randombio.com | science commentary
Sunday, February 11, 2018

Does gender dysphoria have a biological basis?

In one sense it's tautological: everything we do has a biological basis. But what the heck causes it?

S ome people claim that gender dysphoria is a well established biological phenomenon. Others claim that it's a fictitious concept created for political purposes. What's the truth?

One challenge is in making the terminology precise. If there is some huge smorgasbord of ‘genders,’ what does ‘transgender’ mean? Does it mean changing from trans*female to trans*woman (which doesn't sound like much of a change), or does it mean the whole enchilada, with surgery and hormones? Politicization of the language is making it hard to determine whether GD is real, a boutique lifestyle statement, or both.

For example, if evidence were found that sexual identity is real (i.e. biological), calling it gender identity would give credence to those who equivocate the term to promote the idea of multiple genders. Politicization would lead us into falsehoods.

Pink caterpillar

Because of this, I will use the term ‘sex’ here, not because it causes my web hits to spike—not a bit of it—but because it's more precise. I will discuss recent scientific evidence on two questions: (1) Is there such a thing as sexual identity? and (2) What causes gender dysphoria? ‘Gender’ here just means male or female.

One striking thing is how all these articles are filled with more hedging than usual for biology. No one wants to be seen as making a moral judgment. Nevertheless, although there are clearly divergences of opinion, most endocrinologists seem to be converging on a few points:

  1. Medically speaking, for adults with gender dysphoria, the best outcomes are achieved with their requested hormone therapy and surgical sexual transition as opposed to psychiatric intervention alone. However, this conclusion is strongly disputed by many physicians because of the greatly elevated risk of depression and suicide that hormonal treatments cause.

    What “psychiatric intervention” means is somewhat ambiguous. Typically these days it means helping the person to adapt to their new sex, and prescribing antidepressants.

  2. Sexual identity appears real. It's determined biologically by the chromosomes selected at fertilization and tends to persist even after surgical and hormonal intervention.
  3. Hormones can affect the brain physiologically. Exposure to exogenous hormones or hormone-like chemicals early in life could cause gender dysphoria, but the evidence is not clear because it's hard to do controlled studies.
  4. There is no convincing evidence for any genetic basis for gender dysphoria.
  5. Psychological explanations are not given as much credibility as biological ones. Psychology seems to be hanging on to its status as a branch of science by the skin of its teeth.

I didn't find any scientific articles recommending “sexual transition” as a safe or viable option for children. Most people have seen how parents manipulate their kids; subjecting them to surgery and hormones would be skating on ethical thin ice.

The Meyer-Bahlburg study

By far the most influential study was done by Meyer-Bahlburg[1], who studied 388 XY (male) individuals who had been surgically altered into females in childhood due to severe anatomical abnormalities. Some had been assigned to be female and some male. The authors counted the numbers who ended up living as adults as female and as male. They concluded:

Of the female-assigned patients of childhood age, 69% (including those with possible gender dysphoria) or 62% (excluding those) were living as females, of those of adolescent age 91% (including those with possible gender dysphoria) or 68% (excluding those), of those of adult age 65% or 47%, and of those whose age could not be categorized 100%, altogether across all ages 78% or 65%. By contrast, all male-raised 46,XY patients were living as males in all age groups, and only the report on one of these suggests a possible gender dysphoria. The differences in gender outcome between male-raised and female-raised patients are significant in each age category as well as in the total sample (for the latter, p < .001, two-tailed, Fisher's Exact Test), even if the patients with gender dysphoria are included among those with the other gender.

This is certainly a contender for the prize of most badly written paragraph ever written, but what it says is that of 388 patients who had XY on chromosome 46, only 65% of those “assigned” by the surgeon to be female grew up to live satisfactorily as females, and 100% of those “assigned” to their original sex (male) were living satisfactorily as males.

The numbers are as shown in this table.

Assigned sex Living as Female Living as Male
No dysphoriaDysphoriaNo dysphoriaDysphoria
Female 50 10 17 0
Male 0 0 310 1

This showed convincingly that identification with biological sex tends to remain fixed even after surgical feminization. It also means that involuntary sex reassignment does not necessarily change whether a person identifies as a male or a female.

Fisher et al.

But what about voluntary sex reassignment? Is it possible that in 1 in 10,000 males and 1 in 30,000 females, which is the number that undergo sex changes, there could be a mismatch between the genes and the brain, or is this a purely psychological phenomenon?

A.D. Fisher et al. have written a number of articles on this subject, all of which hedge by saying that disorders of sexual development, and gender dysphoria in particular, need to be managed clinically.[2] They also say [3] “Debates continue on whether sexual behavior and gender identity are a result of biological (nature) or cultural (nurture) factors.” This is a roundabout way of saying that we just don't know the answer.

Do brains of persons with gender dysphoria differ from normal ones?

Saraswat et al.[4] reviewed the evidence on whether gender identity is a real, i.e. biological, thing. They note that some researchers reported that a brain region called the bed nucleus of the stria terminalis, or BSTc, is bigger and has more neurons in males than in females. In one study of six males who had been treated with estrogen and surgery, their BSTc more closely resembled the female one.

The problem, of course, is that the sex hormones could have affected their brain physiology. There is disagreement as to whether hormones account for the findings. Zhou et al.[5] conclude that it does not, while Chung et al.[6] say it does.

One study[7] tried to resolve the dilemma by using MRI to study 24 male-to-female live transsexuals who had not had hormone treatment. The results were inconclusive: the subjects had a pattern that was more similar to control males, but in a later study the same authors claimed to have found minor differences in brain structure.

The problem here is that we simply do not know which brain regions, if any, determine whether a person feels like a man or a woman.

Okay then, what about biochemical studies? Here again the evidence is confusing. Many substances perform different functions in the brain than in the periphery. Glutamate and insulin are two well known examples. The amino acid and Chinese food additive glutamate is a major neurotransmitter in the brain. Insulin is made in the brain as well, and its function seems to be different from its function in the pancreas.

Sex hormones such as estradiol also perform different functions in the brain than in the periphery. In the brain, they're important for memory, and both sexes produce them from cholesterol that's made in their brain. They're called neurosteroids, and they're generally kept separate from the hormones that get in through the blood-brain barrier. Studying brain hormones is very tough to do, because it can only be done after the subject dies, and postmortem changes could obscure the results.

Genetic studies

With genetic studies, large population sizes are possible, but these studies too have found contradictory results. One large study of 242 transsexual individuals showed no association with sex steroid receptor genes[8]. However, a study in 151 subjects of CYP17, a gene for an enzyme called 17α-hydroxylase/17,20-lyase, found a correlation in female-to-male but not male-to-female subjects. CYP17 controls sterol synthesis. It's found mainly in the adrenal gland, testes, placenta, and ovaries. There are also suggestions that diethylstilbestrol, an estrogenic anti-miscarriage drug, may induce gender dysphoria in a small percentage of offspring.

There are many problems with this type of study. Since the physiological basis, if any, of gender dysphoria is completely unknown, if a biological cause exists it's more likely to be (a) controlled epigenetically than by a gene polymorphism or (b) related to the person's psychological makeup rather than their sex hormones. The studies also raise statistical questions. Since there are tens of thousands of genes, even a positive correlation with a biochemical abnormality would most likely be a statistical fluke.

Pro-biology bias

Finally, there is significant pro-biology bias in these studies. It's easier to get clear-cut results by studying a receptor than by studying psychological causes, such as absence of a father figure, or environmental causes, such as contraceptive hormones in the drinking water. In recent years psychological explanations of behavior have largely fallen into disrepute, and brain science has largely displaced them. Even so, biological findings, even if they're statistically adequately powered, should still be treated with great skepticism.

Terms like “gender identity” only add to the confusion. When we say gender identity, we are only saying that the person says they feel like a male or a female. Even if the person correctly interprets their feelings and reports them honestly, it does not necessarily follow that the concept refers to anything biologically real. If the past century of scientific wild goose chases started by Sigmund Freud et al. tells us anything, it is that the concepts we use to describe our feelings often have little to do with what is actually happening in the brain.

1. Meyer-Bahlburg HF. (2005). Gender identity outcome in femaleraised 46 X,Y persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav. 34:423–438.

2. Fisher AD, Ristori J, Fanni E, Castellini G, Forti G, Maggi M. (2016). Gender identity, gender assignment and reassignment in individuals with disorders of sex development: a major of dilemma. J Endocrinol Invest. 39(11):1207–1224. Abstract

3. Fisher AD, Ristori J, Morelli G (2017). The molecular mechanisms of sexual orientation and gender identity. Mol Cell Endocrinol. 2017 Aug 25. doi: 10.1016/j.mce.2017.08.008. Abstract

4. Saraswat A, Weinand JD, Safer JD. (2015). Evidence supporting the biologic nature of gender identity. Endocr Pract. 21(2):199–204. doi: 10.4158/EP14351.RA.

5. Zhou JN, Hofman MA, Gooren LJ, Swaab DF. (1995). A sex difference in the human brain and its relation to transsexuality. Nature 378:68–70.

6. Chung WC, De Vries GJ, Swaab DF. (2002). Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. J Neurosci. 22:1027–1033.

7. Luders E, Sánchez FJ, Gaser C, Toga AW, Narr KL, Hamilton LS, Vilain E. (2009). Regional gray matter variation in male-to-female transsexualism. Neuroimage 46:904–907.

8. Ujike H, Otani K, Nakatsuka M, Ishii K, Sasaki A, Oishi T, Sato T, Okahisa Y, Matsumoto Y, Namba Y, Kimata Y, Kuroda S. (2009). Association study of gender identity disorder and sex hormone-related genes. Prog Neuropsychopharmacol Biol Psychiatry 33:1241–1244.

feb 11 2018, 8:49 am; updated feb 12 2018, 5:10 am

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