Sexual development of the brain

작년

This is a continuation of a previous post from last week. I'd recommend reading that one first.

Adapted from CC BY-SA 4.0 source by Quince Media and from CC BY-SA 3.0 source by Marcus Werthmann

The brain is sexually dimorphic

I’m sure you are aware that the brain remains largely a mystery box, but science continues to squeeze nuggets of knowledge out of this fascinating organ. Today, we actually know quite some bit about brain “feminization” and “masculinization.”

As explained in part 1, during embryological development the testicles start secreting steroid sex hormones which usually masculinize the brain. And the hormonal milieu during development is even more complicated than that, fetuses also have to deal with estrogens from the mother and perhaps sex hormones from their twins[a][1,2]. Our current understanding is that testosterone and/or estrogens play a role in brain masculinization in mammals and that alpha-fetoprotein prevents the mother’s circulating estrogens from acting on the developing female brain[3,4].

In part 1 I also mentioned that girls produce no sex hormones until puberty, but things are a bit more complicated. In the immediate months postpartum, boys go through a peak of testosterone and girls through one of estrogens (alpha-fetoprotein declines towards the end of pregnancy), which is understood to largely fix brain circuits and structures[4,5]. By the time puberty hits, the increase in circulating sex hormones modulates these circuits, furthering the neural sexual dimorphisms developed earlier in life[3,6-8].

But, let’s remember that nature doesn’t do categories. The genetic background and hormonal milieu during development differ from person to person, and this can lead to different patterns of brain sexual development and differentiation, similar to how some brains may end up being predisposed to having different mathematical or navigational abilities. So no hormonal milieu is better than any other in principle, we simply have a multifactorial web of different genetic backgrounds and hormonal milieus (plus other environmental factors) coming together and contributing differentially to the brain development of different people.

While development of the central nervous system continues through childhood and adolescence[9], most of the anatomical, physiological and neurochemical gender-related differences in the brain occur prenatally[3,10]. As a general rule, we could say that the earlier a brain feature or structure develops the more “set in stone” it is, though we should emphasize again that brains still develop postnatally and can have some level of plasticity during adulthood.

Decades ago it was shown that treating rats chronically with an androgen or an estrogen analogue from a prenatal timepoint can lead to chromosomically female "XX" rats that have either female or male genitalia, male sexual behaviour and brain structures (such as the preoptic area of the hypothalamus)[b] that can be indistinguishable from that of male rats[11]. It has since been shown that manipulating sex hormone levels during key periods of development can lead to rats displaying conventionally male behaviour, conventionally female behaviour, asexual behaviour, a combination of male and female sexual behaviours and masculinization/feminization of brain regions such as the suprachiasmatic nucleus, bed nucleus of the stria terminalis, and ventromedial hypothalamus[12-14].

Human experimentation such as can be conducted with rats is obviously highly unethical and illegal, but studying human sexual development is important to fine tune counselling, design better treatments and find new options for those who need them. Thankfully, other than post-mortem or more observational studies, nowadays we have technology to conduct tests with non-invasive techniques such as magnetic resonance imaging (MRI). For example, in 2012 a pioneering study showed a strong correlation between testosterone levels during fetal development in 28 boys with the development of typically male brain regions as assessed 8-11 years later via MRI[15]. The results showed that fetal testosterone levels were negatively correlated with grey matter volumes within the planum temporale/parietal operculum and within the posterior lateral orbitofrontal cortex, brain areas known to be larger in typical females. Furthermore, fetal testosterone levels were also associated with a larger right temporal-parietal junction and posterior superior temporal sulcus, areas of the brain known to be larger in typically male individuals.

It has been also shown that girls who had higher than average androgenic exposure in utero display some typically male behaviours, including toy and playmate selection preferences[3,12,16]. These individuals also have higher chances of being lesbian, bisexual or transgender[5,12], though, interestingly, the effects seem to be stronger in terms of sex-typed behaviour and sexual orientation than gender identity[17]. There's a long history of trying to "correct" sexual orientation through terrible means (such as castration or conversion therapy) to no effect, further suggesting that certain aspects of sexual development are essentially fixed[3,5,18].

Transgender individuals

Transgenderism can arise because development of the gonads and external genitalia (as addressed in part 1, taking place around the second and third months of pregnancy) is to an extent decoupled from the feminization/masculinization of the brain[3]. The latter happens afterwards, goes on for an extended period of time and is of a perhaps more delicate and complicated nature.

Adapted from CC BY-SA 3.0 source by Martin Strachoň / Wikimedia Commons

Studies from the mid to late 1990s found that the bed nucleus of the stria terminalis in transgender people matched with their internal gender identification, not the gender typically associated with their external genitalia[19,20]. A later study of a different sexually dimorphic brain region, the interstitial nucleus of the anterior hypothalamus, also matched with the subjective experience of gender of the transgender individuals analysed[21]. A more recent MRI analysis of 24 transgender individuals who identified as females and who had not started hormone treatment (meaning this was not an external confounding factor), also showed brain structures that differed from 24 age-matched cis men controls[22].

Another interesting MRI study analysed the brain response of 12 transgender individuals who identified as females (and who had also not gone through hormone therapy) after a smelling test that’s known to elicit different responses in males vs females. The results? Patterns of brain activation differed significantly in the transgender individuals only from the cis male controls[23]. There's much we still don't know and this is a complex area of study, but the evidence goes on and on, showing that, even when not completely, the brains of transgender people conform in multiple ways with their expressed gender identity rather than with what their genitalia would suggest. This includes brain areas like the right putamen, cerebellum, angular gyrus, corpus callosum and parietal lobe when compared with same natal sex controls[3,18,24,27].

In short, as if their personal testimony wasn’t enough, the scientific evidence today is quite strong: 1) sexual orientation and gender identity are largely fixed early in life and 2) the subjective experience of transgender individuals when it comes to their own gender has a correlate in terms of the sexually dimorphic brain structures and functions we can measure objectively today (in the same way that the subjective experience of gender in cisgendered people has a sexually dimorphic anatomical and functional brain correlate).

Talking about our brains like this may seem weird or even scary to some, but we have to accept reality to the best of our ability to understand it. Most of what we are, ultimately, is our brain, sexuality is no different. Chronic physical pain has well-established effects on the brain[23]. There's evidence that being an asshole to other people and bullying them also leaves real, measurable consequences in people’s brains[24-27]. Different brains will have different reactions and thresholds of resistance and resilience to different stressors.

When it comes to transgender people we know that[25,31,32]:

  • Suicide rates decrease from around 30% to around 3% after treatment
  • Between 1% to 1.5% express regret after treatment

--> This shows that current treatment methods are highly successful but that more research is still needed to hopefully reduce these numbers even further.

  • Most young children who experience gender dysphoria have these feelings subside during puberty

--> This is one of the reasons why treatment begins with counselling, allowing kids to receive the help they need for the distress they are feeling and the guidance they will require to make informed decisions as they reach adolescence and adulthood. Around 10%-20% of children experiencing gender dysphoria will worsen their condition as puberty starts transforming their bodies even further. To prevent this negative outcome, the currently successful approach is to halt puberty in a reversible manner when people need more time to decide whether to transition or not. Treatment is shown to significantly reduce morbidity and mortality.

  • 19% have reported being refused medical care due to their transgender status
  • 28% reported postponing medical care due to discrimination
  • 50% reported having to teach their medical providers about transgender care
  • Around 25% reported being harassed, disrespected or denied equal treatment at a hospital or doctor’s office.

--> This shows that medical professionals still have a long way to go in accepting and treating transgender individuals. More research, outreach programs and governments that don't try to deny the existence of trans people are the way to proceed forward.

If things are already difficult for certain groups of people, the least we can do is not make things worse. This, of course, applies to people from all walks of life, not just LGBT+. I’m not transgender or any other kind of LGTB+ individual, so I can’t claim to know what their life experience is like, but what I can do is at least look at the facts and also exercise a little empathy. Next time you want to support a policy that affects other people’s lives negatively or are about to say something that deep down you know is a hurtful or hateful statement, you should perhaps try and exercise a little empathy instead.

Notes:

[a] It’s important to note that males and females produce both androgens and estrogens, being necessary for the normal sexual development and function of both sexes. Read more here: "Estrogen and the developing brain" by Matthew Davis at BrainFacts and here: "Normal testosterone and estrogen levels in women" at WebMD

[b] A recent research paper suggests that one way in which the preoptic area is masculinized in response to sex hormones is by shutting down a repressor enzyme, thus allowing several genes to become activated. In the absence of sex hormones, said genes remain repressed and the "female" development program occurs as a consequence. Read more here: Brain feminization requires active repression of masculinization via DNA methylation (2015) Nat Neurosci 18(5):690-7. It should also be emphasized that sexual differentiation is a complicated, multifactorial affair. For example, there's evidence suggesting that sexually dimorphic gene expression in the developing brain starts before sex hormones enter the picture. Read more here: It is not all hormones: alternative explanations for sexual differentiation of the brain (2006) Brain Res. 1126(1):36-45.

[c] After posting part 1 last week, I learned of a statement published on October 26th signed by more than 700 biologists, over 100 geneticists, and nine Nobel Prize winners (it's currently signed by more than 2600 scientists) condemning the leaked proposal by the Trump administration to change the definition of gender. You can read the statement here and a news article here.

References:

1 Analysis of the effect of hormones on opposite-sex twin attitudes (1995) Acta Genet Med Gemellol (Roma). 44(1):41-52
2 Evidence that mammalian sex ratios at birth are partially controlled by parental hormone levels around the time of conception (2008) J Endocrinol. 198(1):3-15
3 Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders (2011) Front Neuroendocrinol. 32(2):214-26
4 Role for estradiol in female-typical brain and behavioral sexual differentiation (2008) Front Neuroendocrinol. 29(1):1-16
5 Sexual differentiation of the brain and behavior (2007) Best Pract Res Clin Endocrinol Metab. 21(3):431-44
6 Sex steroids and brain structure in pubertal boys and girls: a mini-review of neuroimaging studies (2011) Neuroscience. 191:28-37
7 Sex differences in adolescent white matter architecture (2011) Brain Res. 1375:41-8
8 The impact of sex, puberty, and hormones on white matter microstructure in adolescents (2012) Cereb Cortex. 22(9):1979-92
9 Pubertal hormones organize the adolescent brain and behavior (2005) Front Neuroendocrinol. 26(3-4):163-74
10 The effects of prenatal sex steroid hormones on sexual differentiation of the brain (2013) J Turk Ger Gynecol Assoc. 14(3):163-7
11 Pre- and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats (1984) Brain Res. 302(2):291-5
12 Prenatal endocrine influences on sexual orientation and on sexually differentiated childhood behavior (2011) Front Neuroendocrinol. 32(2):170-82
13 Sex differences in the brain: the not so inconvenient truth (2012) J Neurosci. 32(7):2241-7
14 The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation. (2008) Horm Behav. 53(5):613-26
15 Fetal testosterone influences sexually dimorphic gray matter in the human brain (2012) J Neurosci. 32(2):674-80
16 Sex-typed toy play behavior correlates with the degree of prenatal androgen exposure assessed by CYP21 genotype in girls with congenital adrenal hyperplasia (2002) J Clin Endocrinol Metab. 87(11):5119-24
17 How early hormones shape gender development (2016) Curr Opin Behav Sci. 7:53-60
18 Evidence supporting the biological nature of gender identity (2015) Endocr Pract. 21(2):199-204
19 A sex difference in the human brain and its relation to transsexuality (1995) Nature. 378(6552):68-70
20 Male-to-female transsexuals have female neuron numbers in a limbic nucleus (2000) J Clin Endocrinol Metab. 85(5):2034-41
21 A sex difference in the hypothalamic uncinate nucleus: relationship to gender identity (2008) Brain. 131(Pt 12):3132-46
22 Increased cortical thickness in male-to-female transsexualism (2012) J Behav Brain Sci. 2(3):357-362
23 Male-to-female transsexuals show sex-atypical hypothalamus activation when smelling odorous steroids (2008) Cereb Cortex. 18(8):1900-8
24 Neuroimaging studies in people with gender incongruence (2016) Int Rev Psychiatry. 28(1):120-8
25 Gender identity development in adolescence (2013) Horm Behav. 64(2):288-97
26 Brain changes associated with cognitive and emotional factors in chronic pain: A systematic review (2017) Eur J Pain. 21(5):769-786
27 Bullying at workplace and brain-imaging correlates (2018) J Clin Med. 7(8)pii:E200
28 Bullying and PTSD symptoms (2012) J Abnorm Child Psychol. 40(6):901-11
29 Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. (2006) Ann N Y Acad Sci. 1071:67-79
30 Long-term effects of bullying. (2015) Arch Dis Child. 100(9):879-85
31 Gender identity and the management of the transgender patient: a guide for non-specialists (2017) J R Soc Med. 110(4):144-152
32 Endocrine News, May 2014 issue by the Endocrine Society

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Cool)) I didn't thought that brain has a gender