Humans with Unusual Early Exposure to Hormones - The Case for Nature

Gender, Nature, and Nurture - Richard A. Lippa 2014

Humans with Unusual Early Exposure to Hormones
The Case for Nature

Do animal results generalize to humans? For example, does early exposure to androgens masculinize human brains and behaviors? One way to answer this question is to study people with unusual exposure to sex hormones.

Congenital Adrenal Hyperplasia Females

Some girls suffer from a condition known as congenital adrenal hyperplasia (CAH). Because of a genetic defect, the adrenal glands of CAH girls enlarge prenatally and produce abnormally high amounts of androgens (male hormones). Although CAH girls are genetic XX females, they have nonetheless been exposed to unusually high levels of androgens prenatally and sometimes postnatally as well; it depends on how early their disorder is diagnosed and treated. CAH girls can experience varying degrees of genital masculinization, depending on the severity of their condition. In some cases (e.g., where labia fuse to produce an empty scrotum or the clitoris enlarges to the point of appearing to be a penis) the genitals may be surgically altered to look more like those of a typical female.

CAH girls generally grow up to have a female gender identity. That is, they think of themselves as girls and women. However, a number of studies suggest that they are often less content with being female and more interested in being males than non-CAH girls (Ehrhardt & Baker, 1974; Slijper, 1984). Although most CAH girls grow up to be heterosexual, CAH women report an increased incidence of bisexual and lesbian attraction compared with non-CAH women (Dittmann. Kappes, & Kappes, 1992; Money & Schwartz, 1977). CAH girls tend to engage in more male-typical play than non-CAH girls. They like rough-and-tumble activities, sports, male clothing (e.g., jeans and plain shirts which allow outdoor activities), and boys' toys, and they like to play with boys (Berenbaum & Hines, 1992; Dittmann, Kappes, Kappes, Borger, et al., 1990; Slijper, 1984). CAH girls often dislike girl-typical activities such as playing with dolls and wearing makeup, jewelry, and frilly clothes.

The degree of masculine behavior shown by CAH females does not seem to be related to their degree of genital masculinization, and this argues against the hypothesis that family reactions to genital masculinization produce their behavioral masculinization (Berenbaum & Hines, 1992; Dittmann, Kappes, Kappes, Borger, Meyer-Bahlburg, et al., 1990; Slijper, 1984). On some personality measures, CAH girls score more like boys than non-CAH girls do. For example, they are higher on aggression scales. CAH girls also sometimes show more male-typical levels of visual-spatial abilities than non-CAH girls (Hampson, Rovet, & Alt man, 1994; Resnick, Berenbaum, Gottesman, & Bouchard, 1986).

Overall, research on CAH girls suggests that early exposure to androgens masculinizes human females in a number of ways. It is important to note that although CAH girls have elevated levels of androgens, their prenatal androgen levels are not always as high as those of boys. Presumably, if XX individuals were exposed to more typical male levels of prenatal androgens, they might show even more masculinization of their behaviors.

Androgen-Insensitive Males

There are a small number of genetic XY males who, because of a genetic error, do not have androgen receptors in their cells (Quigley, et al., 1995). Androgen receptors are special proteins in cells designed to hook up with testosterone and thereby allow it to affect gene expression in the nucleus of the cell. Unless androgen receptors are present, testosterone cannot affect cells. Androgen receptors are present in many cells throughout the body, and this provides evidence for the pervasive impact of testosterone on bodily development and physiology.

The effects of complete androgen irisensitivity are dramatic. Affected XY individuals develop as females, in the sense that their bodies look completely female, and they develop a female gender identity. In terms of their mental abilities, androgen insensitive XY individuals are more like women than men. For example, they show female-typical performance on visual-spatial and verbal tests (Imperato-McGinley, Pichardo, Gautier, Boyer, & Bryden, 1991). They are also similar in personality and gender-role behaviors to typical women (Hines, Ahmed, & Hughes, 2003).

Such individuals are generally romantically and sexually attracted to males (Hines, Ahmed, & Hughes, 2003; Wisniewski, et ai., 2000). However, they have testes (male gonads) that produce normal amounts of testosterone. Their testes do not descend to an external position, however. Typically, androgen insensitivity syndrome is detected at puberty, when affected individuals fail to menstruate as normal women do. Because they have testes and not ovaries, androgen insensitive XY individuals are infertile. Usually their undescended testes are surgically removed because, left inside the body, they have an elevated risk for cancer.

Studies of androgen insensitive individuals show the importance of testosterone in promoting normal male development, and they demonstrate that even in XY humans, development will follow a default female pattern in the absence of successful action by testosterone. Is an androgen insensitive XY individual a man or a woman? In virtually all external physical and behavioral characteristics, the individual is female. And certainly, the androgen insensitive individual thinks of herself as female. As adults, androgen insensitive XY individuals often marry men. However, genetically they are males.

Reductase-Deficient Males

Some XY individuals have a single-gene defect that creates problems with an enzyme (reductase) that, converts testosterone to a related hormone called dihydrotestosterone (Imperato-McGinley, Peterson, Gautier, & Sturla, 1979; Wilson, 1999; Wilson. Griffin, & Russell, 1993). You may recall from Chapter 3 that testosterone masculinizes the brain; however, dihydrotestosterone is responsible for masculinizing the external genitalia. Reductase deficient males experience male-typical levels of testosterone prenatally, and presumably they experience male-typical masculinization of their brains. But because of their lack of dihydrotestosterone, they are born with female or sometimes ambiguous-looking genitals. Such individuals are often reared as girls (as was the case for Callie, the protagonist of Jeffrey Eugenides' novel Middlesex).

However, the androgen surge that occurs at puberty eventually masculinizes their genitals. The reductase deficient individual's clitoris enlarges into a sexually functioning penis, and the formerly undescended testes lower into partially fused labia to form a scrotum. In the Dominican Republic, where isolated communities of people possess high frequencies of the genes that lead to reductase deficiency, the Spanish slang for the condition is guevedoces—"eggs [i.e., testicles] at 12."

Individuals with reductase deficiency are fascinating to study because they have had normal male exposure to prenatal testosterone, but their female-appearing genitals often lead them to be reared as girls. What wins out: prenatal hormones or rearing? The answer varies from individual to individual (Wilson, 1999). However, many of these people choose to change from female to male after puberty, and this suggests that prenatal exposure to androgens can have a potent impact on later gender identity and behavior, even in individuals who are reared as females and who have female-appearing genitals early in life.

Effects of Estrogen: Diethylstilbestrol Children and Turner Syndrome Women

The studies just summarized address the early effects of testosterone (or of related androgens, such as dihydrotestosterone) on human behavior. What about estrogens (female hormones)? Do they also play a role in human sex differences and gender-related behaviors? There are two kinds of evidence relevant to this question: (a) data collected from people exposed prenatally to the artificial estrogen diethylstilbestrol (DES) and (b) data collected from women who suffer from a genetic condition known as Turner syndrome.

Females Exposed to DES.

In the 1950s and 1960s, hundreds of thousands of pregnant women received the synthetic estrogen DES to prevent miscarriages (Edelman, 1986). The use of DES was halted in the early 1970s when it was demonstrated that it was not effective in stopping miscarriages and that it increased the odds for certain kinds of cervical cancer In women exposed to DES prenatally. As noted before, estrogens can sometimes have paradoxical effects. In animal studies, they may masculinize rather than feminize brains and behaviors. The reason for this is that in many animals, testosterone is converted (aromatized) to estrogen inside of cells, and it is the estrogen that directly affects genes and tissue development.

You might wonder what, keeps female fetuses' from being masculinized by their mothers' natural estrogen? The answer is that there are physical and chemical mechanisms that prevent the mothers' estrogen from entering fetal brains and from becoming chemically active in fetuses. For example, there is a chemical called alpha-fetoprotein that binds to estrogen and prevents it from entering fetal nerve cells. However, administration of DES may overwhelm female fetuses' natural defenses against too much estrogen. The net result may be that DES masculinizes female fetuses' brains and behavior in certain ways. Research shows that women prenatally exposed to DES are more likely to have homosexual or bisexual attractions than non-DES women (Ehrhardt, et al., 1985; Meyer-Bahlburg, et al., 1984; Meyer-Bahlberg, et al., 1995), These findings are particularly interesting in combination with similar findings in CAH women. Because women exposed prenatally to DES do not have masculinized genitals, the effects of DES on sexual orientation cannot be due to this factor. Thus prenatal hormones, in and of themselves, can have effects on women's later sexual orientation.

DES exposure seems to have little or no effect on girls patterns of childhood play or on adult women's sex-typed interests or cognitive abilities (Lish, Meyer-Bahiburg, Ehrhardt, Travis, & Veridiano, 1992; Wilcox, Maxey, & Herbst, 1992). Some studies suggest subtle brain differences between DES and non-DES women. For example, one study used a dichotic listening task (where participants are asked to recognize syllables in the right and left ears) and found that DES women appeared to have more lateralized brains, like men (Hines & Shipley, 1984), In animal research, exposure to DES also sometimes makes certain areas of females' brains more like males' (Hines, Alsum, Roy, Gorski, & Goy, 1987; Hines & Goy, 1985).

The effects of DES on men seem to be even weaker than its effects on women. There are hints that prenatal exposure to DES may slightly masculinize boys' childhood activities and reduce certain kinds of spatial abilities (Kester, Green, Finch, & Williams, 1980). In general, however, DES does not seem to have much effect on boys. More broadly, the effects of DES on human sex-typed behaviors are much weaker than the effects of androgens, and this suggests that androgens have more of an impact than estrogens on human brain development.

Turner Syndrome.

Some human females lack estrogen completely because of a condition know as Turner syndrome (Lippe, 1991; Rovet, 1993; White, 1994). Turner syndrome females have only one X chromosome, whereas nonaffected women have two X chromosomes. (Turner syndrome can come in varying degrees. Sometimes, not all the body cells in a Turner syndrome woman lack a second X chromosome. However, these variations need not concern us here. A corresponding syndrome does not exist for males, because a male embryo lacking an X chromosome would not survive.) Turner syndrome females have gonads that typically degenerate during fetal development, and they are born without ovaries or a uterus. Because of their lack of ovaries, they do not produce natural estrogens, and of course, they are infertile. Physically, Turner syndrome women tend to be very short, and they often have somewhat abnormal physical traits (e.g., thick necks, small breasts, childlike faces).

Despite their lack of estrogen, Turner syndrome females develop a strong female gender identity and their sexual orientation is generally heterosexual (Ehrhardt, Greenberg, & Money, 1970). If anything, Turner syndrome girls often display highly feminine interests, dress, and play patterns (Downey, Ehrhardt, Morishima, Bell, & Gruen, 1987). They typically show normal performance on verbal tests but depressed performance on tests of visual-spatial and quantitative abilities (Bender, Linden, & Robinson, 1994; Pennington, et al., 1985). Some Turner syndrome females may show a lack of social skills and difficulties in accurately judging people's facial expressions (Skuse et al., 1997), and in this regard, they are not like typical females. In studies of brain lateralization (e.g., dichotic listening tasks), Turner syndrome women often show a kind of hyper-feminine pattern; that is, their brains seem to be even less lateralized than the average woman's, whose brain is in turn less lateralized than the average man's (Clark, Klonoff, &Hayden, 1990; Gordon & Galatzer, 1980).

In sum, Turner syndrome women showed enhanced femininity in certain ways (childhood play, brain lateralization), but cognitive deficiencies in other ways. Using evidence from these women to infer the effects of estrogen is complicated by the fact that the missing X chromosome may produce genetic effects above and beyond the effects of no estrogen; for example, Turner syndrome females lack testosterone as well as estrogen and other female hormones. One hypothesis that is consistent with data from Turner syndrome women is that some amount of estrogen is necessary for normal development in women, but estrogen does not have the powerful organizational and activational effects that androgens do. Despite the fact that Turner syndrome individuals lack an X chromosome, ovaries, and estrogen, they are still women.