Health Science Reviews

by Sesethu Mbunge

What better time, than the time of the release of the ever so controversial Lil Nas X’s music video for his single titled “Industry Baby”, to write about the neurobiology that underpins human sexuality? This masterpiece features an iconic shower scene, with a group of male bodies dancing in the nude, that had naysayers claiming that Lil Nas X is “turning people gay”. Contrary to popular belief, the nuance subject matter of gender identity and sexual orientation is not as simple as deciding to be gay. Although there is a huge gap in the understanding of the biological underpinnings of human sexuality, many studies have suggested that the prenatal environment, including the maternal immune environment as well as exposure to certain sex hormones, may play a role in gender identity and sexual orientation of the developing foetus. Further studies hypothesize that there is a genetic determinant of human sexuality, although these studies have been difficult to reproduce. It is believed that this resultant maternal, and potentially genetic, environment results in the organizational differentiation of the developing foetal brain. In simple terms, this means that these factors contribute to the structural differences in certain regions of the brain, and that these differences are what is attributed to the difference in the human sexual identity. The assumption with many of these studies was that sexuality is categorizable and binary. For the sake of cohesiveness, this summary will also be written under this assumption, although it is understood that sexuality is a spectrum.

Human sexual identity is categorized as gender identity and sexual orientation. Gender identity refers to one’s perception of oneself as male, female, or non-binary and this can be the same, or different from one’s biological sex. Sexual orientation refers to the pattern of emotional and/or sexual and romantic attractions to males, females, or both. To understand the effects of different factors on sexuality, let’s look at these factors individually.

Pre- and Perinatal Hormone Environment:

Animal studies have demonstrated that prenatal exposure to testosterone resulted in masculinization (male-type development) and that in the absence of testosterone feminization (female-type development) occurred. Masculinization results in permanent neural structural differentiation and occurs within the period when the brain is most sensitive to testosterone. Brain areas that are affected by testosterone levels are thought to be important for sexual differences in various adult behaviours including sexual behaviour, aggression, and cognition as well as gender identity and sexual orientation. Clinical studies have shown that in XY (typical male genotype) children that were born with ambiguous genitals developed into males when exposed to testosterone prenatally, but that if they had an androgen receptor (receptor for testosterone) mutation, they were phenotypically female and identified as female.

Studies in several animal models have shown that perinatal exposure to testosterone resulted in female partner preferences, whereas testosterone deprivation resulted in male partner preferences. In humans, it has been observed that women that were born with congenital adrenal hyperplasia (were exposed to an elevated amount of testosterone) developed masculinized genitals and behaviours and were less likely to be exclusively heterosexual in comparison to unaffected women.

Genetic Factors:

It is difficult to analyse the biological basis of gender identity in animal models, thus this is best studied in individuals that identify with a gender that is different from their biological sex. Although there is very limited evidence, it has been observed that in female-to-male transsexual individuals, there was a higher incidence of the A2 allele polymorphism for the gene that codes for a testosterone-synthesis catalysing enzyme, CYP17A1, compared to male-to-female transsexual individuals.

Familial and twin studies have shown that sexual orientation is moderately accounted for by a genetic component. A recent study approximated that about 40% and 20% of the variance in sexual orientation in men and women respectively was due to a genetic component. In a linkage study performed by Hamer in 1993, it was hypothesised that a locus, namely Xq28, on the X chromosome contained a gene that was loosely associated with homosexuality in men. This was then also confirmed in a larger genome-wide study, and it was also found that there were associations with chromosome 7 and 8. No specific genetic locus has been identified as associated with sexuality yet.

Neuroanatomy:

Studies have found that transgender individuals had structural and functional brain features that are more similar with individuals of the same gender identity, rather than with individuals with the same biological sex.

Rodent models have identified the sexually dimorphic preoptic nucleus (SDN) of the brain as the region associated with sexual partner preferences. In male rodents it was found that the larger the SDN was, the greater its attraction to female rats. It was also subsequently found that destruction of the SDN in male rats and ferrets either resulted in neutral or male preferences. This finding was also confirmed in sheep models, where they found that larger the ovine sexually dimorphic nuclei (oSDN) were associated with more female-oriented rams, whereas male-oriented rams had smaller oSDN. It was found that oSDN due to prenatal exposure to testosterone. Exposure of female lamb foetuses at the proper time was shown to alter oSDN size independently of genetic and phenotypic sex.

In humans, the third interstitial nucleus of the anterior hypothalamus (INAH3) has been implicated in sexuality. Based on its localization and the structure of its cytoskeleton, this nucleus resembles the oSDN of sheep. Studies have shown the INAH3 is smaller in homosexual men in comparison to heterosexual men, and the INAH3 in homosexual men is similar in size to that of women.

Maternal Immune Environment:

One interesting observation that has been made is the effect that the maternal immune environment has been shown to affect the sexual orientation of the developing foetus. It has been observed that homosexual men have, on average, more older brothers that heterosexual men. This is referred to as the fraternal birth order, and incidence of homosexuality increase by about 33% with each older brother. This is hypothesised to be due to the mother developing antibodies against a gene on the Y-chromosome that is a key factor in male brain development, and this immune response increases with each male pregnancy. This is subsequently thought to alter the neural structures that affect sexual orientation in boys that are conceived later. It was found that the mothers of homosexual sons that had many brothers, had a concentration of antibodies against neurolignin 4 (NLGN4Y), a gene that codes for a protein that is assumed to play a role in foetal brain development.

These factors are an indication that the events and environments that occur during early foetal development play a crucial role in determining the sexual identity of the developing foetus. Animal models have been found to display the causality of the effects of prenatal hormones on sexual orientation, but this however has not translated to gender identity. There are so many more biological processes that are implicated in sexual development that are yet to be understood or discovered. As such, it is biologically incorrect to reduce sexuality and sexual identity to a mere choice!

Reference:

Roselli, C., 2018. Neurobiology of gender identity and sexual orientation. Journal of Neuroendocrinology, 30(7).