Classic experiments in the 1950 and 60s showed us how the brains of animals determine whether they would behave as males or females. It wasn’t simply their chromosomes, even though there are striking differences between males, who have one X and one Y chromosome, and females, who have two Xs (and no Y). It turns out that the Y chromosome is essential for the formation of a testis, and it is the testosterone from this testis that acts on the brain. The early experiments showed this by using species, such as rats, in which this happens after birth. Amazingly, giving testosterone to little new-born females resulted in their sexual behavior being much more like that of males when they grew up.  And the opposite was also true: Removing the testes of new-born males resulted in female-like patterns of behavior. Later, it was established that the same process occurred in the brain during pregnancy in those species that are born much more mature than rats (for example, guinea pigs and monkeys). 

This opened up a fascinating debate: Did this apply to humans, and if so, how? We know that the male human embryo forms testes very early during pregnancy (about 10 weeks) and that these new testes promptly start to secrete testosterone. This means that the male brain is exposed to testosterone during a critical time during its development. What are the effects, and are they as long-lasting as in other species?

Human sexuality, of course, is made up of several components, though they overlap. Gender identity—the sex you identify with—is almost impossible to study in animals, though we know that males of many species treat other males differently than females, suggesting some sort of knowledge of gender and an equivalence to gender role in humans.  Sexual preference can be studied, as can patterns of sexual activity.  Both the latter are altered by exposure (or lack of it) to testosterone early in life in the expected direction in animals.   Testosterone, it appears, has a major role on the development of sexuality. In the 1980s, when Germany was still divided into a Western segment and an Eastern one under the domination of the then Soviet Union, a group of East scientists proposed that human homosexuality was the result of insufficient exposure to testosterone in the womb.  Since the moral atmosphere of the time in that country regarded homosexuality with abhorrence, they proposed that all pregnant females should have the fluid surrounding their male foetuses tested for testosterone. Those with low values (they did not specify what these were) should be aborted, thus eliminating gay men from East German society. An excellent example of the misuse of science, though it was never adopted.

But does testosterone play a role in the development of human sexuality? Testosterone acts on the brain (and other organs) by activating a complex protein, the androgen receptor. If a mutation in the latter occurs, the brain may not respond to testosterone: It’s as if it didn’t exist.  There are such examples in humans: XY embryos that are insensitive to their own testosterone.  They are born looking like females, and grow up in that belief (i.e. their gender identity is female).  Often they are only discovered to be XY individuals at puberty, which doesn’t happen (it’s called the ‘androgen insensitivity syndrome’ or AIS). They have normal-looking testes, though hidden inside their abdomen. There isn’t really a converse situation (early excess testosterone in XX embryos) though a condition called congenital adrenal Hypertrophy (CAH) results in abnormally high amounts of testosterone in females, but this occurs much later in pregnancy. These individuals do have a higher than expected incidence of bisexual or homosexual behavior, but not very much. And some may also have doubts about their gender identity, but it’s not nearly so striking as AIS. The difference may be a result of timing: The effects of testosterone become less as development proceeds. We certainly can’t rule out pre-natal testosterone as a powerful (but not the only) determinant of sexuality in humans.

Back to animals; what happens in their brain during early life to predict later sexuality? Recent experimental evidence points to real differences in male and female rodent brains. In the hypothalamus, a part of the brain well-known to be closely connected with sexual behavior (and a variety of others), there are biochemical markers of being a male. These markers (for example, an increase in the amount of a protein in nerve cells that binds calcium) are one result of the differential activity of genes. Gene activity is controlled by many factors: One is whether or not they are suppressed by a process called methylation. This involves the addition of a methyl group (CH3) to a special position in the gene.  If this happens, then the gene is inactivated (‘suppressed’).  The exciting fact is that either environmental or internal events in the body can influence methylation on certain genes.  This is the basis of the contemporary subject called ‘epigenetics’. Epigenetic events can last a very long time, maybe for a lifetime. They put paid to the separation of ‘genes’ and ‘environment’: The two are part of a common mechanism.

The hypothalamus of female rodents has greater levels of methylation than males: that is, more genes are suppressed. Giving such females testosterone post-natally reduces this: in other words, some of the methylation markers are removed, releasing those genes to become active. Such females behave more like males. Furthermore, giving a drug to little males that prevents de-methylation results in them behaving more like females. In seems that the brain may develop with a number of genes in the neurons of the hypothalamus suppressed: If this is left unaltered, then the individual will develop as a female.  This agrees with the long-standing view that the ‘default’ condition is female.  However, testosterone is able to remove selected methylation tags, thus releasing genes that determine male-like behavior.  Now we need to know exactly what these genes do and, even more difficult, why they should specify gender. But it’s a start, and this breakthrough may be a door to much greater understanding of how sexuality develops and what influences it.  Of course, there’s another major question: does this apply to humans? From what we know, we can prophesy that it is likely that it does, but that sexuality in humans in all its forms will also be greatly influenced by social and experiential factors to an extent, perhaps, not so apparent in other species (but which may also involve epigenetic events)  A more technical account is given here.

References

M.J.Baum (2017) Evidence that a sex difference in neonatal methylation organizes two distinct phenotypic characteristics of neurons in the murine forebrain. Endocrinology vol  158 pp 1569-1571

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