Mennonite Health Journal

Biology of Same Sex Attraction

D. J. McFadden, MD, MPH

from Mennonite Health Journal, Vol. 17, No. 3 – August 2015

In the book, As Nature Made Him: The Boy that was Raised as a Girl, the story of Bruce Reimer is poignantly told.  The story recounts the true life story of an attempt to assign a female gender to a male child who is one of two identical twins.  Bruce was mutilated by a misstep during circumcision, and the decision was made to surgically and hormonally make him into a girl, in hopes of giving him a normal life.    The case was presented at scientific conferences as a success and sexologists used this case to say that gender identity at birth is a tabula rasa, a blank slate that we through society imprint or write upon.

The only problem is that scientists did not follow Bruce (now named Brenda) long enough. Bruce/Brenda hated his breasts and refused his hormone treatments.  He felt that something was wrong and at the age of 14 demanded to know what was going on.  He wanted to know the truth about the conflict within himself in regards to his attractions and feelings.  He was eventually told.  And so, at the age of 15, he insisted on being called David.  He had a double mastectomy, began testosterone therapy, and had a phalloplasty to reconstruct his penis.  He admitted that he had always been attracted to women and married, adopted children, and engaged in typical male gender type sex with the help of prosthetics.  He also demonstrated an important principle that science had been working on since the early 1900’s– that the brain is more than a holder of experiences.  It is not just a slate that is written upon.  There are basic, fundamental parts of the brain that are established early on in utero.

The early development of the human brain

From the fields of embryology and neurobiology, we understand that the brain is influenced by hormonal messages and neurotransmitters early in its development.  The local environment of the brain is crucial to how it will develop.  We recall from embryology that differentiation of cells in the earliest stages of development is based in part on where the cells are located and who their neighbors are. These cells (all identical) begin early on to organize.  There is a polarity that forms and is identifiable as early as 4-8 cells into our being.  The brain develops not just in a programmed way as non-scientists might expect.  The brain doesn’t just get the messages from the genetic material and then become the cerebellum, for example.  The brain is programmed genetically to respond to various local messages to become what it will become.  Connections, exposures, and experiences all shape the brain.   Some of the most important and basic features of who we become happen within the womb.

There are several regions of the brain that have been identified as responsible for sexuality.   Beginning with work from 1849, scientists have identified that one of the compounds playing a major role in the differentiation of male from female is testosterone.  We now understand that the male phenotype results from the effects of testosterone or testosterone derivatives.  The brain has a multitude of receptors for sex hormones.  Our sex hormones are critical for influencing sexuality and the behavior of adolescents and adults, but they also appear to be critical for creating what we typically consider to be male and female brains.  The brains of males and females are different, and some of these differences begin in the uterus in response to sex hormones.

In the preoptic region of the limbic system, groups of nerves with receptors to sex hormones have been found.   The location of these nerves is consistent across many species, from birds to mammals.  Through the surgical removal of these regions or through castration and implantation of hormones in these regions, important regions related to sexuality have been identified.  The medial part of the preoptic area is the site of sex steroid activity that is necessary and sufficient to activate male sexual behavior and the ventral medial nucleus of the hypothalamus is the site of sex steroid activity identified as connected to female sexual behavior.

The hypothalami of men and women are different.  Specifically, a difference in the third interstitial nucleus of the anterior hypothalamus (INAH-3) has been found.  This region has a greater volume in men than in women.   A difference between the volume of this region in heterosexual and homosexual men has also been identified (LeVay 1991)

The work of LeVay in the 1990s was ground breaking.  He demonstrated that one area of the brain of homosexual men was different from the brains of heterosexual men.  This region in the brain of a homosexual man had a smaller volume, which is more typical of women.  So he was able to demonstrate a structural difference.  His work was originally criticized because it was done in men that had died of AIDS and so there was concern that the area could have been influenced by AIDS.  Of note, one of the bigger skeptics, Byne, went on to reproduce this work, and, in fact, showed that HIV/AIDS did not play a role in the change. (Byne et al 2001)

So the first piece of the story is that we have regions of the brain that have been shown to be influenced by the sex hormones in utero.  These regions have been shown to be important in the sexual behavior that we consider to be heterosexual male and heterosexual female.  Furthermore, it has been demonstrated that there is a difference in the preoptic area of males and females, and that the preoptic region of homosexual males, specifically the INAH3, is different from heterosexual men.

The effect of testosterone

So what might happen if a female child is exposed to testosterone in utero?  Congenital adrenal hyperplasia (CAH) does help us consider this question.  Early in development, fetuses with CAH are exposed to higher than usual concentrations of adrenal steroids including testosterone.  Fetuses that are XX are born with physical characteristics which are variable, but can include a scrotum and a penis.  Phenotypically, they can range from typical female to nearly typical male.  As we understand more about developmental neuroendocrinology, we realize that the term phenotype may be lacking as we describe the brain.  One study of adult women found that 37% of women with CAH identified as homosexual or bisexual. (Money et al 1984)  More than 20% of the women did not answer the question regarding sexuality.

From the embryologic influences of hormones, the brains of men and women have different intrauterine experiences.  These are due in large part to endogenous influences.  However, exogenous influences should also be considered.  Can environmental factors in the womb impact development of the fetus?

The effect of stress on the fetus

Some of the earliest observations included the impact of stress on a fetus.  Cortisol can inhibit testosterone production.  There has developed a maternal stress theory of male homosexuality; it has been theorized that high levels of maternal cortisol inhibit the testosterone of their developing offspring.  This theory is based on animal models that demonstrated that maternal stress at critical periods results in males that exhibit female sexual behaviors. (Ward and Weisz 1984)  In laboratory animals it is possible to create levels of stress and make observations that we can’t easily make in humans.  The animal model points to the release of maternal stress hormones and the inhibitory effect of these steroids on the surge of testosterone on male rats through the intrauterine exposure to the steroids.  Several retrospective studies have been done to examine this theory in humans.  The results have not been conclusive (de Rooij et al. 2009).   However, one study from WWII Germany did demonstrate a link between severe stress (or perhaps “toxic stress” to use language of today) and having a homosexual son. (Dorner et al 1980)  While only 10% of mothers of heterosexual men remembered stressful events during pregnancy, 2/3 of mothers of homosexual males could recount such a stress. We ae left with the suggestion that perhaps external factors could impact the development of the fetal brain in regards to sexual preference.

The effect of intrauterine testosterone

Another interesting line of thought concerns the effect of intrauterine testosterone on a developing female child.  In animal models, females that develop adjacent to multiple male siblings are more likely to be masculinized and have male sexual behavior and preferences more like males. (Pei et al 2006)  However, this has not been shown in humans.  Perhaps the intrauterine testosterone from one male is not enough and multiple gestations beyond twins is uncommon in humans.

The effect of birth order

I would include in the exogenous intrauterine exposure category the ideas brought forth in the older brother theory or the birth order studies.  A strong link between birth order and male homosexuality has been found.  In 1996 evidence was found that gay men have a greater number of older brothers than heterosexual men. (Blanchard and Bogaert 1996)  This finding exists even if the older brothers are not raised in the same household as their younger homosexual sibling. And there was no increase if the older brothers were adopted or not biologic.  (Bogaert 2006) The birth order effect on male homosexuality is perhaps the most reliable finding in decades of research on sexual orientation.  The finding has led to the maternal immune hypothesis which has been based upon the medical model of Rh factor and hemolytic disease of the newborn.  In the maternal immune hypothesis, it is proposed that mothers, since they do not have a Y chromosome will not have the proteins created by the Y chromosome.  As a result, these proteins will be foreign and antibodies will develop to them.  With subsequent pregnancies these antibodies will enter the fetus and cross the blood/brain barrier and inhibit the development of a male with typical male sexual behavior.

Genetics and sexual attraction

While neurobiology and neuroendocrinology have added much to our understanding of sexuality and same sex attraction, genetics has also provided valuable insight.  Dean Hammer made an observation that some families seemed to have an increased number of gay males in the maternal line.  This suggested that the X chromosome may play a role.  Using these observations, Hammer applied molecular genetic techniques to identify where the similarities lay. He found that pairs of openly gay brothers shared a tiny region on the end of the X chromosome and proposed this gene may predispose a male to homosexuality. (Hammer et al 1993)  Recently a much larger study of gay brothers confirmed the findings of Hammer after 20 years. (Sanders et al 2014) The larger study also identified another region on chromosome 8 that may also be involved.

Since the purpose of sexuality is to perpetuate the species, it is wise to briefly address some of the proposed theories on why homosexuality may persist across all cultures and countries.  The question is one of evolutionary fitness.  How can the genetics be perpetuated?  E.O. Wilson, a sociobiologist, has gone as far as to say that society has needed non-breeders to advance society.  Individuals, unhampered by parental roles could take on roles such as shamans, seers, artists, matchmakers, advisors, diplomats.  He argued that clans or families with such individuals were more able to survive and thrive, and thus through their clan members, a homosexual’s genes were surviving and being transmitted.  This would be a variation on the kin selection hypothesis which is seen in very communal social organizations like wolves and bees.

Another thought is that these genes are similar to the genes that cause conditions like sickle cell anemia.  Perhaps such might be beneficial in certain situations, so they are passed on since they provide some level of health under other natural pressures.   Perhaps they are sexually antagonistic genes that provide increased ability to have children in one gender, and no children in another.  In one study, it was found that female relatives of gay men have more children than relatives of straight children. There could be many reasons for this, but perhaps one of them is a drive to be with males that is so strong that they have earlier families and more children.

Epigenetics

Recently, there has been a host of discussions about the field of epigenetics.  While historically we spoke of our phenotype being determined by our genotype, we have begun to understand that many factors influence the expression of genes.  Epi marks are extra chemical groups that regulate how tightly the DNA is bound.  If DNA is unable to unwind and be translated, protein cannot be produced from the DNA. Epi marks are impacted by life experiences.  The study of stress, violence, and meditation on our genetic expression of disease has been ground breaking.  These epi marks, usually accumulated throughout life, are also able to be transmitted to children.  Epi marks have been proposed as a potential explanation of how genotype might not be sufficient for the expression of homosexuality.  (Rice et al 2012)  While a recent area of study, epi marks may help to unravel some of the inconsistent findings from twin and other genetic studies.

Summary

The data so far do not lead to one cause of all homosexuality.   There does appear to be a distinct difference in male and female sexuality, so it makes sense that there would be distinct differences in male and female homosexuality.  There appear to be numerous steps along the way where heterogeneity can occur.  Some of those differences are genetic, some of those differences are from intrauterine hormonal factors, and some are from external factors.

It is interesting that the work of Levay, who demonstrated a difference in the INAH3 of male heterosexuals and male homosexuals, centers on the preoptic region of the brain.  This is an area of the brain that is noted to be responsible for attraction to males.  I also find it interesting that women who have the Xq24 change that Hammer noted in the familial link of homosexuality have more children. (Camperio-Ciani et al 2004)  Is it possible that this gene somehow translates for male attraction?

As we look at the biology of homosexuality, I believe we may be actually looking at the biology of sexual attraction.  Thus, it may be that some humans (male and female) are going to be created to be attracted to males–their erotic love will be centered on males, and some humans will be created to be attracted to females–their erotic love will be centered on females.  As we focus our attention on the love and attraction to which the biological evidence is leading us, I think it begins to change the discussion.

What does it mean for us as Christians if we realize that persons with a homosexual attraction have been created by God and are a part of the spectrum of sexual attraction?  The scientific community has provided tools for the church.  As the church continues to discern, it seems prudent to use all of the tools available to inform the process.

Sources

Blanchard R and Bogaert, AF (1996).  Biodemographic comparisons of homosexual and heterosexual men in Kinsey Interview Data.  Arch Sex Behav. 25, 551-579.

Blanchard R and Bogaert, AF (1996).  Homosexuality in men and number of older brothers.  Am J Psychiatry. 153, 27-31.

Bogaert, AF (2006). Biologic versus nonbiological older brothers and men’s sexual orientation.  Proc Natl Acad Sci USA. 103, 10771-10774.

Byne, W. et al. (2001). The interstitial nuclei of the human anterior hypothalamus:  an investigation of variation with sex, sexual orientation, and HIV status.  Horm Behav. 40, 86-92.

Camperio-Ciani A et al. (2004).  Evidence for maternally inherited factors favouring male homosexuality and promoting female fecundity. Proc Biol Sci. 271,2217-2221.

de Rooij, SR et al. (2009)  Sexual orientation and gender identity after prenatal exposure to the Dutch famine.  Arch Sex Behav. 38, 411-416.

Dorner, G et al. (1980) Prenatal stress as possible aetiogenetic factor of homosexuality in human males.  Endokrinologie.75, 365-368.

Hamer, DH et al (1993). A linkage between DNA markers on the X chromosome and male sexual orientation.  Science. 261, 321-327.

LeVay, S. (1991). A difference in hypothalamic structure between heterosexual and homosexual men. Science. 253, 1034-1037.

Money, J. et al. (1984) Adult erotosexual status and fetal hormonal masculinization and demasculinization: 46, XX congenital virilizing adrenal hyperplasia and 46, XY androgen insensitivity syndrome compared. Psychoneuroendocrinology.9, 405-414.

Pei, M et al. (2006)  Intrauterine proximity to male fetuses affects the morphology of the sexually dimorphic nucleus of the preoptic area in the adult rat brain.  Eur J Neurosci. 23, 1234-1240.

Rice, WR et al. (2012)  Homosexuality as a consequence of epigenetically canalized sexual development.  The Quarterly Review of Biology. 87, 343-368.

Sanders, AR et al. (2015) Genome-wide scan demonstrates significant linkage for male sexual orientation. Psychological Medicine. 45, 1379-1388.

Ward, IL and Weisz, J. (1984).  Differential effects of maternal stress on circulating levels of coricosterone, progesterone, and testosterone in male and female rat fetuses and their mothers.  Endocrinology.114, 1635-1644.

Books

Balthazart, J. (2012)  The Biology of Homosexuality.  Oxford University Press, New York.

LeVay, S. (2010) Gay, Straight, and the Reason Why: The Science of Sexual Orientation. Oxford University Press, New York.

About the author

D. J. McFadden, MD, MPH, is a family physician and epidemiologist.  He received his medical degree from Duke University School of Medicine and his MPH from the University of North Carolina School of Public Health.  He is a member of Millersburg Mennonite Church, in Millersburg, Ohio where he lives with his wife and children.