Issues with the Trans Brain Sex Hypothesis: Part 1 - The BSTc
This is part one in a series analyzing the evidence for the “brain sex hypothesis.”
Illustration by Cynthia (@PTElephant).
Introduction
One prevailing hypothesis within online communities and among gender activists is the ‘brain-sex hypothesis’, which posits that gender dysphoria is rooted in having a brain that aligns with a different sex (for instance, a male body with a female brain). This theory often leans on two studies conducted in the mid-1990s and early 2000s: Zhou et al. (1995) [1] and Kruijver et al. (2000) [2]. Both studies delved into an area of the brain within the hypothalamus called the central sub-division of the bed nucleus of the stria terminalis (BSTc), a region traditionally associated with fear responses and closely linked to neural circuits involved in anxiety and depression [3]. Despite these studies’ popularity among activists, their utility in providing clear answers is subject to scrutiny. This brief essay sets out to explore the potential role, if any, that the BSTc plays in gender dysphoria. It aims to shed light on the intricate factors contributing to the variability in the BSTc within the context of gender dysphoria.
Main text
The initial paper (Zhou et al. [1]) examined the BSTc volume in six male-to-female transsexuals (MtFs) by studying vasoactive intestinal polypeptide (VIP) fibre innervation originating from the amygdala. The VIP is involved in neuronal coupling and the generation of circadian rhythms, expressed primarily within the suprachiasmatic nucleus located within the hypothalamus. The findings of the study indicated that the BSTc in males was 44% larger than in females (2.49 mm3 vs 1.73 mm3, respectively) . In MtFs undergoing cross-sex hormone treatment, the BSTc volume aligned with the female range (even showing a non-significant trend to be even smaller than females; P = 0.13) and appeared independent of sexual orientation, as homosexual males exhibited sex-typical volumes (MtFs had mixed sexuality’s). Moreover, it was suggested that cross-sex hormone treatment had no effect on BSTc volume as seen via the female-typical BSTc from a 46-year-old woman with an adrenal tumor (for 1 year) that produced high blood testosterone. Furthermore, two post-menopausal women (>70 years) also exerted sex-typical BSTc volume.
In the second paper (Kruijver et al. [2]), the authors evaluated the same six MtF brains to investigate the number of neurons expressing the peptide somatostatin (SOM). Control males were found to have 71% more SOM-expressing neurons than females (32.9 x10^3 vs 19.2 x10^3, respectively). Further, the volume of the BSTc was this time found to be 4.60mm3 in males and 3.38mm3 in females (the larger reported volume here is presumably because SOM expression arises in the cell nuclei of the BSTc, whereas VIP fibre innovation is downstream of the amygdala and may not reflect a true BSTc sex difference). Presumed homosexual males displayed male-typical patterns (5.00mm3), while MtFs fell within the female range (3.58mm3), albeit non-significantly (P = 0.83). No difference was observed between early on-set (homosexual) vs late on-set (heterosexual) transexual sub-groups.
Both studies suggested that sexual orientation may not have a significant impact on BSTc size in MtFs. This idea gains some support (at least for this nuclei) from the observation that homosexual males displayed BSTc volumes consistent with their biological sex. However, it is important to reevaluate the reported sexual orientation of the MtFs, which may not be as mixed as initially assumed. Homosexual transsexuals tend to initiate hormone therapy at a younger age, around 26 years [4], while heterosexuals do so later, around 34 years [4]. Considering this, the six MtFs in the studies were relatively older at the commencement of hormone therapy (refer to Table 2 in Kruijver et al. [2]), suggesting they may align more with the heterosexual subtype. This raises the possibility that reduced BSTc volume could be associated with Autogynephilia (AGP; a male’s propensity to be sexually aroused by the thought of himself as a woman [5]).
Nevertheless, the most likely factor contributing to these findings appears to be the cross-sex hormones themselves. It is crucial to note that the duration and intensity of hormone exposure in the woman with the adrenal tumour and post-menopausal women significantly differed from that of MtFs, who were exposed to sex-atypical hormone levels for up to 20 years. Consequently, the effects of BSTc volume may not be directly comparable.
Subsequent research has illuminated the influence of cross-sex hormones on brain volumes, particularly within hypothalamic regions, consequently affecting the BSTc. In a study by Hulshoff et al. (2006) [6], eight MtFs and six female-to-male transsexuals (FtMs) underwent magnetic resonance imaging (MRI) before and during a four-month interval of cross-sex hormone therapy. MtFs received anti-androgens (cyproterone acetate; 2 x 50 mg/day) and synthetic estrogen (ethinylestradiol; 2 x 50 µg/day), while FtMs received parenteral testosterone esters (250 mg/2weeks). Compared to control males, MtFs exhibited reduced hypothalamic and overall brain volumes, shifting towards female proportions. Conversely, testosterone administration to FtMs led to increased brain volumes. These effects appeared to be associated with changes in ventricular volume, a finding that has been replicated [7].
Another critical challenge in utilizing the BSTc as a causal mechanism to explain gender dysphoria lies in its delayed sexual differentiation. In rodents, the BST shows sexual dimorphism within the first two weeks of life [8], whereas in humans, this differentiation occurs much later in adulthood [9]. A study by Chung et al. (2002) [9] examined post-mortem brains from twenty-five males and twenty-five females, spanning an age range from 26 weeks of gestation to 48 years, by staining the BSTc for VIP and SOM . While the volume of the BSTc increased in both sexes during the transition from fetal to pubertal development, only the male BSTc continued to expand into adulthood, typically around 30 to 35 years of age, ultimately establishing sexual dimorphism. Given that gender dysphoria is believed to manifest at a relatively young age [10], the notion that the BSTc, which undergoes sexual differentiation late in human development, plays a causal role in this condition becomes increasingly improbable.
Lastly, it is worth noting that the original study by Zhou et al. was not hypothesis-driven but rather exploratory. They examined multiple hypothalamic regions, including the suprachiasmatic, supraoptic, and paraventricular nuclei, and found no significant differences. In essence, the BSTc was not the primary region of interest in their analysis. Furthermore, neither of the two papers (Zhou & Kruijver) has undergone attempted replication since their initial publication. This is a significant point to consider, particularly given that since the discovery of four neural clusters in the hypothalamus, coined as the interstitial nuclei of the anterior hypothalamus (INAH 1-4) [11], the same research group initially believed that the INAH-1 was homologous to the sexually dimorphic nuclei of the preoptic area (SDN-POA) seen in rodents due to observed sexual dimorphism [12]. However, subsequent attempts to replicate these findings did not consistently support this hypothesis [11, 13]. As a result, it is now widely assumed that INAH-3 is the correct homologous nucleus [13, 14], underscoring the critical importance of replication studies, especially when working with small samples.
Conclusion
In summary, the sexual orientation of the MtFs in these studies appears to have leaned more towards heterosexuality, challenging the assumption of mixed orientation. Moreover, the utilization of cross-sex hormones likely played a significant role in the observed variations in BSTc size and neural composition. Taking this into consideration, the existing data do not provide conclusive evidence to support the notion that the BSTc in transgender individuals is inherently determined or directly linked to the experience of gender dysphoria. While the BSTc has been the focus of significant research interest, it is clear that multiple factors, including the hormonal exposure and the timing of hormone therapy initiation, play vital roles in shaping the brains structural characteristics within this context. As such, the complex relationship between brain structure and gender dysphoria continues to be an area of on-going investigation and debate.
We are 100% independently funded. If you like our work, consider making a donation.
References
Zhou, J.N., et al., A sex difference in the human brain and its relation to transsexuality. Nature, 1995. 378(6552): p. 68-70.
Kruijver, F.P., et al., Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab, 2000. 85(5): p. 2034-41.
Lebow, M.A. and A. Chen, Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders. Mol Psychiatry, 2016. 21(4): p. 450-63.
Smith, Y.L., et al., Transsexual subtypes: clinical and theoretical significance. Psychiatry Res, 2005. 137(3): p. 151-60.
Lawrence, A.A., Autogynephilia and the Typology of Male-to-Female Transsexualism. Controversial Issues in Human Sexuality Research: The State of the Science, 2017. 22(1): p. 39-54.
H., H., et al., Changing your sex changes your brain: influences of testosterone and estrogen on adult human brain structure. European Journal of Endocrinology, 2006. 155: p. 107-114.
Seiger, R., et al., Subcortical gray matter changes in transgender subjects after long-term cross-sex hormone administration. Psychoneuroendocrinology, 2016. 74: p. 371-379.
Chung, W.C., D.F. Swaab, and G.J. De Vries, Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain. J Neurobiol, 2000. 43(3): p. 234-43.
Chung, W.C., G.J. De Vries, and D.F. Swaab, Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. J Neurosci, 2002. 22(3): p. 1027-33.
Nieder, T.O., et al., Age of onset and sexual orientation in transsexual males and females. J Sex Med, 2011. 8(3): p. 783-91.
Allen, L.S., et al., Two sexually dimorphic cell groups in the human brain. J Neurosci, 1989. 9(2): p. 497-506.
Swaab, D.F. and E. Fliers, A sexually dimorphic nucleus in the human brain. Science, 1985. 228(4703): p. 1112-5.
LeVay, S., A difference in hypothalamic structure between heterosexual and homosexual men. Science, 1991. 253(5023): p. 1034-7.
Saper, C.B., The intermediate nucleus in humans: Cytoarchitecture, chemoarchitecture, and relation to sleep, sex, and Alzheimer disease. Handb Clin Neurol, 2021. 179: p. 461-469.
