Like all other mammals, the default pattern for sexual development in humans is female. Under the influence of the testis determining factor gene in fetuses with Y chromosomes, the indifferent gonads assume the characteristic structure of testes. Once formed, sometime around gestational week six to seven, the testes begin to secrete androgenic hormones and Müllerian-inhibiting substance (MIS).

Both male and female embryos possess Wolffian and Müllerian duct systems, which have the potential to form the male and female genitalia, respectively. In males, androgens secreted by the developing testes support the development of the Wolffian duct system, which becomes the male internal genitalia (seminal vesicles, vas deferens, and epididymis) and external genitalia (penis and scrotum); MIS suppresses the development of the Müllerian duct system. This combination of hormonal influences results in a normal male genital phenotype. In females, development of the Wolffian duct system is not stimulated, and development of the Müllerian duct system is not inhibited. Therefore, the fallopian tubes, uterus, and top third of the vagina develop in the fetus.

Increasing evidence demonstrates that the brain is sexually differentiated by gonadal hormones during prenatal life. In animals, experimental manipulations that alter gonadal hormone levels in developing fetuses affect the display of speciestypical sexual and related behaviors in adulthood. When examined as adults, males deprived of androgens as fetuses are neurologically and behaviorally demasculinized, and females exposed to androgens as fetuses are neurologically and behaviorally masculinized (Berenbaum, 1998; Goy & McEwen, 1980).

Brain differentiation occurs later in gestation than does genital differentiation. In humans, it is believed to occur during the second trimester, and it results in gender differences in the hypothalamus, anterior commissure, corpus callosum, and thalamus (see Fig. 5-2) (Halpern, 2000). The significance of these sex differences in the brain is not clear, but they may be related to the expression of gender identity, gender role, and sexual orientation (Institute of Medicine, 2001) (Table 21-1).

Experimental hormonal manipulations such as those done in animals obviously cannot be carried out in humans. However, clinical disorders of sexual development can give clues to the effects of gonadal hormones on sexual differentiation of the human brain.

At birth, most infants can be clearly identified as male or female. However, in some rare conditions, phenotypic sex does not accurately reflect genetic sex. One such condition is androgen insensitivity syndrome (AIS), formerly known as testicular feminization. In AIS, despite an XY genotype and testes that secrete androgen, a genetic defect results in failure of the fetal cells to respond to this androgen. As in normal females, the absence of androgenic stimulation results in a female phenotype. Because individuals with AIS have female external genitalia and a blind vaginal pouch, the disorder may not be identified during childhood. At puberty, normal breast development occurs (due in part to conversion of testosterone to estradiol); however, menstruation fails to occur and, in some individuals, the descending testes appear in the inguinal region or labia as masses. Like the body, the behavior of individuals with AIS is feminine; most have a female gender identity and gender role. Most are also heterosexual with respect to their female phenotype.

In congenital virilizing adrenal hyperplasia (CAH), formerly called adrenogenital syndrome, the presence of excessive adrenal androgen secretions (resulting from 21-hydroxylase [21-OH] deficiency in more than 90% of cases) in a genetically normal (XX) female results in prenatal masculinization of the female genitalia. At birth, infants with this disorder may have enlarged
phalluses and fused labia and are sometimes identified initially as males. As adults, individuals with CAH generally have a female gender identity and adopt a female gender role. The fact that about one-third of these individuals have a lesbian sexual orientation suggests that early exposure to androgens may affect sexual orientation (Berenbaum, 1998, 1999).

Traditionally, parents of children with ambiguous genitalia caused by these or other conditions were advised to have their child sexually reassigned early in infancy. Most such children were assigned to be female because it is easier to surgically form female than male genitalia. However, increasing evidence from these individuals as adults suggests that their gender identity does not necessarily fit with their reassigned sex. This implies that early exposure of the brain to gonadal hormones is a significant factor in gender identity. In addition, this indicates that the nature of hormonal exposure of the brain should be considered before surgically reassigning the gender of an infant (Reiner & Gearhart, 2004).

In contrast to individuals with AIS or CAH, people with gender dysphoria (GD), commonly called transgender or transsexual individuals, are physically normal with respect to their biological sex. However, these people have a pervasive and persistent feeling of having been born into the body of the wrong sex. This feeling causes so much discomfort that, in adulthood, people with GD may take sex hormones and seek sex-change surgery. Although the etiology of this disorder is not known, it has been hypothesized that GD is associated with decreased availability of androgens in males and increased availability of androgens in females during the prenatal period of brain sexual differentiation. It is of interest that men with GD are more likely to have older brothers (but not older sisters) than heterosexual men (Green, 2000). The mechanism of this birth order phenomenon, reported also in homosexual men (see later text), is not known. However, it may be related to a progressive maternal immune reaction to fetal testosterone or to a fetal male-specific antigen (e.g., the H-Y antigen) that leads to changes in sexual differentiation of the brain of subsequent fetuses (Blanchard, 1997; Blanchard et al., 2002).

There are no ethnic differences in the occurrence of homosexuality, and social factors are not believed to play a significant role in its etiology. Some psychoanalytically oriented theories speculate that homosexuality is related to social and family factors during development; however, they currently have little clinical or research support. The most pervasive current belief is that homosexual individuals are born and not made.

Although sex hormone levels in adulthood are generally not different between homosexual and heterosexual people, early chemical influences may play a role in the etiology of homosexuality. Anatomic changes in hypothalamic nuclei resulting from alterations in levels of prenatal sex hormones in both male and female homosexuals (LeVay, 1993, 2010), and a preponderance of older brothers (see previous text) in male homosexuals have been reported. Finally, genetic factors may be involved; both markers on the X chromosome and higher concordance rates for homosexuality in monozygotic than in dizygotic twins have been demonstrated (Whitam et al., 1993).

In the 1970s, homosexuality was removed from the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders. Today, homosexuality is considered by most clinicians to be a normal variant of sexual expression. This view is supported by several factors, including absence of evidence that the homosexual population has more emotional problems or psychiatric abnormalities than the heterosexual population.

Many individuals with a homosexual orientation have been married in the past and have had children. Their sexual orientation can become a legal issue in custody decisions. In particular, those
with a homosexual orientation have been denied custody or even access to their own children in states with laws that consider some of their sexual practices (e.g., anal sex) forms of criminal behavior (Carter & McGoldrick, 1999). In a landmark decision in 2003, the United States Supreme court struck down all such criminal “sodomy” laws.

Masters and Johnson proposed a four-stage model for sexual response in both men and women. The proposed stages of the sexual response cycle included excitement, plateau, orgasm, and resolution. Other categorizations of sexual response show similarities and differences when compared with Masters and Johnson’s stages (Table 21-2). In other schemes, “desire,” including interest and sexual fantasies, is the first stage. The second stage, “excitement,” has characteristics of the Masters and Johnson excitement and plateau stages combined. In both schemes, “orgasm” and “resolution” are the final stages. Because most sexual dysfunctions can be linked to difficulty with aspects of this cycle, understanding the physiological events of each stage can help establish a clinical perspective for these dysfunctions.

Medical conditions or medical treatments that alter circulating levels of gonadal hormones can have significant effects on sexual behavior in both women and men. However, the hormones that might be expected to affect sexuality are not always the ones that do. For example, in women, estrogen is only minimally involved in sexual interest. As evidence for this, menopause, which involves cessation of ovarian estrogen production, is usually not associated with a reduced sex drive if a woman’s general health is good. However, estrogen is involved in maintaining the physiological condition of the vagina and external genitalia. Thus, menopause can result in vaginal thinning and dryness, making sexual activity uncomfortable or even painful. This can lead to avoidance of such activity. Although estrogen alone or estrogen plus progesterone replacement therapy (ERT, EPRT) can reverse these vaginal problems and reduce the incidence of hot flashes, it apparently provides little or no overall benefit to health-related quality of life (Hays et al., 2003). Furthermore, association of ERT with increased risk of breast cancer (when combined with progesterone) (Chlebowski et al., 2003; see Chapter 3) and a slightly increased risk of dementia (Rapp et al., 2003) limit the use of hormone replacement therapy for symptoms of menopause for most women. At least one of the antidepressants, paroxetine (Paxil), may be effective in reducing postmenopausal symptoms such as hot flashes (Stearns et el., 2003).

Testosterone, secreted by the adrenal glands (as well as the ovaries and testes) throughout adult life, appears to play a major role in sexual interest and drive in women as well as in men. Addition of testosterone to ERT or use of testosterone alone may improve sexual functioning in some postmenopausal women (Vastag, 2003).