Reprinted fromThe Gendered Self--Further commentary on the transsexual phenomenon

May 23, 2011

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Current Thinking on the Etiology of Gender Dysphoria

By Anne Vitale Ph.D.

(2010, pp 13-16)

There is no clearly understood cause for gender variance. However, we have enough information about fetal brain development and the procedure the embryo goes through in becoming either male, female or intersexed, to implicate the complexity of the procedure itself as a cause of the spontaneous sex reversal or potential sex/gender discontinuity (1). What follows is an abbreviated sample of what we now know about what goes on relative to being gendered physiologically.

Genderizing the Brain: Evidence of sexual differentiation of the brain has been documented by research. Two studies in particular are of note.

Zhou J.-N, et al. (2) examined the volume of the central subdivision of the bed nucleus of the stria terminalis (BSTc), and found that a female-sized BSTc was found in male-to-female transsexuals. This led them to declare that a female brain structure exists in genetically male transsexuals, supporting the hypothesis that gender identity develops in the fetus as a result of an interaction between the developing brain and sex hormones.

In a follow-up study Kruijver, et al.(3) wanted to know if the reported difference according to gender identity in the central part of the bed nucleus of the stria terminalis (BSTc) was based on a neuronal difference in the BSTc itself or a reflection of a difference in vasoactive intestinal polypeptide innervation from the amygdala.

To do this they looked at 42 subjects to determine the number of somatostatin-expressing neurons in the BSTc relative to sex, sexual orientation, gender identity, and past or present hormonal status. They found that regardless of sexual orientation, men had almost twice as many somatostatin neurons as women. The number of neurons in the BSTc of male-to-female transsexuals was similar to that of the females, while the neuron number of a female-to-male transsexual was found to be in the male range. Hormone treatment or sex hormone level variations in adulthood did not seem to have influenced BSTc neuron numbers. They go on to declare that:

"Findings of somatostatin neuronal sex differences in the BSTc and its sex reversal in the transsexual brain clearly support the paradigm that in transsexuals sexual differentiation of the brain and genitals may go into opposite directions and point to a neurobiological basis of gender identity disorder."

Even though the brain has both androgen and estrogen receptors, the male brain has been found to be markedly different from the female brain. Not only is the male brain larger and more capable of spatial perception, researchers studying the brains of male and female rats have found evidence that prior to being masculinized, the genetic male brain must first be defeminized,(4-7) a process by which males lose the ability to display female-type behavior.

Once in the fetal brain, testosterone is either metabolized into dihydrotestosterone by an enzyme named 5 alpha reductase or converted to estradiol by an enzyme called aromatase. Counterintuitively, increased estrogen receptor activation is responsible for defeminization while increased androgen receptor activation seems to be responsible for masculinization.(8,9) All this makes clear that there is nothing straightforward about an individual being born with a gender identity that matches their biological sex.

This leads one to consider the possibility that male hormonal surges must occur not only in sufficient amounts in the developing fetus, but must be timed to take advantage of the short time the brain is open to being defeminized/masculinized, forming a predominantly male gendermap. If there is insufficient androgen, or the surge comes too late, the gendermap may be only partially imprinted as male. These disruptions of hormonal surges may come from a variety of sources, including a disorder in the mother's endocrine system such as a hormone-secreting tumor, common maternal stress, medications or some other toxic substance or adverse event yet to be identified.

Being the default condition, genderizing the genetic female brain is far less complex but still subject to having something stray from the norm. If nothing untoward happens, the brain remains female and the individual feels no dis-ease with her body. However, there remains the possibility of a defeminizing/masculinization event to occur for both sexes in utero.

Gender identity, far from being absolute, appears to occur on a continuum, with most people gathered at either end, the rest being somewhere in between. Feelings of discomfort or complete inappropriateness about one's assigned sex do not mean the individual is wrong or ill. It simply means that the assignment made at birth almost universally on the shape of one's genitals can, on occasion, differ from the unseen brain imprint.


1.) K. D. Dohlera, S. S. Srivastavaa, J. E. Shryneb, B. Jarzaba, A. Siposa, R. A. Gorskib (1984). Differentiation of the sexually dimorphic nucleus in the preoptic area of the rat brain is inhibited by postnatal treatment with an estrogen antagonist. Neuro Endocrinology Vol. 38, No. 4, pp 297-301

2.) J-N Zhou, J., A. Hofman., L. Gooren, and D. F. Swabb (1995). A sex difference in the brain and its relation to transsexuality. Nature, Vol. 378, pp 68-70.

3.) F. M. Kruijver, J-N Zhou, C. W. Pool, M. A. Hofman, L.J.G. Gooren, and D. F. Swaab (2000). Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endo Metab Vol. 85, No. 5, pp 2,034Ð2,041.

4.)R. C. Pillard and J. D. Weinrich (1987). The periodic table model of the gender transpositions: Part I. A theory based on masculinization and defeminization of the brain. J Sex Res, Vol. 23, No. 4, pp 425-454.

5.) O. B. Ward (1992). Fetal drug exposure and sexual differentiation of males. In Handbook of behavioral neurobiology, Vol. 11: Sexual differentiation (A. A. Gerall, H. Moltz, and I. L. Ward, eds.). New York: Plenum.

6.)K. E. Kudwa, C. Bodo, J-A. Gustafsson, and E. F. Rissman (2005). A previously uncharacterized role for estrogen receptor: defeminization of male brain and behavior. PNAS Vol. 102, No. 4, pp 608-4,612.

7.) A. P. Auger, M. J. Tetel, and M. M. McCarthy (2000). Steroid receptor coactivator-1 (SRC-1) mediates the development of sex-specific brain morphology and behavior. PNAS Vol. 97, No. 13, pp 7,551-7,555.

8.) D. G. Zuloaga, D. A. Puts, C. L. Jordan, and S. M. Breedlove (2008). The role of androgen receptors in the masculinization of brain and behavior: what we've learned from the testicular feminization mutation. Hormones and Behavior Vol. 53, pp 613Ð626.

9.) J. Imparto-McGinley, R. Peterson, T. Gautierm and E. Sturla (1979). Androgens and the evolution of male-gender identity among male pseudohermaphrodites with 5-alpha reductase deficiency genetics. Genital anomalies and intersexuality. Obstetrical & Gynecological Survey. Vol. 34, No. 10, pp 769-773

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