like or female-like bodies and behavior. indifferent gonads The undifferentiated gonads of the early mammalian fetus, which will eventually develop into either testes or ovaries. SRY gene A gene on the Y chromosome that directs the developing gonads to become testes. The name SRY stands for sex-determining region on the Y chromosome. genital tubercle In the early fetus, a "bump" between the legs that can develop into either a clitoris or a penis. wolffian duct A duct system in the embryo that will develop into male reproductive structures (epididymis, vas deferens, and seminal vesicle) if androgens are present. müllerian duct A duct system in the embryo that will develop into female reproductive structures (oviducts, uterus, and upper vagina) in the absence of AMH. anti-müllerian hormone (AMH) A peptide hormone secreted by the fetal testes that inhibits müllerian duct development. dihydrotestosterone (DHT) The 5-alpha-reduced metabolite of testosterone. DHT is a potent androgen that is principally responsible for the masculinization of the external genitalia in mammals.
However, analysis of the animal literature revealed that in fact there is more variability in males than females (Prendergast et al., 2014), and many biomedical "facts" established in men do not hold for women (Cahill, 2014). For example, heart attacks in women tend to produce symptoms that are very different from those symptoms, derived from observations of men, that were the only ones publicized until recent years. The fatality rate of COVID-19 infections is higher in men than in women. In the USA, the National Institutes of Health (NIH) require grant applicants to either include both sexes or provide a sound rationale for excluding one sex (Sandberg et al., 2015). Sex chromosomes direct sexual differentiation of the gonads Sexual differentiation is the process by which individuals develop either male or female bodies and behaviors. In mammals, this process begins before birth and continues into adulthood. In mammals, every egg carries an X chromosome from the mother; fusion with an X- or Y-bearing sperm is the key event in establishing the course of subsequent sexual differentiation of the body. With rare exceptions, mammals that receive an X chromosome from the father will become females with an XX sex chromosome complement; those that receive the father's Y chromosome will become XY males. The first major effect of sex chromosomes is on the gonads. Very early in development, each individual has a pair of indifferent gonads, glands that vaguely resemble both testes and ovaries. During the first month of gestation in humans, differential genetic instructions determine whether the indifferent gonads begin changing into ovaries or testes. In mammals, the Y chromosome contains the SRY gene (for sex-determining region on the Y chromosome), which is responsible for the development of testes. If an individual has a Y chromosome, the cells of the indifferent gonad begin making the Sry protein, inducing the organ to develop into a testis. In XX individuals (or XY individuals with a dysfunctional SRY gene), no Sry protein is produced, and the indifferent gonad becomes an ovary. This early event of forming either testes or ovaries has a domino effect, setting off a chain of actions that usually results in either a male or a female. Gonadal hormones direct sexual differentiation of the body For all mammals, including humans, the gonads secrete hormones to direct sexual differentiation of the body. Fetal ovaries produce very little hormone, but fetal testes produce several hormones. If other embryonic cells are exposed to the testicular hormones, they begin developing masculine characters; if the cells are not exposed to testicular hormones, they develop feminine characters. We can chart masculine or feminine development by examining the structures that connect the gonads to the outside of the body: these are quite different in adult males and females, but at the embryonic stage all individuals have the precursor tissues of both systems. The early fetus has a genital tubercle (a "bump" between the legs) that can form either a clitoris or a penis, as well as two sets of ducts that connect the tubercle to the indifferent gonads: the wolffian ducts and the müllerian ducts (FIGURE 8.24A). In females, the müllerian ducts develop into the oviducts (or fallopian tubes), uterus, and inner vagina (FIGURES 8.24B and C right), and only a remnant of the wolffian ducts remains. In males, hormones secreted by the testes orchestrate the converse outcome: each wolffian duct develops into an epididymis, vas deferens, and seminal vesicle (see Figure 8.24B and C left), while the müllerian ducts shrink to mere remnants. The system is masculinized by two testicular secretions: testosterone, which promotes development of the wolffian system; and anti-müllerian hormone (AMH), which causes regression of the müllerian system. In the absence of testosterone and AMH, the genital tract develops in a feminine pattern, in which the wolffian ducts regress and the müllerian ducts develop into components of the female internal reproductive tract. Testosterone masculinizes other structures too, acting on exterior tissues to form a scrotum and penis. These effects are aided by the local conversion of testosterone into a more potent androgen, dihydrotestosterone (DHT), promoted by an enzyme
(A) 6 weeks of gestation (undifferentiated fetus) Indifferent gonad Wolf an duct Müllerian duct Kidney Urogenital sinus Genital tubercle Genital fold
(B) 8 weeks of gestation Male Testis Vas deferens Bladder Glans penis
(C) 15 weeks of gestation Male Epididymis Seminal vesicle Prostate Penis Scrotal swelling
Clitoris Labia minora Labia majora Vagina
Ovary Oviduct Uterus Bladder Glans clitoris
FIGURE 8.24 Sexual Differentiation in Humans
that is found in the genital skin, 5-alpha-reductase. We'll see later that without the local production of DHT, testosterone alone is able to masculinize the genitalia only partially. If androgens are absent altogether, the genital tissues grow into the female labia and clitoris. Changes in sexual differentiation processes result in predictable changes in development Some people have only one sex chromosome: a single X (embryos containing only a single Y chromosome do not survive). This genetic makeup results in Turner's syndrome, in which an apparent female has underdeveloped but recognizable ovaries, as you might expect because no SRY gene is available. In general, unless the indifWfeatrseonnt/Bgroenedaldovbeecomes a testis and begins secreting hormones, mammalian fetuses TdheevMeilnodp'saMsafcehmineales in most respects. So the sex chromosomes determine the sex of Foundations of Brain and Behavior 4e the gonad, and gonadal hormones then drive sexual differentiation of the rest of the MbMod4ey_(0F8.I2G4UR06E/187./2250). Congenital adrenal hyperplasia (CAH) causes developing girls to be exposed to excess androgens before birth. In CAH, the adrenal glands produce considerable amounts of androgens, somewhere between those of normal females and males, so the newborn often has an intersex appearance: a phallus that is intermediate in size between a normal clitoris and a normal penis, and skin folds that resemble both labia
5-alpha-reductase An enzyme that converts testosterone into dihydrotestosterone (DHT). Turner's syndrome A condition, seen in individuals carrying a single X chromosome but no other sex chromosome, in which an apparent female has underdeveloped but recognizable ovaries. congenital adrenal hyperplasia (CAH) Any of several genetic mutations that can cause a female fetus to be exposed to adrenal androgens, resulting in partial masculinization at birth. intersex Referring to an individual with atypical genital development and sexual differentiation, whose genitalia are generally intermediate in form between typical male and typical female genitalia.
1 The presence of a Y chromosome will direct indifferent gonads to develop as testes. 2 Without a Y chromosome, the indifferent gonads develop as ovaries.
FIGURE 8.25 The Sequence of Sexual Differentiation
androgen insensitivity syndrome (AIS) A syndrome caused by an androgen receptor gene mutation that renders tissues insensitive to androgenic hormones like testosterone. Affected XY individuals are phenotypic females, but they have internal testes and regressed Watson/Breedlove internal genital structures. The Mind's Machine Foundations of Brain and Behavior 4e MM4e_08.25 06/16/20
Hormones Testosterone ? No testosterone ?
3 Hormones from the fetal testes masculinize the body... 4 ...and the brain (at least in nonhuman mammals).
5 The fetal ovaries do not secrete androgens, so the body develops in a feminine fashion...
and scrotum (FIGURE 8.26). Such babies are usually recognizable at birth because, even in severe cases in which penis and scrotum appear well formed, no testes are present inside the "scrotum"; instead, these individuals have normal abdominal ovaries. Once born, children with CAH are given medicine to prevent further androgen production. There is controversy, however, over whether the best course of action for the parents of girls with CAH is to opt for immediate surgical modification of the genitalia or to wait until adulthood, when the CAH-affected individuals can decide for themselves whether to have surgery that is purely cosmetic (Hughes et al., 2006; Human Rights Watch, 2017). In spotted hyenas, females are always exposed to prenatal androgens, resulting in highly masculinized genitalia. You can read about these fascinating animals in A STEP FURTHER 8.6, on the website. Reduced androgen signaling can block masculinization of the body The importance of androgens for masculine sexual differentiation is illustrated by the condition known as androgen insensitivity syndrome (AIS). AIS results when an XY zygote inherits a dysfunctional gene for the androgen receptor, so the embryo's tissues cannot respond to androgenic hormones like testosterone. The gonads of people with AIS develop as normal testes (as directed by Sry), and the testes produce AMH (which inhibits müllerian duct structures) and plenty of testosterone. However, in the absence of working androgen receptors, the wolffian ducts fail to develop and the external genital tissue forms labia and a clitoris. At puberty, women
FIGURE 8.26 An Intersex Phenotype Watson/Breedlove
The partially masculinized genitalia of this woman with CAH are the result of excessive androgen production by her adrenal glands before birth.
Hormones and Sex 275 FIGURE 8.27 Women with AIS
Courtesy of Kimberly Saviano/AISSG-USA. CC BY 3.0
with AIS develop breasts but fail to start menstruating, because neither ovaries nor uterus are present. Women with AIS are infertile, but otherwise they look like other women (FIGURE 8.27) and behave like other women. Babies are occasionally born with a rare genetic mutation that disables 5-alphareductase, the enzyme that converts testosterone to DHT. An XY individual with this condition will develop testes and normal male internal reproductive structures (because testosterone and AMH function normally), but the external genitalia will fail to masculinize fully. The reason for this failure is that the genital epithelium, which normally possesses 5-alpha-reductase, is unable to amplify the androgenic signal by converting testosterone to the more active DHT. Consequently, the phallus is only slightly masculinized and resembles a large clitoris, and the genital folds resemble labia, although they contain the testes. Usually there is no vaginal opening (FIGURE 8.28).
In the Dominican Republic, some individuals, called guevedoces, are born with ambiguous genitalia and are raised as girls.
At puberty, however, the phallus grows into a recognizable penis, and the individuals begin acting like young men.
FIGURE 8.28 Guevedoces
276CHAPTER8 guevedoces Literally "eggs at 12" (in Spanish). A nickname for individuals who are raised as girls but at puberty change appearance and begin behaving as boys.
A particular village in the Dominican Republic is home to several families that carry the mutation causing 5-alpha-reductase deficiency. Children born with this appearance seem to be regarded as girls in the way they are dressed and raised (Imperato-McGinley, 2002). At puberty, however, the testes increase androgen production, and the external genitalia become more fully masculinized. The phallus grows into a small but recognizable penis; the body develops narrow hips and a muscular build, without breasts; and the individuals begin acting like young men. The villagers have nicknamed such individuals guevedoces, meaning "eggs (testes) at 12 (years)." These men never develop beards, but they usually have girlfriends, indicating that they are sexually interested in women. We will discuss the sexual behavior of guevedoces, as well as women with CAH or AIS, later.
SIGNS & SYMPTOMS Defining an Athlete's Sex Raised as a girl, Olympic runner Mokgadi Caster Semenya naturally enough considers herself a woman. But after the South African athlete blew away the competition in a women's 800-meter race, rumors began circulating that she might have an intersex condition like AIS or CAH, giving her an unfair advantage. Olympic officials investigated and cleared her to compete, enabling Caster to win gold medals in 2012 and 2016. For the sake of her privacy, details about Caster's examination were never released, but she apparently has higher levels of circulating androgen than most women (Padawer, 2016), so the question of whether Caster and other women with "hyperandrogenism" should be allowed to compete as women continues. The International Association of Athletics Federations ruled that Caster and other women with "hyperandrogenism" (Chiu, 2018) should not compete as women in certain events unless they reduce their androgen levels either through surgery (e.g., removing testes in cases of AIS) or through drugs to suppress androgen production. Most efforts to regulate sports events have centered on preventing athletes from taking drugs to enhance their performance ("doping"), but now we are in the strange position of requiring athletes to take drugs, or even to have surgery, as a prerequisite for competition. As others have pointed out, every elite athlete is very unusual in some regard, otherwise they wouldn't be elite athletes. Should men with especially high testosterone be disqualified from competition? Should Michael Phelps be excluded from swim competitions because his arms are so long (Dreger, 2018)? In Caster's case, we can identify a particular factor, testosterone, that might be helping her compete (G. Huang and Basaria, 2018), but the other women runners doubtless have some physiological advantage that contributes to their performance; the difference is we don't happen to know what their physiological advantage is. As we've seen in this chapter, many people are a mixture of masculine and feminine features, so who gets to decide whether a person is a "real" woman or man? Caster made her position clear in an interview: "I just want to be me. I was born this way. I don't want any changes."
Caster Semenya Growing up, the South African athlete considered herself female, but questions were raised about whether she should be allowed to compete among women.
How should we define sex--by genes, gonads, genitals? Most humans are either male or female, and whether we examine their chromosomes, gonads, external genitalia, or internal structures, we see a consistent pattern: each one is either feminine or masculine in character. But as the various syndromes we've been discussing demonstrate, different physical features in a single person can be either
masculine or feminine, so from a scientific perspective, legal efforts to categorize all people as either male or female are doomed. Women with androgen insensitivity have male XY sex chromosomes and internal testes, and like most males they do not have oviducts or a uterus. But they do have a vagina and breasts, and in most respects their behavior is typical of females: they dress like females, they are attracted to and marry males, and perhaps most important, even after they learn the details of their condition, they strongly identify themselves as women (Hines, 2011). They are males in some respects, but females in others. If laws define marriage as only between a man and a woman, whom should these individuals be allowed to marry? How about XY individuals with 5-alpha-reductase deficiency, born and raised as girls--with birth certificates to prove it? Should they be restricted to marrying men, even if, at 12 years of age, they sprout a penis? This recognition that a single individual may be masculine in some regards and feminine in others is especially important as we consider hormonal effects on the brain, next.
organizational effect A permanent alteration of the nervous system, and thus permanent change in behavior, resulting from the action of a steroid hormone on an animal early in its development. sensitive period The period during development in which an organism can be permanently altered by a particular experience or treatment. neonatal Referring to newborns.
1. Describe the process of fetal sexual differentiation in males and females, especially the role of hormones. 2. What might be the advantage of having a single signal, such as androgens, masculinize the entire body? 3. What are some of the syndromes that can affect sexual differentiation, and what do they tell us about the problems of defining a person's gender?
View Animation 8.6: Organizational Effects of Testosterone
Gonadal hormones direct sexual differentiation of behavior and the brain
As scientists began discovering that testicular hormones direct masculine development of the fetal body, behavioral researchers found evidence for a similar influence on the fetal brain. A female guinea pig, like most other rodents, normally displays the lordosis posture in response to male mounting (see Figure 8.16) for only a short period around the time of ovulation, when her fertility is highest. If a male mounts her at other times, she does not show lordosis. Experimenters can induce female rodents to display lordosis by injecting them with ovarian steroids in the sequence they normally follow during ovulation-- giving the animals estrogens for a few days and then progesterone (see Figure 8.17). A few hours after the progesterone injection, the female will display lordosis in response to male mounting.
Phoenix et al. (1959) exposed female guinea pigs to testosterone in utero. As adults, these females did not show lordosis. Even if their ovaries were removed and they were given the steroid regimen that reliably activated lordosis in normal females, these fetally androgenized females did not show lordosis. From these data the researchers inferred that the same testicular steroids that masculinize the genitalia during early development also masculinize the developing brain. In other words, they proposed that the brain was just one more target tissue that is masculinized by androgens acting early in life (see Figure 8.24). This type of lasting change due to steroid exposure is known as an organizational effect. A steroid has an organizational effect only when present during a specific sensitive period, generally in early
development. Unlike the transient nature that characterizes the activational effects of hormones, which we discussed earlier, the organizational effects of hormones tend to be permanent (FIGURES 8.29A-C). The exact boundaries of the sensitive period of development depend on which behavior and which species are being studied. For rats, androgens given during the neonatal period (just after birth) can affect later behavior. Guinea pigs, however, must be exposed to androgens before birth for adult lordosis behavior to be affected. In mammals, puberty can be viewed as a second sensitive period; for example, steroid exposure during puberty causes the addition of new cells (an organizational effect) to sex-related brain regions of rats (Schulz and Sisk, 2016). (Continued )
FIGURE 8.29 Organizational Effects of Testosterone on Rodent Behavior (After C. H. Phoenix et al., 1959. Endocrinology 65: 369.)
Hypothesis Early in life, androgens organize the brain, and therefore adult behavior, in a masculine fashion.
Test Manipulate androgen exposure in genetic male and female rodents early in life, then ask whether hormones in adulthood can elicit male and/or female behaviors.
Conception Birth Sensitive period (B) Untreated female
Tested Tested with with male receptive female
Results · Normally male rodents eagerly mount receptive females but do not show lordosis behavior in response to another male, even when given ovarian steroids. · Conversely, female rodents show little masculine sexual behavior, but they display lordosis when treated with an estrogen and progesterone in adulthood.
(C) Treated female during the sensitive period... again in adulthood.
Castrated (i.e., deprived (D) Castrated male of testosterone) at birth.
· However, female rodents exposed to testosterone early in life show little or no lordosis, even when given steroids that activate that behavior in normal females. When given testosterone, these androgenized females eagerly mount other females. · Conversely, males deprived of androgens early in life are demasculinized as adults, showing little copulatory behavior, and are also feminized, displaying lordosis when given the proper steroids to activate that behavior.
Conclusion When the developing brain is exposed to androgens, the animal's brain is organized in a masculine fashion, so, as an adult, it is more likely to show male-like behaviors, and less likely to show female-like behaviors.
Watson/Breedlove The Mind's Machine Foundations of Brain and Behavior 4e MM4e_08.29 06/17/20
Early testicular secretions result in masculine behavior in adulthood What has come to be called the organizational hypothesis provides a unitary explanation for sexual differentiation: that a single steroid signal (androgen) diffuses through all tissues, masculinizing the body, the brain, and behavior (see Figure 8.24). From this point of view the nervous system is just another type of tissue listening for the androgenic signal that will instruct it to organize itself in a masculine fashion. If the nervous system does not detect androgens, it will organize itself in a mostly feminine fashion. What was demonstrated originally for the lordosis behavior of guinea pigs has been observed in a variety of vertebrate species and for many behaviors. Exposing
female rat pups to testosterone either just before birth or during the first 10 days after birth greatly reduces their lordosis responsiveness as adults. This explains the observation that adult male rats show very little lordosis, even when given estrogens and progesterone. Conversely, male rats that are castrated during the first week of life readily display lordosis responses in adulthood if injected with estrogens and progesterone (FIGURE 8.29D). In rats, many behaviors conform to the organizational hypothesis: animals exposed to androgens early in life behave like males, whereas animals not exposed to androgens early in life behave like females. In most cases, full masculine behavior requires androgens both during development (to organize the nervous system to enable the later behavior) and in adulthood (to activate that behavior). Only animals exposed to androgen both in development and in adulthood show fully masculine behavior. Several regions of the nervous system display prominent sexual dimorphism The fact that male and female rats behave differently means that their brains must be different in some way, and according to the organizational hypothesis this difference results primarily from androgenic masculinization of the developing brain. Scientists soon found many sex differences in the brain, including differences in the number, size, and shape of neurons. Darwin coined a term, sexual dimorphism, to describe the condition in which males and females show pronounced sex differences in structure. In all species studied so far, androgens are responsible for the sexual dimorphism seen in the brain: androgens masculinize the brain region, and the absence of androgens leads to a female-typical brain anatomy. We'll discuss two well-studied models. THE PREOPTIC AREA (POA) OF RATS Roger Gorski examined the POA of the hypothalamus in rats because of the earlier reports that the number of synapses in this region was different in males and females and because lesions of the POA disrupt ovulatory cycles in female rats and, as we mentioned earlier, reduce copulatory behavior in males. Sure enough, he found a nucleus within the POA that has a much larger volume in males than in females (Gorski, 2002). This nucleus, dubbed the sexually dimorphic nucleus of the POA (SDN-POA), is much more evident in male rats than in females (FIGURE 8.30). The SDN-POA conformed beautifully to the organizational hypothesis: males castrated at birth had much smaller SDN-POAs in adulthood, while females androgenized at birth had large, male-like SDN-POAs as adults. Castrating male rats in adulthood, however, did not alter the size of the SDN-POA. Thus, testicular androgens somehow alter the
sexual dimorphism The condition in which males and females of the same species show pronounced sex differences in appearance. sexually dimorphic nucleus of the preoptic area (SDN-POA) A region of the preoptic area that is 5 to 6 times larger in volume in male than in female rats.
The sexually dimorphic nucleus of the preoptic area (SDN-POA) is much larger in male rats than in females.
Corpus callosum Anterior commissure (AC) Third ventricle (V) Hypothalamus Optic chiasm (OC)
FIGURE 8.30 The Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA)
development of the SDN-POA, resulting in a nucleus permanently larger in males than in females (FIGURE 8.31). One quirk of sexual dimorphism in the brains of some lab species, including rodents, is that testosterone reaching the brain is converted into estrogens that act on estrogen receptors, not androgen receptors, to masculinize the SDN-POA and some other brain regions. For example, XY rats that are androgen-insensitive (like the people with AIS discussed earlier) have testes but a feminine exterior. These rats have a masculine SDN-POA because their estrogen receptors are normal. Androgen-insensitive rats also do not display lordosis in response to estrogens and progesterone, because the testosterone that they secreted early in life was converted to an estrogen in the brain and masculinized their behavior. Instead, the androgen-insensitive rats show normal male attraction to receptive females, with whom they may attempt to mate, despite the lack of a penis (Hamson et al., 2009). Estrogenic metabolites of testosterone do not seem to play a role in masculinizing the primate brain (Grumbach
A normal male rat shows a testosterone peak perinatally (just before and around birth)...
A normal female rat lacks both the perinatal and pubertal rises in testosterone levels...
A female injected with testosterone at the time of the male perinatal surge...
Testosterone can permanently enlarge the SDN-POA in rats, but only if it is given during a "sensitive period" early in life. (D) Female
Injections at later times, such as puberty...
...have no effect on the size of a female's SDN-POA.
FIGURE 8.31 Organization of the SDN-POA
and Auchus, 1999), so we won't deal with that mechanism any further, but you can learn more about it in A STEP FURTHER 8.7, on the website. THE SPINAL CORD IN MAMMALS In rats, the bulbocavernosus (BC) muscles that surround the base of the penis are innervated by motor neurons in the spinal nucleus of the bulbocavernosus (SNB). Male rats have about 200 SNB cells, but females have far fewer motor neurons in this region of the spinal cord. On the day before birth, female rats have BC muscles attached to the base of the clitoris that are nearly as large as the BC muscles of males and that are innervated by motor neurons in the SNB region. In the days just before and after birth, however, many SNB cells die, especially in females, and the BC muscles of females die (FIGURE 8.32).
spinal nucleus of the bulbocavernosus (SNB) A group of motor neurons in the spinal cord of rats that innervate muscles controlling the penis.
Spinal cord Motor neuron Neuromuscular junction Bulbocavernosus muscle
1 In both sexes, spinal motor neurons make connections with the bulbocavernosus muscle early in development.
2 In both sexes, the muscle expresses androgen receptors.
3 In males, circulating testosterone binds to the androgen receptors. In females, the receptors remain unoccupied. 4 In males, the activated receptors promote the survival of the muscle and cause it to secrete unknown factors, which are picked up by the motor neurons. In females, the lack of receptor activation causes the muscle to die, and no factors are produced. 5 In males, the factors picked up by the motor neurons promote their survival. In females, the lack of these factors causes the motoneurons to die.
FIGURE 8.32 Sexual Differentiation of the Spinal Nucleus of the Bulbocavernosus (SNB)
Onuf's nucleus The human homolog of the spinal nucleus of the bulbocavernosus (SNB) in rats.
A single injection of androgens delivered to a newborn female rat permanently spares some SNB motor neurons and their muscles. Castration of newborn males, accompanied by prenatal blockade of androgen receptors, causes the BC muscles and SNB motor neurons to die as in females. The system also dies in newborn androgen-insensitive rats, so estrogens seem to be unimportant for masculine development of the SNB. Androgens act on the BC muscles to prevent their demise, and this sparing of the muscles causes the innervating SNB motor neurons to survive (J. A. Morris et al., 2004). Thus the developmental rescue of SNB motor neurons is accomplished indirectly as a consequence of actions on muscle. Adult SNB neurons contain androgen receptors and retain androgen sensitivity throughout life. In adulthood, androgen acts directly on the neurons to cause them to grow (Watson et al., 2001) and to express genes that help new spinal connections to form (Monks and Watson, 2001). In nonrodents, the BC motor neurons are found in a slightly different spinal location and are known as Onuf's nucleus. Surprisingly, most female mammals retain a BC muscle into adulthood; in women, for example, the bulbocavernosus (or constrictor vestibuli) helps constrict the vaginal opening. But, as in rodents, the system is sexually dimorphic. Men have larger BC muscles and more Onuf's motor neurons than do women, probably because of androgen exposure during fetal development (Forger et al., 2018). These systems and several others all demonstrate the power of androgens to affect the gender of the brain. By controlling the amount and timing of testosterone exposure, researchers can make the various brain structures as masculine or feminine as they like. However, despite the crucial role of androgens in masculinizing sexually dimorphic nuclei in the nervous system, there's evidence that experience affects them too. Social influences also affect sexual differentiation of the nervous system Environmental factors of many sorts, including social experience, can modulate the masculinization produced by steroids. The development of the SNB offers a classic example. Celia Moore et al. (1992) noticed that rat dams spend more time licking the anogenital regions of male pups than of females. If the dam is anosmic (unable to smell), she licks all the pups less and does not distinguish between males and females. Males raised by anosmic mothers thus receive less anogenital licking, and remarkably, fewer of their SNB cells survive the period around birth. The dam's stimulation of a male's anogenital region helps to masculinize his spinal cord. On the one hand, this masculinization is still an effect of androgens, because the dam identifies male pups by detecting androgen metabolites in their urine. On the other hand, this effect is clearly the result of a social influence: the dam treats a pup differently because he's a male, and this differential treatment masculinizes his developing nervous system. Perhaps this example illustrates the futility of trying to distinguish "biological" from "social" influences. Attention from the dam has a different organizing effect on female rat pups. In adulthood, females that were licked frequently as pups show enhanced estrogen and oxytocin sensitivity in brain regions associated with maternal behavior, and they tend to be attentive mothers themselves. Females that were licked less as pups are less attentive mothers later (Champagne et al., 2001). What about humans? (No, no, not the licking part--the social influence part.) Humans are at least as sensitive to social influences as rats are. In every culture, most people treat boys and girls differently, even when they are infants. Such differential treatment undoubtedly has some effect on the developing human brain and contributes to later sex differences in behavior. Of course, this is a social influence, but testosterone instigated the influence when it induced the formation of a penis. If prenatal androgens have even a very subtle effect on the fetal brain, then adults interacting with a baby might detect such differences and treat the baby differently. Thus, originally subtle sex differences might be magnified by social experience,
especially early in life. Such interactions of steroidal and social influences are probably the norm in the sexual differentiation of human behavior. So does fetal testosterone play a role in masculinizing human behavior? Let's examine that question by zeroing in on human sexual orientation, the final topic of this chapter. 1. How does exposure to androgens early in life masculinize the brain and spinal cord in rats? 2. Why is it difficult to distinguish between social and biological influences on sexual differentiation? Do fetal hormones masculinize human behaviors in adulthood? As with rats and other animals, the fact that men and women behave differently implies that something about them, probably something about their brains, must also be different. Indeed, many parts of the brain are different between men and women (FIGURE 8.33). But are these sexual dimorphisms in the human brain caused by prenatal exposure to hormones, as in other animals, or by social influences? In other words, does prenatal exposure to steroids affect the adult behavior of humans? This is a tricky problem because although prenatal androgens may act on the human brain, they certainly act on the rest of the body too. For example, recall that people with androgen insensitivity syndrome (AIS) are usually raised as girls because their XY genotype is not discovered until puberty. We said earlier that women with androgen insensitivity tend to be very feminine, including being sexually attracted to men, and they often seek a family through adoption. Are they feminine because they received the social tutoring to be females, or because their brains, without androgen receptors, could not respond to testosterone? Their behavior is consistent with either hypothesis. Females with congenital adrenal hyperplasia (CAH), who are exposed to androgens before birth, are much more likely to be described by their parents (and themselves) as tomboys than are other girls, and they exhibit enhanced spatial abilities on cognitive tests that usually favor males (Berenbaum, 2001). In adulthood, most women
Courtesy of Jill Goldstein, based on data from Goldstein et al., 2001. Cereb. Cortex 11: 490
This composite image is based on data obtained from MRI scans of numerous male and female volunteers. Overall, sex differences tend to be evident in regions that are known to possess receptors for sex steroids.
Structures that are larger in the healthy female brain, relative to cerebrum size Structures that are larger in the healthy male brain, relative to cerebrum size
FIGURE 8.33 Sexual Dimorphism in the Human Brain
284CHAPTER8 Training Girls to Be Verbal Adults tend to spend more time talking to a baby if they believe the baby is a girl (whether it actually is a girl or not) (Seavey et al., 1975).
with CAH describe themselves as heterosexual, but they are more likely than other women to report being lesbians. Interestingly, as females with CAH grow older, the proportion who report being lesbians increases (Meyer-Bahlburg, 2011), suggesting that they start off trying to follow the socially approved role of heterosexual female but then become more comfortable with a gay orientation later in life. Do women with CAH exhibit those behaviors because early androgens partially masculinized their brains? Or did their ambiguous genitalia cause parents and others to treat them differently from infancy? The guevedoces of the Dominican Republic, who are raised as girls but grow a penis at puberty, behave like males as adults, dressing like men and seeking girlfriends. There are two competing explanations for why these people raised as girls later behave as men. First, prenatal testosterone may masculinize their brains; thus, despite being raised as girls, when they reach puberty, their brains lead them to seek out females for mates. This explanation suggests that the social influences of growing up--assigning oneself to a gender and mimicking role models of that gender, as well as gender-specific playing and dressing--are unimportant for later behavior and sexual orientation. An alternative explanation is that early hormones have no effect--that the local culture simply recognizes and teaches children that some people can start out as girls and change to boys later. If so, then the social influences on gender role development might be completely different in this society from those in ours. Of course, a third option is that both mechanisms contribute to the final outcome. At the opening of the chapter, we discussed the dilemma of cloacal exstrophy, in which genetic boys are born with functional testes but without penises. Historically in these cases, neonatal sex reassignment has been recommended on the assumption that unambiguously raising these children as girls, and surgically providing them with the appropriate external genitalia, could produce a more satisfactory outcome. In a long-term follow-up of 14 such cases, however, Reiner and Gearhart (2004) found that 8 of these "girls" eventually declared themselves to be boys, even though several were unaware that they had ever been operated on. Although this finding indicates that prenatal exposure to androgens strongly predisposes subsequent male gender identity, 5 of the remaining 6 cases were apparently content with their female identities, suggesting that socialization can also play a strong role. However, almost all of these teenagers, including those who felt comfortable as girls, reported being sexually attracted to girls. These reports are part of a growing body of evidence suggesting that prenatal testosterone does in fact influence sexual orientation in humans, as we'll see next. What determines a person's sexual orientation? There are two kinds of developmental influences that could shape human sexual orientation. Sociocultural influences instruct children about how they should behave when they grow up (think of all those charming princes wooing princesses in Disney movies). But, as we discussed in the previous section, differences in fetal exposure to testosterone could also organize developing brains to be attracted to females or males in adulthood. For that great majority of people who are heterosexual, there's no way to distinguish between these two influences, because they both favor the same outcome. Gay people provide a test, because people attracted to the same sex (and other sexual minorities) remain stigmatized by various social groups and cultural institutions (Herek and McLemore, 2013). Is there evidence that early hormones are responsible for causing some people to ignore society's prescription and become gay? If so, then maybe hormones play a role in heterosexual development too. Homosexual behavior is certainly seen in other species--mountain sheep, swans, gulls, and dolphins, to name a few (Bagemihl, 1999). Interestingly, same-sex sexual behavior is more common among apes and monkeys than in prosimian primates like lemurs and lorises (Pfau et al., 2019), so perhaps greater complexity of the brain makes homosexual behavior more likely. In the most-studied animal model--sheep--some
(A) 1 These nuclei in humans are seen in the same part of the hypothalamus where the SDN-POA is found in rats.
(B) 2 INAH-3 is larger in men than in women, and larger in straight men than in gay men. 0.20 = AIDS victims 0.15
FIGURE 8.34 Interstitial Nuclei of the Anterior Hypothalamus (INAH) (After S. LeVay, 1991. Science 253: 1034.)
3 Although most of the gay men in this study had died of AIDS, note that heterosexual men who died of AIDS still had a larger INAH-3, indicating that the differences between straight and gay men are not due to AIDS.
rams consistently refuse to mount females but prefer to mount other rams. There are
differences in the POA of "gay" versus "straight" rams (Roselli et al., 2004), apparently
organized by testosterone acting on the brain during fetal development (Roselli and
Simon LeVay (1991) performed postmortem examinations of the POA in humans
and found a nucleus (the third interstitial nucleus of the anterior hypothalamus, or
INAH-3) (FIGURE 8.34A) that is larger in men than in women, and larger in hetero-
sexual men than in gay men (FIGURE 8.34B). All but one of the gay men in the study
had died of AIDS, but the brain differences could not be due to AIDS pathology, be-
cause straight men with AIDS still had a significantly larger INAH-3 than did the gay
men (Byne et al., 2001). To the press and the public, this
fWinadtsionng/Bsoreuednldoevde like strong evidence that sexual orientation
iTsh"ebMuiinldt 'isnM."aIcth'isnsetill possible, however, that early social ex- Foundations of Brain and Behavior 4e perience affects the development of INAH-3 to determine
lMatMer4es_e0x8u.3a4l or0i8e/n2t5a/t2io0 n. Furthermore, sexual experiences as 2D
an adult could affect INAH-3 structure, so the smaller nu-
cleus in some gay men may be the result of their gay orien-
tation, rather than the cause, as LeVay himself was careful to
In women, purported markers of exposure to andro-
gen as a fetus--sounds emitted from the ears (McFadden,
2011), patterns of eye blinks (Rahman, 2005), and finger
length patterns (FIGURE 8.35)--all indicate that lesbians,
The ratio of the length of the index nger divided by the ring nger (2D:4D) is affected by prenatal androgen and indicates that lesbians, on average, were exposed to more prenatal testosterone than were straight women. 0.97 0.96 0.95
FIGURE 8.35 Bodily Indicators of Prenatal Androgen Note that these are group differences in averages; you cannot reliably determine an individual's orientation by examining digit ratios. (After T. J. Williams et al., 2000. Nature 404: 455.)
fraternal birth order effect A phenomenon in human populations, such that the more older biological brothers a boy has, the more likely it is he will grow up to be gay.
on average, were exposed to slightly more fetal androgen than were heterosexual women. These findings suggest that fetal exposure to androgen increases the likelihood that a girl will grow up to be gay. There is always considerable overlap between the two groups, so you cannot use these features to predict whether a particular woman is gay, and clearly fetal androgens cannot account for all lesbians. But if early androgen exposure results in later being attracted to women, maybe the reason most men are attracted to women is because they were exposed to prenatal androgen. Yet there's little evidence that variation in prenatal androgen can account for gay versus straight men; some markers suggest that gay men were exposed to less prenatal testosterone, and others suggest that they were exposed to more prenatal testosterone than were straight men. However, another nonsocial factor influences the probability of homosexuality in men: the more older brothers a boy has, the more likely he is to grow up to be gay (Blanchard et al., 2006). Your first guess might be that this is a social influence of older brothers, but it turns out that older stepbrothers that are raised with the boy have no effect, while biological brothers (sharing the same mother) increase the probability of the boy's being gay even if they are raised apart (Bogaert, 2006). Furthermore, this fraternal birth order effect is seen in boys who are right-handed, but not in left-handed boys (Blanchard et al., 2006; Bogaert, 2007), providing another indication of differences in early development between gay and straight men. Statistically, the birth order effect is strong enough that about one in every seven gay men in North America--about a million people--is gay because his mother had sons before him (Cantor et al., 2002). One theory is that the immune system of a mother carrying a son is exposed for the first time to proteins from the Y chromosome, so it may produce antibodies that affect development of subsequent sons (Bogaert et al., 2018). From a political viewpoint, the question--whether sexual orientation is determined before birth or determined by early social influences--is irrelevant. Laws and prejudices against homosexuality are based primarily on religious views that it is a sin that some people "choose." But almost all gay and straight men report that, from the beginning, their interests and romantic attachments matched their adult orientation. So any social influence would have to be acting very early in life and without any conscious awareness (do you remember "choosing" whom to find attractive?). Furthermore, despite extensive efforts, no one has come up with a reliable way to change sexual orientation (Spitzer, 2012). These findings, added to evidence that older brothers and prenatal androgens affect the probability of being gay, have convinced most scientists that we do not choose our sexual orientation.
1. What does the sexual orientation of people with various syndromes of sexual differentiation suggest about hormonal influences on human sexual orientation? 2. If human sexual orientation were shown definitively to be influenced by prenatal factors such as hormones and the fraternal birth order effect, would you be more or less inclined to accept homosexuality? Recommended Reading Colapinto, J. (2006). As Nature Made Him. New York, NY: Harper Perennial. Eugenides, J. (2002). Middlesex: A Novel. New York, NY: Farrar, Straus, and Giroux. Komisaruk, B. R., and González-Mariscal, G. (2017). Behavioral Neuroendocrinology. Boca Raton, FL: CRC Press.
LeVay, S., Baldwin, J., and Baldwin, J. (2021). Discovering Human Sexuality (5th ed.). Sunderland, MA: Oxford University Press/Sinauer. Nelson, R. J., and Kriegsfeld, L. J. (2016). An Introduction to Behavioral Endocrinology (5th ed.). Sunderland, MA: Oxford University Press/Sinauer. Patisaul, H. B., and Belcher, S. M. (2017). Endocrine Disruptors, Brain and Behavior. New York, NY: Oxford University Press.
8 · VISUAL SUMMARY You should be able to relate each summary to the adjacent illustration, including structures and processes. The online version of this Visual Summary includes links to figures, animations, and activities that will help you consolidate the material.
1 Hormones are chemicals that are secreted by endocrine glands into the bloodstream and taken up by receptor molecules in target cells. Unlike neurotransmitters in neuronal signaling, hormones spread more slowly and act throughout the body. Review Figures 8.1-8.3, Table 8.1, Activity 8.1, Animations 8.2 and 8.3 3 Negative feedback systems control hormone secretion. Neuroendocrine cells in the hypothalamus send axons down the pituitary stalk to the posterior pituitary, releasing two hormones--oxytocin and vasopressin--into the bloodstream. Release of the hormones is regulated by synaptic influences on those neuroendocrine cells. Review Figures 8.8-8.11 5 Many behaviors require the coordination of neural and hormonal components. Messages may be transmitted in the body via neural-to-neural, neural-to-endocrine, endocrine-to-endocrine, or endocrine-to-neural links. There are continual, reciprocal influences between the endocrine system and the nervous system: experience affects hormone secretion, and hormones affect behavior and therefore future experiences. Review Figures 8.15 and 8.16
Nerve impulses to hypothalamus Oxytocin from pituitary gland
2 Most hormones act on receptors in a wide variety of cells, coordinating influences throughout the body. Peptide hormones and amine hormones bind to receptor molecules at the surface of the target cell membrane and activate second-messenger molecules inside the cell. Steroid hormones pass through the membrane and bind to receptor molecules inside the cell, ultimately regulating gene expression. Review Figures 8.4-8.7, Animation 8.4
4 Other hormones are controlled by a releasing hormone from the hypothalamus that stimulates the anterior pituitary to release tropic hormones, which in turn control the secretion of hormones by endocrine glands. The endocrine gland hormone then provides negative feedback to the hypothalamus and pituitary. Review Figures 8.11-8.13, Animation 8.5
extends from the ventromedial hypothalamus (VMH) to
and medial amygdala, and they project axons widely to regulate
7 In humans, very low levels of testosterone are required for either men or women to display a full interest in sex, but additional testosterone has no additional effect. In animals, hormones significantly influence maternal behavior by acting on the same brain regions that are important for sexual behavior (mPOA, VMH). Review Figures 8.18 and 8.21-8.23 9 In animals, androgens also organize the developing brain, masculinizing regions such as the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the spinal nucleus of the bulbocavernosus (SNB). There is evidence that prenatal androgens also masculinize the human brain. Review Figures 8.29-8.32, Animation 8.6
8 Sex chromosomes (XX or XY) control whether the indifferent gonads of an individual develop as testes or ovaries, the beginning of the process of sexual differentiation. Then, hormonal secretions from the testes masculinize the rest of the body in males. This means that some people, for example, women who carry a Y chromosome but have androgen insensitivity syndrome (AIS), may be masculine in some parts of the body but feminine in others. Review Figures 8.24-8.28 10 Several regions of the human brain are sexually dimorphic, but we do not know whether these dimorphisms are organized by fetal steroids or by sex differences in the social environment. Research demonstrates that human sexual orientation is affected by prenatal influences and is not simply a matter of individual choice. Review Figures 8.33-8.35
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