Chris Cooper PhD

Origins of Sexual Orientation II – Biological Views

This is part of a paper written in 1992, and discusses research reported up to 1992 pertaining to why people experience same-gender or different-gender attraction. An up-date (1993-present) is in process. See also “Origins of Sexual Orientation I – Historical Overview,” “Origins of Sexual Orientation – Psychological and Sociological Views” and “Origins of Sexual Orientation – Synthesis”

BIOLOGICAL RESEARCH AND VIEWS REGARDING THE ORIGIN OF SEXUAL ORIENTATION

Theories about the biological origins of sexual orientation fall into four categories. First are the human family and twin studies which look at the genetic/heritable components of sexual orientation. Second are the physiological/functional studies that look primarily at the human endocrine system, which are subdivided into studies of adult hormone levels and studies of perinatal hormone environments and their effect on the developing embryo or fetus. The third type of study concerns structural differences in the human brain that might co-occur with or be causally associated with different sexual orientations. Finally, there numerous studies which look at non-human development by manipulating hormonal levels both perinatally and in adult animals with the goal of bringing about changes in sexual behavior. A number of these non-human studies are reviewed elsewhere (Ellis and Ames, 1987; Feder, 1984; Money, 1988). This paper will focus on the first three types of investigation. Although a more current review of animal studies would be a welcome contribution to the literature, such a review is outside the scope of this paper which will discuss animal studies only as they relate to the generation of hypotheses in human studies.

HERITABLITY: GENETIC RESEARCH

One of the most obvious questions to ask about sexual orientation (like many other things) is: Does it run in families? And if so, is there a heritable genetic component or is it the family environment that is the determining factor? Researchers have addressed this question by studying the occurrence of different sexual orientations in families, and by looking at monozygotic (MZ) and dizygotic (DZ) twins.

Family Studies
The familial relationship of sexual orientation was examined by Pillard and colleagues (Pillard, Poumadere and Carretta, 1981) who looked at 36 gay males and 80 of their siblings. They found 10 of 45 brothers to also be gay, while only one of 35 sisters was lesbian, suggesting that homosexuality runs in families for men, but not women. In a family study done by Pillard and Weinrich (1986) 101 unmarried men responded to newspaper ads for a study of “personality, sexual behavior and mental abilities.” These men had 238 siblings of whom 176 (74%), including half siblings and adopted siblings, participated. No association was found between sexual orientation of index males and their sisters. In fact there was a trend towards heterosexual men having more lesbian sisters than homosexual men. There was, however, a significant association between sexual orientation of index men and their brothers, with 22% of the brothers of homosexual men also being homosexual. Eliminating adopted or half siblings from the analysis did not change the results. These results are similar to those of Bailey and Pillard (1991) who found that 21% of the brothers of non-heterosexual males were also non-heterosexual, while only 4% of the brothers of heterosexual males were non-heterosexual.

A familial effect was also shown by Buhrich, Bailey and Martin (1991) in their univariate analysis of data on 161 MZ and DZ twin pairs. It appears from this work that male homosexuality runs in families (but not lesbianism). However, it has not been determined whether the factor involved is genetic or environmental, and the possible effect of self-selection of subjects into the studies had not been investigated.

Twin Studies
Twin studies are of two types. The first includes those which deal with only one twin pair–usually discordant for sexual orientation–in an attempt to discover what environmental differences might account for the difference in sexual orientation in genetically identical people. These are rather anecdotal in nature and shed little light on the genetic aspects of sexual orientation. The second type of study looks at a number of pairs of MZ and/or DZ twins to see how many are concordant and discordant for sexual orientation and thus come to some conclusion about the extent to which sexual orientation is genetically determined.

Single Pair Studies
One of the first approaches taken was to examine the gross structure of chromosomes of people with different sexual orientations. This was suggested by the theorizing of Hirschfeld (1948) and Kallman (1952a, 1952b) who proposed that homosexual men might be a third sex or intersex having only one sex chromosome (X_). As soon as people were able to look at karyotypes it was apparent that this was not the case, however, there might be some sort of structural difference between the X or Y chromosomes of heterosexual and non-heterosexual people. To test this, Perkins (1973) looked at the karyotypes of a pair of MZ lesbian twins and found that they both had normal-appearing sex chromosomes.

Later studies focused not on the visible structure of chromosomes, but on biochemical products several steps removed from the chromosomes themselves. For example, Friedman, Wollesen and Tendler (1976) looked at adult levels of testosterone, estradiol and androstenedione in one pair of male MZ twins discordant for sexual orientation and found no differences. Two other studies have looked at single pairs of male MZ twins discordant for sexual orientation with the conclusion that although the twins are genetically identical they are not biologically identical (MacCulloch, 1980; Zuger, 1976). In other words, the genetic blueprints may be the same, but gene expression may be different for the two twins, resulting in different biological constitutions. Zuger pointed out that his pair of twins suffered from different medical problems and must,therefore, be biologically different. MacCulloch believed that because the homosexual member of his twin pair was completely resistant to conversion therapy, he must be “innately” homosexual. Further, because the twins were discordant for sexual orientation, the “innateness” must not be genetic, but biological. Both researchers postulated that biological differences were the result of different in utero environments causing different gene expression and thus biological differences. This view is further explicated by McConaghy and Blaszczynski (1991) who studied the sexual responses of one pair of male MZ twins to films of nude males and females by measuring changes in penile volume. Having concluded that these twins were actually discordant for sexual orientation, these authors then speculated that the discordance might be have been due to different environments in utero. For example, one twin might be more crowded than the other. Or, because they share the same placenta, placental blood vessels could become anastomosed shunting blood from one twin to the other resulting in significant developmental differences (Moore, 1973).

Groups of Twins
The first efforts to look at a number of twin pairs were done with small numbers of male twins, and generally showed more concordance for sexual orientation among MZ than DZ twins (Eckert, Bouchard, Bohlen and Heston, 1986; Heston and Shields, 1968). A summary of the results of studies reviewed in this paper is shown in Table 1.
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see Table 1 (to be inserted here)
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The largest concordance between MZ twins was found by Kallman (1952a; 1952b) who demonstrated nearly 100% concordance for homosexuality in 40 pairs of MZ twins. Other researchers have found rates of concordance for homosexuality in males to be in the range of 40% to 50% for MZ twins, and between 14% and 22% for DZ twins. Kallman himself (1952b) pointed out that because of his topic and the existing social/political climate, subject selection was a concern. Current researchers agree that Kallman’s concordance rate for MZ twins is artificially high–possibly because of selection of subjects from a heavily homosexual area of New York resulting in a sample that did not represent the general population (for example, Bailey and Pillard, 1991). Heston and Shields’ (1968) study also suffers from subject selection difficulties. Their twins were identified from the twin register of the Psychiatric Genetics Research Unit of a London hospital. All admissions to the inpatient and outpatient services of the hospital were asked if they were members of a twin pair. If so, they were added to this register. At the time of the Heston and Shields study there were five male MZ twins in the register who also said they were homosexual in orientation. Of the five pairs, two were clearly concordant for homosexual orientation.

Another aspect of subject selection bias has to do with an increased willingness of twin pairs who are more alike to take part in research studies. It has been shown that if there are differences between twins on certain traits such as IQ and social skills, the formal comparison portended by participation in the research is a deterrent to those twins to participate (Lykken, McGue and Tellegen, 1987). This greater willingness to participate of twins who are more alike results in artificially high concordance rates, with DZ twins showing a larger effect than MZ twins. Along with subject selection, the small numbers of subjects have been a concern in this research. Bailey and Pillard (1991) have attempted to deal with both problems by recruiting a large number of twins (56 MZ and 54 DZ) with newspaper advertisements in several cities in the Midwest and Southwest United States. Their results are not enormously different from preceding studies, with 52% of MZ twins and 14% of DZ twins concordant for homosexual orientation. However, because of the larger number of subjects and recruitment from non-hospital settings located away from major centers of gay social life, their research makes these numbers much more convincing.

There are, however, still a number of problems with this research. For example, one cannot conclude much from the MZ to DZ concordance ratio because there is no clear idea of the base rate of various sexual orientations (see Kendler, 1989). In addition, some assumptions are made in twin studies that should be viewed with caution. First, as pointed out in some of the single pair studies, MZ twins may share the same genome, but genes may be expressed differently in response to different environments. A rather gross example might be taken from another area of biology (visual perception) where it has been shown that animals brought up in rooms with only horizontal lines to look at do not develop the neural circuitry to process and interpret vertical lines – although they have the genetic makeup to do so (Black and Greenough, 1986; Kandel and Schwartz, 1985). Such an animal’s MZ twin who peaked out the window would have a markedly different phenotypic development. There is no reason why the same kind of thing could not happen with other developmental processes. Second, it is invariably stated that DZ twins share half their genome. This is true on average for a very large number of DZ twins, but any given pair of DZ twins may share virtually all or virtually no genes. In twin studies that look at two or five or even fifty DZ twins, interpretations based on the half-genome idea should be made very cautiously. Finally, Bailey and Pillard state that their twins, because they were reared together were “all perfectly correlated for shared environment” (Bailey and Pillard, 1991, p. 1093). It seems patently obvious that no two people have exactly the same environments — different events occur in their lives, different people interact with them, the same people interact with them in different ways, and they interact with each other. Still, concordance is there, and the next question is whether the concordance that is present is genetically based, or whether it is due to similarities in environment or some effect of being part of a twin pair.

An attempt to answer this question was made by Eckert, Bouchard, Bohlen and Heston (1986) who looked at twins who were separated in infancy and raised apart. These researchers found 50% concordance in homosexual male twins, however they looked at only 2 pairs. This concordance rate is certainly similar to other findings, and suggests that the concordance is due to genetic factors, however, it would be far more convincing if a larger study showed the same result. The Eckert et al. paper addresses another interesting question: Is the genetic component as influential in women as it seems to be in men? Most studies of possible genetic factors in the determination of sexual orientation have focused on men and for that reason (a) we do not know much about the situation with women and (b) researchers tend to go on studying men (see Bailey and Pillard, 1991). Eckert et al. did, however, include three lesbian twins and one female bisexual twin in their study, and found that the cotwins were all heterosexual. Their conclusion was that genetic factors are implicated in the development of sexual orientation in men, but not in women. Researchers (Eckert et al., 1986; Bailey and Pillard, 1991) point out that the difference in results for male and female twins would be consistent with neuroendocrine theories of the development of sexual morphology and orientation in which male but not female development depends on the fetal hormonal environment which would be determined genetically (see the section on Neuroendocrine Research below).

Summary: Heritability and Genetic Research
It appears that male homosexuality runs in families (but not lesbianism). No conclusion can be drawn from family studies about whether the familiality is genetic or environmental. Twin studies, subject selection and methodological difficulties notwithstanding, demonstrate more concordance for sexual orientation in male MZ twins than DZ twins and that the MZ concordance is between 40 to 50%. Concordance among male DZ twins is at the level of 15 to 25%. In addition, it appears that genetic factors are implicated in the sexual orientation of men, but not–or not to any great extent–in women.

NEUROENDOCRINE RESEARCH
Functional (physiologic) studies of the neuroendocrine aspects of development of sexual orientation have focused on three areas. First, the levels of circulating hormones in adults. Second, the effects of various levels of hormones on the developing embryo or fetus in utero resulting in functional changes in the brain. Third, anatomical studies of structural brain differences (which might be caused by endocrine action). These three categories of research are described in the next sections.

Adult Circulating Hormones (Women)
Recently, a carefully designed and controlled study done by Dancey (1990) showed no difference between lesbian and heterosexual women or between different groups of lesbian women. Subjects were 40 unmarried women. Thirty of these indicated that their primary emotional and sexual attractions were fulfilled by women. Within the group of 30, 10 (group 1) had no heterosexual experience and had a low score (below 20) on the heterosexual component of the Sexual Orientation Method questionnaire (SOM; Sambrooks and MacCulloch, 1973); 10 (group 2 ) had prior heterosexual experience, but a score below 20 on the SOM, and 10 (group 3) had both prior heterosexual experience and a score above 20 on the SOM. The final 10 participants (group 4) identified themselves as heterosexual and scored above 20 on the SOM. Age, levels of stress, and timing during the menstrual cycle were all taken into consideration. Blood sample were assayed to determine the levels of circulating testosterone, androstenedione, estrogen, LH, FSH, cortisol and progesterone. In addition the testosterone to progesterone (T/P) ratio was computed. Univariate analysis of variance on data and on logrithmically transformed data resulted in no significant differences in any of the hormone concentrations or the T/P ratio between any of the groups. The author’s conclusion that there are no significant differences in blood plasma concentrations of these hormones between lesbian and heterosexual women or between different groups of lesbian women appears to be well founded.

In addition, even in the studies in which lesbian women were found to have higher concentrations of male hormones than comparison groups, this concentration was still within clinically normal limits for women (Gladue, 1987). Observation of situations where women are subjected to very high or very low levels of testosterone (for example, hormone treatment for certain types of cancers or adrenalectomy) have demonstrated that the level of the sex drive is affected, but not object choice (Meyer-Bahlburg, 1979), and there are also indications that circulating levels of androgens in women may be associated with occupation. The latter has been seen as a possible confound because lesbian women are more likely to be “career women” than their heterosexual counterparts (Gladue, 1987).

Summary: Neuroendocrine Studies of Women
There is, overall, no compelling evidence for differences between lesbian and heterosexual women or different groups of lesbian women in terms of blood plasma or urinary concentrations of hormones including testosterone, estrogens, progesterone, LH and FSH. Although there are some studies which do show differences, these have serious methodological problems and efforts to replicate them have failed. Finally, observations of women with unusually high or low concentrations of circulating androgens demonstrate changes in level of sex drive, but not changes in object choice.

Adult Circulating Hormones (Men)
It has also been proposed that there may be differences in levels of circulating hormones (for example, testosterone) and gonadotrophins (for example, LH and FSH) in adult gay men. Meyer-Bahlburg (1982) reviewed 24 studies published between 1971 and 1981. Four of these showed lower mean testosterone levels for gay men than heterosexual men, 18 showed no differences in testosterone level, and two showed elevated testosterone levels in the gay men.

Fifteen studies of gonadotrophin levels failed to show any differences. The reasonable conclusion drawn by Meyer-Bahlburg was that sexual orientation in males is not associated with levels of circulating hormones which differ from those found in heterosexual men. Additionally, Meyer-Bahlburg comments that attempts at finding hormonal differences in effeminate versus masculine homosexuals or between men taking on “active” and “passive” sexual roles have failed.

A 1987 review by Gladue (1987) describes one additional study finding lower testosterone levels in gay men and two additional studies showing no differences in adult hormone levels between heterosexual and gay men. Gladue, like Meyer-Bahlburg, concludes that it is “highly unlikely” that adult variations in testosterone concentration or estrogen concentration cause homosexuality in males.

Fetal Environment
Based on clinical observation and animal research, many authors have proposed that the level of exposure to certain hormones (most notably testosterone or estrogens) at a critical time in fetal development causes a somatically based change in adult affectional preference and partner choice (Bailey and Pillard, 1991; Dorner, 1975; Gladue, 1987; Hendricks, Graber and Rodriguez-Sierra, 1989; MacCulloch, 1980; Meyer-Bahlburg, 1982; Money, 1988). Theories are based on the fact that a human fetus will, with no hormonal intervention, develop into a female. If, at approximately 45 days of gestation (6-7 weeks), the embryo is exposed to H-Y antigen (a Y-chromosome gene product) differentiation of the testes commences. After differentiation of testicular cells capable of secreting androgens, male morphology begins to develop (approximately 9 weeks). Peak concentrations of fetal testosterone are reached at approximately 16 weeks and are comparable to levels in the adult male (Wilson and Foster, 1985). This fetal testosterone is hypothesized to interact with the brain causing male-typical or female-typical behaviors in adulthood. Among these behaviors are sexual partner selection.

The earliest studies of hormone concentrations in lesbian and heterosexual women reported significant hormonal differences. Two papers by Loraine and colleagues (Loraine, Ismail, Adamopoulos, and Dove, 1970; Loraine, Adamopoulos, Kirkham, Ismail, and Dove, 1971) reported on one study of circulating hormone concentrations in two lesbian couples as compared to hormone levels in an unspecified number of members of the research staff who “admitted no homosexual behavior.” Hormone levels were assayed using urinary excretion rates and the concentration found for each of the lesbian women was compared to the mean concentration for the comparison group. Elevated levels of testosterone and low levels of estrogen were found for all four lesbian women. Assays were also done for epitestosterone, pregnanediol, estrone, estradiol follicle simulating hormone (FSH) and luteinizing hormone (LH). A significantly low level of estradiol and elevated level of LH was found in two of the lesbian women (p < .05). In all other cases a significant difference was found in only one of the four lesbian women. The conclusion of the authors was that a significant difference existed in levels of adult circulating hormones between lesbian and heterosexual women. It is important to note that analyses compared each of the assay measures of each lesbian to an average value for the comparison group. This would mean 32 separate tests of significance (test unspecified) on eight measures for the four women. In addition, the authors state that three of the four lesbian women had a history of irregular menstrual cycles–which could have an important effect on hormone levels. Timing within the menstrual cycle was apparently not taken into consideration. The authors’ conclusion that all of these women show hormonal abnormalities is, therefore, not convincing.

Significant differences between blood plasma testosterone levels in heterosexual and lesbian women were found by Gartrell and colleagues (Gartrell, Loriaux, and Chase, 1977), with the lesbian women having levels 38% higher. Women were about the same age and in good health. Blood samples were taken on the first, second and third days of each woman’s menstrual cycle.

A review by Meyer-Bahlburg (1979) concluded that information about circulating hormone levels in adult women was inconsistent, with approximately two-thirds of the lesbian subjects in such studies showing no differences from heterosexual women, and one-third showing significant differences. Among the one-third of subjects showing hormonal differences (especially elevated testosterone levels), researchers included a number of female-to-male transsexuals. These could easily confound results both in having different somatic and psychological development from lesbian women and because these transsexuals would have been treated with quantities of male hormones in the process of the sex change. Reviewers, at this point, suggested that carefully controlled studies designed to replicate results were needed (Gladue, 1987; Meyer-Bahlburg, 1979).

To this end a study was designed to replicate the Gartrell et al. results while controlling for additional important factors, and failed to find any differences in levels of the hormones between lesbian and heterosexual women (Downey, Ehrhardt, Schiffman, Dyrenfurth, and Becker, 1987). In this study levels of testosterone, androstenedione and cortisol were measured in six lesbian and six heterosexual women. The authors reported finding no significant differences and no trend towards a difference between the two groups. Although the sample was small, the authors believe that the results represent the actual situation. The difference between these findings and those of Gartrell and her colleagues was attributed to changes in the experimental design that controlled for sexual activity, stress, depression, level of physical activity, and anxiety.

There are three ways in which it has been suggested that this might happen. First, is the proposal that there are two separate brain structures one of which is “feminine” and the other “masculine.” Exposure to testosterone would cause the de-feminization of the feminine center and further masculinization of the masculine center. Conversely, under the right conditions, the feminine structure could be further feminized and the masculine structure de-masculinized resulting in feminized behavior. Bisexuality would be associated with incomplete hormonal effects leaving an equal balance of masculine and feminine brain structure (Ellis and Ames, 1987; Money, 1988). Specific centers have been identified in rodents and are the ventromedial nucleus (female sexual behavior center), and the medial preoptic nucleus and anterior hypothalamus (male sexual behavior center) (Meyer-Bahlburg, 1982). These brain centers have been hypothesized to have similar functions and developmental histories in humans. Behaviorally, Pillard and Weinrich (described in Pillard, 1991) have observed that behavior patterns of gay men may be more feminine, but no less masculine that their heterosexual counterparts, while lesbian women tend to be more masculine while no less feminine than their heterosexual counterparts. It can be argued that this is simply a matter of social learning, or interpreted (as Pillard does) as further evidence for differential activation of a pair of brain centers (masculine and feminine).

The second possibility is that there is one brain center which, in undifferentiated form, is “feminine.” Presence of testosterone causes a differentiation to a “masculine” form (Gladue, 1987; MacCulloch and Waddington, 1981). The third supposes a “feminine” brain center which under the influence of testosterone becomes significantly larger (and thus masculinized) (LeVay,1991; Swaab and Hofman, 1988). These theories imply a physiological or functional difference in the hypothalamus or pituitary associated with different sexual orientations.

Another finding in rodents is that perinatal treatment with androgen suppresses the cycling behavior of the hypothalamic/pituitary axis. In females, the pituitary secretes its gonad-stimulating hormones (FSH and LH) in a cyclic pattern, with secretion of LH occurring in response to signals from the hypothalamus which monitors hormone concentrations in the blood and responds to high concentrations of estrogens. The cyclic nature of the hypothalamus/pituitary response is directly responsible for the menstrual cycle. In rats, exposure to testosterone shortly after birth suppresses this cycling resulting in (1) a hypothalamus which is insensitive to blood concentrations of estrogens, and (2) a pituitary which secrets a constant amount of LH. It has been proposed that this is the case in humans, too, and therefore low levels of testosterone at the time the human brain is differentiating (pre-natally) would result in a non-masculinized hypothalamic/pituitary response (Gladue, 1987). Studies investigating this hypothesis were first undertaken by a controversial German researcher, Dorner, who claimed to find that some gay men show pituitary responses to estrogen resulting in the secretion of LH (Dorner, Rohde, Stahl, Krell and Masius, 1975). The strength of these findings and the quality of this research have been sharply criticized by Sigusch, Schorsch, Dannecker and Schmidt (1982) as official representatives of the German Society for Sex Research. A In addition, Dorner’s findings are reviewed by Meyer-Bahlburg (1982) who points out that Dorner’s sample included transsexuals as well as gay men and suggests that replication is necessary. Meyer-Bahlburg (1982) states that there is strong evidence that human and primate brains do not differentiate in response to pre-natal hormones but respond to sex hormone levels in adulthood. Gladue, however, reports that studies in his laboratory have shown that “lifelong homosexual men” show an LH responding pattern intermediate to that of “most heterosexual men and women” (Gladue, 1987, p. 137).

A study done in 1989 by Hendricks, Graber and Rodriguez-Sierra again tested the cycling pituitary in 16 gay men and 39 heterosexual men. These researchers found no differences between the two groups with both groups responding to the estrogen with secretion of LH. These researchers did find some differences in testosterone production in response to the LH secretion, with the gay men showing less responsiveness. They believe that this was because of stress caused by the procedure used in the experiment which involved hospital visits for vienupunctures used to introduce estrogen and withdraw blood for sampling. The heterosexual males were medical students and hospital staff members who were used to the environment and the procedures, whereas the gay men were not associated with the hospital and appeared to be stressed.

As previously stated, it is not the pituitary itself which determines secretory cycling and responses to estrogen, but the hypothalamus which stimulates (or doesn’t) the pituitary. In humans there is no convincing evidence of masculinization of the hypothalamus. In addition, human females who are exposed to high levels of androgen because of congenital adrenal hyperplasia do not develop masculinized brains and do cycle normally. Further, the current consensus is that, unlike the case with laboratory rats, estrogen administered to human males (both homosexual and heterosexual) does produce a surge in LH secretion (Wilson and Foster, 1985).

Human Models
In order to test the fetal environment hypothesis, an effort has been made to study humans in whom the fetal environment differed measurably from the norm. Three situations have emerged: (1) cases in which the mother was highly stressed during pregnancy thus lowering her androgen production, (2) cases in which mothers were treated with diethylstilbestrol (DES) in order to maintain the pregnancy, and (3) congenital endocrine disorders of the fetus which would lead to unusual endocrine environments.

Stressed Mothers
Research on children of mothers who were stressed during pregnancy is described by Bailey and colleagues (Bailey, Wellerman, and Parks, 1991). Stressed mothers presumably have a reduced capacity to produce androgens. The lowered androgen concentration would then be associated with incomplete masculinization of the fetal brain in male children, thus leading to a homosexual orientation. Up to 1991 there were two published studies reporting that gay men were more likely to have mothers who had been stressed during pregnancy (Dorner, Schenk, Schmiedel, and Ahrens, 1983; Ellis, Ames, Peckham, and Burke, 1988). One of these (Dorner et al., 1983), based its conclusions on sons’ reports of how stressed their mothers had been during pregnancy. In his discussion, Dorner observed that 73% of the prenatal stressful events were related to war or unwanted pregnancy. Therefore, he concluded, war and unwanted pregnancy should be prevented as a way of reducing the number of (or eliminating) homosexual men. This research has been called into serious question methodologically because of the unreliability of sons’ reports of their mothers’ mental state before they were born (Feder, 1984). The Ellis et al. (1988) study was an attempt to reproduce Dorner’s work without this major methodological problem. Two hundred eighty-five women were asked about the number and severity of stressors they experienced during a period from 12 months prior to their pregnancies to parturition. The mothers of gay men reported fewer stressors during this period. However, when stressors were weighted for severity, mothers of gay men reported the highest levels of stress, with the second trimester being the significant time. No maternal stress effect was found for lesbian women.

Two other studies were described at conferences and are cited by Bailey et al. (Schmidt and Clement, 1988 in Bailey et al., 1991; Wille, Borchers and Schultz, 1987 in Bailey et al., 1991). These reported no association between maternal stress and sexual orientation. Bailey et al. did their own study of 116 non-heterosexual men, 25 non-heterosexual women, 84 heterosexual men and 72 heterosexual women. (Bailey et al., 1991) and found no association between maternal stress and sexual orientation in the men. They did, however find an association in the women. These results are perplexing because there is no theoretical mechanism by which low maternal androgens could be expected to influence female sexual morphology or orientation. Further, it has been established that fetal development depends on androgen secreted by the fetal testes and that this secretion provides a blood concentration of testosterone that is equivalent to that in an adult male (Wilson and Foster, 1985). It is hard, therefore, to imagine why a lowering of maternal androgen would have any effect on a typical fetus.

Hormonal Treatment of Pregnant Women (DES)
Treatment of pregnant women with DES is proposed to have a masculinizing effect on female offspring. This might occur because DES, unlike naturally occurring estrogens is not bound by a carrier protein in the blood. The carrier proteins normally protect the fetus from maternal estrogens. Estrogen allowed to enter the fetal brain is converted to testosterone and can then have a masculinizing effect (Ehrhardt, Meyer-Bahlburg, Rosen, Feldman, Veridiano, Zimmerman, and McEwen, 1985; Gladue, 1987).

One study of 30 women whose mothers took DES during their pregnancies showed them to have more life-long lesbian or bisexual erotic responses than non-DES sibling controls and non-DES, unrelated controls. (Ehrhardt et al., 1985). The authors warn that the study suffers from considerable potential sampling bias and methodological problems and should be interpreted with extreme caution. In addition, they point out that although the DES-exposed women showed more homoerotic behavior and interest, 75% of these women were exclusively or almost exclusively heterosexual and that only one of the 30 was exclusively lesbian. In addition, these women, because of subject selection, are part of a group that would have been exposed to the highest levels of DES over the longest period of time. This indicates that if prenatal exposure to DES as a masculinizing agent does affect adult sexual orientation in women, the effect must be very small and it must be only one of many factors that do so.

Endocrine Disorders
Since humans cannot be manipulated experimentally, researchers in this field have looked carefully at congenital endocrine abnormalities which cause variations in fetal hormonal environment. These looks have generated as much controversy as insight. Some are described below.

Androgen insensitivity syndrome is a condition in which the fetus has a normal hormonal environment, but the fetal cells are unable to respond to the presence of testosterone or other androgens. This is a problem for genetic males only. Boys having this condition have abnormal development of genitalia which are female in appearance, but which are corrected by surgery shortly after birth. These children may be raised as boys or girls, and are usually heterosexual in relation to the gender in which they have been raised (Gladue, 1987). Some authors conclude that the orientation towards men is because the androgens were not able to masculinize the brain (Ellis and Ames, 1987), others see this as evidence that social roles and social learning are primary in determining sexual orientation (Feder, 1984).

5-alpha-reductase deficiency is a deficiency of an enzyme which mediates the intracellular conversion of testosterone to its more potent analog, dihydrotestosterone (DHT). DHT is known to be important in the differentiation of male genital structures. Ellis and Ames (1987) state further that it is not much involved in brain differentiation. Wilson and Foster (1985) are in agreement with this analysis, but add that the extent to which any androgen (dihydrotestosterone or testosterone) is involved in brain differentiation and sexual behavior is not established. (Wilson and Foster, 1985, p. 272). Boys who do have this deficiency grow to puberty with genitalia that are female in appearance and they are often raised as girls. At puberty, the high concentrations of testosterone secreted cause masculinization of the genitalia. The boys subsequently adopt a male identity and are usually heterosexual with regard to that adult identity. Ellis and Ames interpret this as evidence that the brain was appropriately masculinized. Others point out that in the culture in which these males were identified (the Dominican Republic) they had been stigmatized from birth. Normal male development at puberty would have released them from that stigma and they might then have chosen to continue life as “normal” males in a culture that valued males more highly than females and which had no place for either women who were unable to bear children or gay men (Hoult, 1984; Money, 1988).

Faulty testosterone biosynthesis is cited by Ellis and Ames (1987) as a problem with the potential to cause sexual “inversion.” Biosynthesis of testosterone is mediated by a number of enzymes, and mutations which affect any of the enzymes could cause complete failure to produce testosterone or production at a lower than normal concentration. Ellis and Ames assure us that “although reports of neurological, and thereby behavioral, inversions associated with faulty testosterone biosynthesis were not found, there is every reason to expect that they will be found” (Ellis and Ames, 1987, p. 247). This is hardly convincing until effects are found.

Congenital adrenal hyperplasia (CAH) is a condition in which the adrenal glands produce excess quantities of androgens. This is a problem for genetic females who are born with masculinized genitalia which are corrected with surgery shortly after birth and again in adolescence (Migeon and Donohoue, 1991). Most of these girls are heterosexual in adulthood, but there is some evidence that there is a higher than usual prevalence of bisexual activity and fantasy among these women (Gladue, 1987; Migeon and Donohoue, 1991) and that they are more aggressive and involved with sports than other girls (Ellis and Ames, 1987; Feder, 1984).

Endocrine Disorders: Conclusions. Ellis and Ames (1987) cite other examples of anatomical and behavioral “inversions,” however many of the same objections can be made to their exclusively biological conclusions. In some cases, there is something morphologically wrong with the children born with these syndromes which necessitates surgery and which guarantees that the child will be treated differently from children who had uneventful births. In other cases, the situation arose as a response to an important event. For example, a case in which a mother, about to lose her child via spontaneous abortion, elects to be treated with a drug like DES. This could have an effect on how the mother or parents view the pregnancy and how she or they treat the child once born. In addition, the connection between “masculinization” or “feminization” and sexual orientation has not been clearly made. Storms (1980) found no differences in masculine and feminine behaviors between groups of homosexual and heterosexual women or homosexual and heterosexual men, and concluded that whatever produces sexual orientation, it is a different process from that which causes masculine and feminine behaviors.

Summary: Neuroendocrine Research
Some researchers have concluded that neuroendocrine processes are the primary ones involved in the determination of adult sexual orientation. Ellis and Ames have concluded that “hormonal and neurological variables, operating during human gestation, are the main determinants of sexual orientation” (Ellis and Ames, 1987, p. 235). These authors concede that experiential and social variables can be important in cases where individuals have been exposed to intermediate levels of prenatal hormones, however, they believe that very extraordinary postnatal experiences would be required to change the innate disposition to one sexual orientation or another. This seems an extreme position.

Most authors believe that prenatal hormone concentrations may have some significant part to play in the development of sexual orientation, but are not the sole determining factor (see Feder, 1984; Friedman, 1988). In addition, the role played by neuroendocrine factors is seen to be more significant in males than in females.

NEUROANATOMICAL RESEARCH
Brain structural differences that have been implicated with sexual orientation include the extent of brain lateralization and structural changes in the hypothalamus or pituitary.

Lateralization
Recently claims have been made that there are significant differences in brain lateralization between heterosexual and homosexual people. McCormick and colleagues did a study of hand preference in 32 lesbian women and 38 gay men in which they used a 12-item measure of hand preference (Annett Hand Preference Questionnaire, Annett, 1970), to determine “non-consistent right hand use” (McCormick, Witelson and Kingstone, 1990). They concluded that more gay men and lesbian women show a left hand preference than the general population, and that this is indicative of a more strongly lateralized brain in homosexual men and women than in their heterosexual counterparts. They further suggest that neural tissue is more sensitive to perinatal hormones than other tissue, thus allowing for differences in brain development mediated by perinatal hormones that would not be accompanied by any visible anatomical changes. There would, then, be an association among pre-natal exposure to higher than normal levels of androgens, left-handedness, and homosexual orientation in both men and women.

In this study when the criterion used for handedness was the hand used for writing, no differences were seen between lesbian women and the general population. If, however, non-right hand preference on any one of the 12 items of the questionnaire was the criterion, a significant difference was found between lesbian women and the general population. There are two problems here. First, McCormick’s use of the terms “left-handedness” and “left-hand preference” seems misleading given that a person needed to score a left-hand preference for only one of 12 tasks to qualify. Second, Annett (1970) states that three of the 12 items on the questionnaire (left-handed sweeping, shoveling, or threading a needle) “… when they are the only left preferences reported, do not indicate tendencies toward greater skill with the left hand and for most purposes these actions can be ignored” (p. 317). Annett postulates that right- and left-handedness occurs on a continuum, as does brain lateralization. If differences in brain lateralization are shown by the McCormick et al. data, they appear to be very small, indeed.

In another study, McCormick and Witelson postulate that cognitive differences exist between homosexual and heterosexual men and that these are indicative of differences in brain development and structure (McCormick and Witelson, 1991). Measures of spatial ability and verbal fluency were used as indicators reflecting underlying differences in cerebral lateralization caused by perinatal hormone exposure. This lateralization presumably involves structural differences in male-type and female-type brains. Findings supported their hypothesis that gay men would score lower on tests of spatial ability than heterosexual men. No significant differences were found between homosexual and heterosexual men on the tests of verbal fluency. The authors interpreted the results to demonstrate that there is a brain structural difference (“neurobiological component”) associated with male homosexuality and that this difference is brought about by exposure to lower than normal androgens during fetal development.

There are two questionable assumptions involved in this conclusion. First, the connection between perinatal hormonal environment, adult brain structure, and adult sexual behavior has not been unequivocally made (see sections on Fetal Environment and Generalization from Non-Humans to Humans). Second, the use of spatial ability and verbal fluency measures presumes (a) that these abilities genuinely differ between males and females, and (b) that the difference between male and female performance on these tasks is biological, not learned. To support this view, McCormick and Witelson cite the review by Maccoby and Jacklin (1974). Research subsequent to this review indicates that the finding that there are pervasive differences between males and females in these abilities is not supported, and that the differences that are seen are more likely due to learning or psychological factors than biology (Deaux, 1985; Tavris, 1991). Support for this latter conclusion comes from cross-cultural work (Fleming, 1985-1986) and from a number of other studies showing performance to be related to how well the person expects to perform (Meehan and Overton, 1986), whether the person views him- or herself as masculine or feminine (Jamison and Signorella, 1987), and the amount of gender stereotyping the person has encountered and incorporated (Signorella, Jamison and Krupa, 1989). It has also been suggested that spatial and verbal abilities are learned and that the differences between males and females may have been influenced by school curricula that put boys into mechanical drawing and shop while the girls were in home economics classes. As school curricula are changing, so is the difference between males and females on tasks of spatial ability (Reesink, 1985). A similar closure in the male/female difference in verbal ability is seen by Hyde and Lynn (1988) in their meta-analysis of 167 studies. These studies included those reviewed by Maccoby and Jacklin (1974) and more current ones (1973 to 1986). There remain some who claim that verbal and spatial differences between males and females are reflections of brain differences (Holden, 1991), however, there is convincing evidence that these abilities are learned and that the gap is narrowing.

Hypothalamic Structure
Interest in comparing the sizes of brain structure between males and females and between homosexual and heterosexual people was spurred by the discovery that the medial preoptic nucleus (MPON) in the male rat is significantly larger than it is in the female rat (Gorski, Gordon, Shryne and Southam, 1978). These researchers also showed that the increased size of the male MPON was associated with perinatal hormonal environment. A search began to find a “sexually dimorphic nucleus” (SDN) in the human hypothalamus. Swaab and Hofman (1988) performed autopsy studies on brains of 104 subjects whose ages ranged from 22 weeks after conception to 93 years. Forty-two male and 38 female subjects had no neurological disease. The remaining subjects had a number of neurological diseases including Dementia of the Alzheimer’s type (4 men, 7 women), pituitary aplasia (1 female neonate), AIDS (9 gay men) and Prader-Will syndrome (1 woman). In addition, 2 subjects were male to female transsexuals. Size of the nucleus was measured both in terms of volume and cell number which were directly proportional. They found that the nucleus is of equal size in males and females prenatally and at birth. The cell number proliferates until age 2-4 and until this age the number is the same in males and females. At age 2-4 there is a decrease in the number of cells in the female with the result that the adult male has a SDN approximately 2.5 times as large as that of the female. The cell number in homosexual men did not differ from that of the other men. The implications of this research are twofold: (1) there is no support here for the notion that the brain is feminized or masculinized by hormones perinatally, and (2) male homosexuals do not differ from other males in SDN brain structure. Subject selection is a concern in this research because homosexual subjects were AIDS patients and because there is no way of knowing the sexual orientation of the men in the comparison group. Interestingly, this picture differs from other descriptions of biological development in which the female is the default with male development requiring an active process acting on this default plan. In this case it appears that the active process (elimination of brain cells) belongs to the female. In any case, this says little about differences between people of different sexual orientations, and although the authors were looking for such differences, there is nothing to implicate this brain area in sexual behavior (Gibbons, 1991).

In the course of looking at size difference in another brain nucleus (the Suprachiasmic Nucleus; SCN) in dementia patients, Swaab and Hofman (1990) did, if somewhat serendipitously, discover a size difference between heterosexual and homosexual men. Although the ranges overlapped considerably, the SCN of gay men on average was 1.73 times larger than that of a reference group of men presumed to be heterosexual. Two cautions are in order. First, the large overlap means that some gay men had smaller SCNs than the presumed heterosexuals and some gay men had larger SCNs than the presumed heterosexual men. In other words there is no simple, clear relationship between size of this structure and sexual orientation. Second, the SCN is not known to be associated with sexuality or sexual orientation, and the authors strongly caution that their results cannot be interpreted at this point.

Recently, another histological study has been done looking at small groups of cells which have been shown to be significantly larger in males than females and which, it is then supposed, might be involved in the generation of male-typical sexual behavior (LeVay, 1991). These brain areas are called INAH2 and INAH3 and are located in the anterior hypothalamus. Needless to say, other structures have been found to differ between men and women (for example, the corpus callosum) and have not been supposed to be involved in sexual behavior. In any case, the hypothesis tested in this study was that the size of INAH2 and INAH3 would vary with sexual orientation (not with anatomical sex), with these structures being larger in people (male or female) oriented towards women (showing male-typical behavior). Because the laboratory could obtain tissue only from gay males and not lesbian women, the part of the hypothesis concerning women attracted to women (exhibiting male-typical behavior) was not tested. Tissue was taken from 41 males undergoing routine autopsies in seven New York hospitals. Eighteen were gay men who died of complications of AIDS, 1 was a bisexual man with AIDS. Six were presumed heterosexual men who had died of complications from AIDS; 10 were presumed heterosexual men who died of causes not related to AIDS. Six subjects were presumed heterosexual women, one of whom had died from complications of AIDS. Only the volume of each nucleus was tested, not cell number. Volumes of INAH1, INAH2, INAH3 and INAH4 were tested with only INAH2 and INAH3 expected to show differences based on sexual orientation. Univariate analysis of variance showed that only INAH3 differed significantly among the three groups (gay men, heterosexual men, and heterosexual women). Post hoc tests showed significant differences between gay men and heterosexual men, between gay men and heterosexual men with AIDS, and between heterosexual men and heterosexual women. There were no differences between heterosexual men with and without AIDS or between gay men and heterosexual women. The conclusions were that INAH3 in people sexually oriented towards men differs significantly from INAH3 in persons oriented towards women and that this difference is not due to the action of the AIDS virus. It is emphasized that the heterosexual men in this study were presumed to be heterosexual. In addition, the author points out the following difficulties: (1) selecting AIDS patients could also be selecting a particular group of gay men in some other (behavioral) ways, (2) There are exceptions in the study. Results are based on average values, but there was considerable overlap between groups so, for example, there were some presumed heterosexual males with “small” INAH3 volume. (3) The results suggest an association, but do not prove cause (4) There could be a third factor mediating the effect which has not yet been discovered. The study provides some interesting material, but clearly needs replication and further exploration. For example, the relationship between morphological sex differences in the human brain and human sex-dimorphic behavior has not yet been established (Reinisch, Ziemba-Davis and Sanders, 1991), therefore determining the function of this brain area physiologically could provide support (or not) for the hypothesis. In addition, histological study of many more subjects with clearer sexual histories would be a boon.

Summary: Neuroanatomical Research
A number of researchers have been investigating the possibility that there are brain structures which differ in heterosexual and gay men or heterosexual and lesbian women. Studies looking at cerebral lateralization purport to have found differences, but are unconvincing. There is more evidence for differences in the size of certain brain nuclei between heterosexual and gay men. These studies need replication before the conclusion that these differences exist can be comfortably accepted, and some demonstration that these centers actually have to do with sexual behavior is needed.

ANIMAL STUDIES
Animal studies of perinatal endocrine environments have been mentioned at various points above. Such studies have been systematically and thoroughly reviewed by Ellis and Ames (1987) who put them into five categories in which: (1) the hormonal environment is manipulated by castration of the newborn (rodent), (2) primate fetuses are administered testosterone prior to birth, (3) androgens are administered to rodents perinatally, (4) pregnant mothers are stressed, thus reducing their androgen levels (rats), and (5) mothers and fetuses are immunized against androgens which are thus removed from their circulation.

Animal studies have also been summarized and reviewed by Denniston (1980), Feder (1984) and Meyer-Bahlburg (1982). A complete review of animal studies are beyond the scope of this paper, but because they do form the basis of a number of hypotheses in the biological origins of sexual orientation, a few words will be said about their applicability to human biology.

Generalization from Non-Humans to Humans
One must be cautious when extrapolating from animal studies–especially those using rats or other non-primates (Dancey, 1990; Sigusch, Schorsch, Dannecker and Schmidt, 1982). To presume that a rodent and a human are physiologically identical is a questionable presumption, indeed.

Feder (1984) points out that sexually dimorphic areas in the brains of rats are associated with copulatory motor patterns which have no counterpart in human sexual behavior. Perhaps researchers are looking for the “masculinization” of brain centers that humans do not possess. There is some question about how “wired in” sexual behaviors are–even in rodents. Certain social situations elicit behaviors which others do not. This must be greatly magnified in people–who may even be liberated from the predeterministic effects of prenatal hormones or brain centers.

Further, even in the case of rats, one finds homosexual adult behavior in anatomically normal male rats only if they are castrated within a short time after birth and then treated with hormones in adulthood (Meyer-Bahlburg, 1982; Ellis and Ames, 1987). Alternatively, if enough hormone manipulation is done perinatally to produce homosexual behavior in the grown rat, abnormal gonads also result (Meyer-Bahlburg, 1982). Clearly, most gay men are anatomically normal and have not been castrated at birth. Meyer-Bahlburg (1982) suggests that perhaps we just are not doing these manipulations correctly in terms of timing or hormonal concentration–or perhaps we are looking at too simple a mechanism to explain the phenomenon of sexual orientation.

Finally, as in any research, care must be taken to observe and not to suppose. An example comes from the generally excellent review by Ellis and Ames (1987). In discussing studies manipulating perinatal hormones by immunizing animals they cited an example in which rabbits were immunized against testosterone in utero. These male rabbits were born with anatomical (genital) aberrations and were sacrificed to study these aberrations. Ellis and Ames go on to say, “[n]evertheless, the fact that the hypothalamus was not receiving testosterone makes it all but certain that these genetic males would have largely preferred sexually interacting with males when they reached sexual maturity (Ellis and Ames, 1987, p. 243-245, italics mine). One would prefer to use experimental situations where the proposed later behavior could actually have been observed.

SUMMARY: BIOLOGICAL THEORIES
Although agreement is not unanimous, most researchers and theorists in both genetic and neuroendocrine fields (1) believe genetic and neuroendocrine factors may be important in the determination of sexual orientation, (2) believe genetic and neuroendocrine factors to be more salient to the development of sexual orientation in men than women, and (3) believe that environmental and experiential factors are also important in the development of sexual orientation. Anatomically oriented researchers have looked for differences in brain lateralization and in the size of brain nuclei between homosexual and heterosexual men and women, with some success in the area of brain nuclei. These studies need further replication and demonstration that structures implicated actually have something to do with sexual orientation.

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