Endocrinological factors in homosexuality − Rakyat Biologi

There are three to four times as many homosexual men as there are lesbians. Most homosexuals have a sexual identity concordant with their genotype. In other words, they feel psychologically like men if they are XY and like women if they are XX. Is there something biological that can happen to an XY fetus that will invariably make him a homosexual ? Absolutely. There exists a condition called androgen-insensitivity syndrome. This X-linked hereditary condition consists of inability of any of the body's cells to respond to androgens (the main androgen is testosterone). This is a very specific metabolic disorder. Normally, the male or female fetus receives a small but significant dose of androgens through the blood stream from the mother -who secretes them with her adrenal gland and to a lesser extent with her ovaries. Then, if the fetus is male, he will develop gonads (testicles) and secrete his own androgens in much greater concentrations (in addition to those he secretes with his own adrenal glands). If the fetus is female, she will secrete the same small amount of androgens with her adrenal gland as a male fetus will with his own adrenal gland. However, the XY fetus with androgen insensitivity syndrome does not respond to the androgens at all. The result is that this fetus, who was genotypically destined to become a boy and a man, does not appear to do any such thing. Sadly, the internal reproductive organs are more male-like, but are sterile. These cases used to be taken for girls and were identified only due to the discovery during adolescence of an insufficiently deep vagina, or because of absence of menstruation. The male with androgen insensitivity syndrome is born looking exactly like a female, though taller. The sexual identity and orientation are both like those of normal females (Money, 1993).

One form of androgen insensitivity syndrome is male pseudo-hermaphroditism. This inherited enzyme deficiency syndrome causes males to develop as females until puberty. However, at puberty, the individual turns into a male. His testicles descend, a penis develops, the voice deepens, facial and body hair appear and the musculature becomes masculine. These individuals, raised as girls until puberty, have little difficulty adjusting to the male identity after puberty. They are even sexually attracted to females like normal men. Often more in hindsight than otherwise, it has been noted that these people had already started shifting toward a male identity by 5 or 6 years of age.

Is there a form of estrogen receptor insensitivity in humans ? Until recently, such a condition was thought lethal. However, a few cases have been described including one man by Smith and colleagues (1994) who presented an abnormal estrogen receptor gene and cellular insensitivity to estrogen. This man developed relatively normally but had osteoporosis and slowed development of his physiognomy. He was sexually functional, had a male sexual identity and a normal male sexual orientation towards women. Another man with the same syndrome developed cardiovascular disease supporting the widespread belief to the effect that estrogen protects against vascular disease. A few female cases have been described as well. These cases were pseudohermaphroditic (very enlarged clitoris), but eventually did manage to partially cross puberty with estrogen replacement but female secondary sexual characteristics appeared with a delay and incompletely. Only one report comprised assessment of sexual identity, and none of sexual preference. Conte and colleagues (1994) mentioned that their case of an adolescent with mutant P450 aromatase gene (necessary for estrogen synthesis) had a female identity despite her masculinized appearance. This corrobotates the generally acknowledged fact that sexual identity is more robust in the human female than in the male.

In short, in the genotypic human male, species-specific sexual identity and sexual orientation is determined by a cascade of events following from the androgen infusion (probably independent of estrogen), into the blood stream, coming from the mother and/or the fetus's own gonads, but which may also require a receptiveness on the part of all those cells which will eventually partake in sex differences. In addition though, there remain many mechanisms of these developmental cascades which remain obscure.

A vignette on a case of incomplete androgen insensitivity syndrome

In 1991, Gooren and Cohen-Kettenis published an account of case F. He was born looking like a girl, but had an enlarged clitoris. The infant was diagnosed as having a male genotype (XY) with androgen insensitivity syndrome (AIS), and was assigned to the female sex and raised as a girl. This case is particular in that the insensitivity to androgens was not complete (thus the enlarged clitoris). The small amount of androgen activity going on in F’s brain may have been sufficient to instill a male sexual identity and sexual preference for women. Indeed, from early childhood, F incoercibly behaved as a boy: F was belligerent, turbulent, very sports oriented, and at 14, started having sexual relations with girls. F felt attracted exclusively by girls. A few years later, F underwent a sex-change operation, had “ her ” breasts surgically removed. F is now satisfied to be living a stereotypically male life: he owns a house, he has three female sexual partners simultaneously, he is an aggressive and successful businessman, he is free and independent, and he is perceived as a “strongman” by family and friends.

N.B. The authors of this report suggest, reasonably, I think, that this case argues against (but does not definitively disprove) the “prenatal androgen” theory of male homosexuality.

Can genotypic females also be made homosexual by a metabolic quirk of nature ? The answer is yes, but less uniformly so. There are several medical conditions which cause hypertrophy (enlargement) and over activity of the adrenal glands. One of these is Cushing's disease. When this happens to a pregnant woman, she can produce too many androgens, which are secreted into the blood stream, and of course, eventually travel through the umbilical cord to the fetus. If the fetus is a genotypic female, she will be masculinized, but never completely so. This is because even an over-productive maternal adrenal gland will secrete nowhere near the concentration of testosterone that the male fetus's gonads will. For example, the daughter will be born with a very enlarged clitoris which may look more like a penis. The female reproductive system is intact in these cases however. So it is only logical that these androgenized females are usually treated with feminizing surgery, feminizing hormones, and are raised as girls. However, about half of them develop a very androgynous identity, and as many are sexually attracted to women -though not as many opt for overt homosexuality Money et al, 1984). Another condition which has similar effects is congenital adrenal hyperplasy. This is an autosomal recessive condition. In other words, it is hereditary, affects both sexes, and requires that both parents be carriers of the mutant gene. The fetus develops an enlarged adrenal gland which secretes too many androgens. You may wonder what happens to boys affected by maternal Cushing's disease or congenital adrenal hyperplasy (CAH). In the first case, nothing much happens because the excess of androgens stops at birth. In the second case, when the condition is not well controlled, the boy may develop precocious puberty and somewhat excessive secondary sexual characteristics. Sexually, these boys and men are normal. It appears that there exists a mechanism whereby androgen receptors on cells reach a saturation point at which an increase in androgens produces no additional effect. As for CAH women, a higher than normal proportion of them have homosexual dispositions (Money et al, 1984).

A vignette on a case of congenital virilizing adrenal syndrome (CVAS)

In 1987, Money and Lewis published a detailed case report of a woman with CVAS. At age two, her clitoris measured 2.8 x 1.2 centimeters and comprised a well formed glans and prepuce. CVAS was diagnosed and she was treated with hydrocortisone and had her clitoris reduced (as well as other cosmetic surgery of the external genital area). She had a normal (though slightly underdeveloped) reproductive system and had normal puberty. She was informed of her diagnosis and medical history. She was a healthy, bright, energetic, tomboyish girl, and had an excellent relation with her loving adoptive parents. She had an explicitly and exclusively female sexual identity and was even considered rather seductive. She explored heterosexual and homosexual petting in adolescence, but developed a clearly homosexual trajectory culminating in a stable homosexual relationship in adulthood. She never underwent copulation and wished not to do so. She had a clear and rather exclusive sexual attraction to females from puberty on. She felt quite comfortable with her life as a lesbian. She was only slightly regretful of not having children and had no plans to have children at age 31.

During the forties and fifties some doctors tried to help women avoid miscarriage by treating them with synthetic hormones. One of these synthetic hormones was diethylstilbestrol (DES), another was synthetic progestin (another female hormone which plays a role in preparing the uterus to carry the embryo). These drugs had the effect of masculinizing female fetuses. DES-exposed male subjects appeared however to be slightly psychologically feminized and/or demasculinized. The masculinization of DES-exposed females, as in adrenal hyperplasia, was never complete and was usually, in fact, far from complete. These girls were generally treated in the same manner as those masculinized by adrenal hyperplasia, as explained above. Roughly the same proportion had homosexual ideation. Research on the brains of these women -compared to non DES-exposed controls is very sparse. One study found that ear advantages in dichotic listening differed quite significantly between two such groups, with the DES-exposed women resembling the typical male profile of greater right ear differences. Very recently, a group of 175 women who had been exposed to diethylstilbestrol prenatally were compared with 219 unexposed control subjects on four laterality indices: handedness, footedness, eyedness, and earedness. It was found that there was a higher incidence of left-handedness among the DES-exposed subjects than among the controls. A recent report by Melissa Hines specifies that the effect of DES treatment producing left handedness seems to have occured when the treatment was given prior to nine weeks of gestation. Findings with masculinizing progestin-treated fetuses and with feminizing progesterone-treated fetuses have been more subtle than those reported following DES treatment. The body morphology is completely unaffected, and the psychological make-up shows only subtle changes.

There is no question that prenatal sex steroid exposure, especially testosterone, has something to do with brain development of heterosexuality and homosexuality. Blood testosterone or estrogen levels in adult heterosexuals and homosexuals do not differ by much. At most, there seems to exist a sub-group of homosexual men with low testosterone (nothing extreme), and a sub-group of lesbians with high testosterone (again not extreme). In fact, most homosexuals have normal hormone levels. Surgical or chemical castration in adults never changes the sexual orientation. However, a single injection of testosterone into a female rat fetus masculinizes her sexual behavior in adulthood. Factors which reduce a pregnant woman's production of androgens, such as protracted stress, seem to result in more male progeny of homosexual orientation than the norm would dictate (the norm is about one in ten). It is believed by a famous endocrinologist named Gunther Dörner (1978, 1988) that German men born of wartime mothers are more frequently homosexual than prior or later generations. I have to say that this theory of maternal stress causing homosexuality is very controversial -and it is indeed very difficult to validate in humans. Only recently have serious attempts been made to test this model in humans. Bailey et al (1991) failed to find evidence in support of Dörner’s model but Ellis et al (1988) found supporting evidence, for males only. Melissa Hines and colleagues, on the other hand, found no effect of maternal stress on sexual orientation of boys, but it did find that girls were slightly masculinized. This finding does not fit with Dörner’s postulated testosterone mechanism. Nevertheless, it has repeatedly been found that male rats born of experimentally stressed mothers manifest significantly more sexual mounting of other males than do the control group, and the low testosterone production levels of these stressed rat mothers was documented as well. As I explain in chapter 4, maternal stress during pregnancy demasculinizes several of the sexually dimorphic brain nuclei in rats. Furthermore direct fetal stress via alcohol consumption of the pregnant mother reduces male rat fetal testosterone and also demasculinizes the development of sexually dimorphic brain nuclei. This predicts that human males with fetal alcohol syndrome could be more at risk for homosexuality, an eventuality which has not yet been investigated as far as I could tell. However, more telling findings have accrued from research on exposure to pregnant mammals to opiates (ex: heroin). Maternal consumption of opiates during pregnancy reduces male fetal testosterone, and demasculinizes the development of the dimorphic brain nuclei in rats. In addition, boys born of mothers addicted to opiates during pregnancy have been found in three separate studies to be more feminine than controls on psychological tests. Whether these boys are more at risk for homosexuality remains a matter of conjecture at present. Also concordant with Dörner’s proposed mechanism of fetal testosterone deficiency as a vector of male homosexuality is the fact that there are significantly more homosexual men among last born children (whose mothers secrete less testosterone) than among first born children (Blanchard et al, 1995, Zucker et al, 1994). This finding has been often replicated and is well established. Several attempts to find this relation in lesbians have all failed (Gundlach, 1977; Perkins, 1978; Hare & Moran, 1979). Women produce less and less testosterone as they get older, and as they bear more children, but the testosterone factor seems to affect only the male sex. Unfortunately, the story is a bit more complex than just that. Ray Blanchard recently (1997) reviewed the birth order effect in homosexuals and found that the birth order effect is present even when maternal age is statistically controlled. Furthermore, it remains substantial, also when the birth interval is statistically contolled, such that it appears implausible to argue for a simple explanation of the birth order effect in homosexuality coming from low maternal testosterone. Finally, Ray’s most recent work establishes that this birth order effet is significant only for male siblings. In other words, the number of previously born sisters is of no import in risk for homosexuality, only the number of previously born brothers. Intriguingly, Blanchard’s reflexions led him to adopt an immunological explanation. He believes that the mother’s antibodies to her male fetus’s testosterone affect his prenatal brain development -causing the homosexuality. Here, as elsewhere, the evidence suggests that female species-specific sexual orientation is more robust. It could be that the neural developmental cascade determining sexual orientation somehow antedates the development of the fetal gonad. There are many types of underdevelopment of the testicles. But regardless of the type of hypogonadism, hypogonadal males are no more often homosexual than males with gonads. So, what may be critical in the determination sexual orientation of males, as Dörner proposes, may indeed be maternal hormonal androgenization rather than self-androgenization by one’s own hormones. One thing that must be noted though, about hypoganadism (ex: Klinefelter’s and Turner’s syndrome, as well as other forms) is that the sex drive is typically rather low. The maternal testosterone factor in homosexuality lends itself to a number of research questions which would make for fine PhD theses: 1) does heroin or alcohol consumption deplete testosterone in pregnant women, and do these women have more homosexual male offspring than normal ?, 2) do fraternal and/or identical male twins receive reduced maternal testosterone, and are they more frequently homosexual than non twin progeny ? 3) are mothers who give up their babies for adoption more stressed, are they testosterone depleted, and do their male offspring become more often homosexual ? 4) are mothers with naturally or disease-related testosterone insufficiency during pregnancy more likely to have male offspring who become homosexual ?

Testosterone cannot directly determine sexual orientation, of course. Testosterone is just a stupid hormone. Sexual orientation comes from the activity of neurons in the brain. The reader might recall my having mentioned that testosterone is a dopamine agonist and that estrogen is a serotonin agonist. It has been found recently that the female adult rat can be masculinized in her sexual behavior by a dopamine agonist or by a serotonin antagonist. Furthermore, a male rat can be partially feminized in its sexual behavior by castration just after birth. Now the sexual brain machinery of a rat is far more simple and stereotyped than is that of a human, and I doubt very much that manipulations of serotonin or dopamine would have a similar effect in humans. Nevertheless, this piece of evidence fits in nicely with the rest of the neurobiological explorations of gender differences we have made in this book, and it points in the general direction of the future: we need to build a neurophysiology of sexual orientation and of sexual identity.