Organization/Activation Hypothesis

Does prenatal (or neonatal) exposure to particular steroid hormones impose permanent sex-specific changes on the central nervous system? Such sex-specific neural changes have been shown in regions of the brain that regulate “involuntary” sexual physiology. The cyclic secretion of luteinizing hormone by the adult female rat pituitary, for example, is dependent on the lack of testosterone during the first week of the animal's life. The luteinizing hormone secretion of female rats can be made noncyclic by giving them testosterone 4 days after birth; conversely, the luteinizing hormone secretion of males can be made cyclical by removing their testes within a day of birth (Barraclough and Gorski 1962). It is thought that sex hormones may act during the fetal or neonatal stage of a mammal's life to organize the nervous system in a sex-specific manner, and that during adult life, the same hormones may have transitory, activational effects. This idea is called the organization/activation hypothesis.

Interestingly, the hormone chiefly responsible for determining the male brain pattern is estradiol, a type of estrogen.^* Testosterone in fetal or neonatal blood can be converted into estradiol by the enzyme P450 aromatase, and this conversion occurs in the hypothalamus and limbic system—two areas of the brain known to regulate hormone secretion and reproductive behavior (Reddy et al. 1974; McEwen et al. 1977). Thus, testosterone exerts its effects on the nervous system by being converted into estradiol. But the fetal environment is rich in estrogens from the gonads and placenta. What stops these estrogens from masculinizing the nervous system of a female fetus? Fetal estrogen (in both males and females) is bound by a-fetoprotein. This protein is made in the fetal liver and becomes a major component of the fetal blood and cerebrospinal fluid. It will bind and inactivate estrogen, but not testosterone.

Attempts to extend the organization/activation hypothesis to “voluntary” sexual behaviors are more controversial because there is no truly sex-specific behavior that distinguishes the two sexes of many mammals, and because hormonal treatment has multiple effects on the developing mammal. For instance, injecting testosterone into a week-old female rat will increase pelvic thrusting behavior and diminish lordosis—a posture that stimulates mounting behavior in the male—when she reaches adulthood (Phoenix et al. 1959; Kandel et al. 1995). These behavioral changes can be ascribed to testosterone-mediated changes in the central nervous system, but they could also be due to hormonal effects on other tissues. Testosterone enables the growth of the muscles that allow pelvic thrusting. And since testosterone causes females to grow larger and to close their vaginal orifices, one cannot conclude that the lack of lordosis is due solely to testosterone-mediated changes in the neural circuitry (Harris and Levine 1965; De Jonge et al. 1988; Moore 1990; Moore et al. 1992; Fausto-Sterling 1995).

In addition, the effects of sex steroids on the brain are very complicated, and the steroids may be metabolized differently in different regions of the brain. Male mice lacking the testosterone receptor still retain a male-specific preoptic morphology in the brain, and male mice lacking the aromatase enzyme are capable of breeding (Breedlove 1992; Fisher et al. 1998). These studies show that there is more to sex-specific morphology and behavior than steroid hormones. Despite best-selling books that pretend to know the answers, we have much more to learn regarding the relationship between development, steroids, and behavior. Moreover, extrapolating from rats to humans is a very risky business, as no sex-specific behavior has yet been identified in humans, and what is “masculine” in one culture may be considered “feminine” in another (see Jacklin 1981; Bleier 1984; Fausto-Sterling 1992). As one review (Kandel et al. 1995) concludes:

Male Homosexuality

Certain behaviors are often said to be part of the “complete” male or female phenotype. The brain of a mature man is said to be formed such that it causes him to desire mating with a mature woman, and the brain of a mature woman causes her to desire to mate with a mature man. However, as important as desires are in our lives, they cannot be detected by in situ hybridization or isolated by monoclonal antibodies. We do not yet know if sexual desires are primarily instilled in us by our social education or are fundamentally “hardwired” into our brains by genes or hormones during our intrauterine development or by other means.

In 1991, Simon LeVay proposed that part of the anterior hypothalamus of homosexual men has the anatomical form typical of women rather than of heterosexual men. The hypothalamus is thought to be the source of our sexual urges, and rats have a sexually dimorphic area in their anterior hypothalamus that appears to regulate their sexual behavior. Thus, this study generated a great deal of publicity and discussion. The major results are shown in Figure 17.14. The interstitial nuclei (neuron clusters) of the anterior hypothalamus (INAH) were divided into four regions. Three of them showed no signs of sexual dimorphism. However, one of them, INAH3, showed a statistically significant difference in volume between males and females; it was claimed that the male INAH3 is, on average, more than twice as large as the female INAH3. Moreover, LeVay's data suggested that the INAH3 of homosexual men was similar in volume to that of women and less than half the size of heterosexual men's INAH3. This finding, LeVay claimed, “suggests that sexual orientation has a biological substrate.”

There have been several criticisms of LeVay's interpretation of the data. First, the data are from populations, not individuals. One can also say that there is a statistical range and that men and women have the same general range. Indeed, one of the INAH3 from a homosexual male was larger than all but one of those from the 16 “heterosexual males” in the study. Second, the “heterosexual men” were not necessarily heterosexual, nor were the “homosexual men” necessarily homosexual; the brains came from corpses of people whose sexual preferences were not known. This brings up another issue: homosexuality has many forms, and is probably not a single phenotype. Third, the brains of the “homosexual men” were taken from patients who had died of AIDS. AIDS affects the brain, and its effect on the hypothalamic neurons is not known.

Fourth, because the study was done on the brains of dead subjects, one cannot infer cause and effect. Such data show only correlations, not causation. It is as likely that behaviors can affect regional neuronal density as it is that regional neuronal density can affect behaviors. If one interprets the data as indicating that the INAH3 of male homosexuals is smaller than that of male heterosexuals, one still does not know whether that is a cause of homosexuality or a result of it. Indeed, Breedlove (1997) has shown that the density and size of certain neurons in rat spinal ganglia depend on the frequency of sexual intercourse. In this case, the behavior was affecting the neurons. Fifth, even if a difference in INAH3 does exist, there is no evidence that the difference has anything to do with sexuality. Sixth, these studies do not indicate when such differences (if they exist) emerge. The question of whether differences among the heterosexual male, female, and homosexual male INAH3 occur during embryonic development, shortly after birth, during the first few years of life, during adolescence, or at some other time was not addressed.

In 1993, a correlation was made between a particular DNA sequence on the X chromosome and a particular subgroup of male homosexuals: homosexual men who had a homosexual brother. Out of 40 pairs of homosexual brothers wherein one brother had inherited a particular region of the X chromosome from his mother, the other brother had also inherited this region in 33 cases (Hamer et al. 1993). One would have expected both brothers to have done so in only 20 cases, on average. Again, this is only a statistical concordance, and one that could be coincidental. Moreover, the control (the incidence of the same marker in the “nonhomosexual” males of these families) was not reported, and the statistical bias of the observations has been called into question, especially since other laboratories have not been able to repeat the result (Risch et al. 1993; Marshall 1995). More recent studies (Hu et al. 1995; Rice et al. 1999) found little or no increase in the incidence of this DNA sequence when homosexual men were compared to their nonhomosexual brothers. Hu and colleagues concluded that this sequence is “neither necessary nor sufficient for a homosexual orientation.” Thus, despite the reports of these studies in the public media, no “gay gene” has been found.

Genes encode RNAs and proteins, not behaviors. While genes may bias behavioral outcomes, we have no evidence for their “controlling” them. The observance of people with schizophrenia, or people whose personalities change radically after a religious conversion or a traumatic experience, indicates that a single genotype can support a wide range of personalities. This is certainly a problem with any definition of a “homosexual phenotype,” since people can alternate between homosexual and heterosexual behavior, and the definition of what is homosexual behavior differs between cultures (see Carroll and Wolpe 1996). Thus, whether homosexual desires are formed by genes within the nucleus, by sex hormones during fetal development, or by experiences after birth is still an open question.