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Testosterone Toxicity Implicated

Testosterone Toxicity Implicated

  By Anne Vitale Ph.D. -- Mar 17, 2022

Notes on Gender Role Transition
Anne Vitale PhD, Editor

T-Note 15
Testosterone Toxicity Implicated in Male-To-Female Transsexuals? Some thoughts.

Anne Vitale Ph.D.
March 21, 2009

Long before I saw my first case involving a Male-To-Female (MTF) transsexual who decided to take testosterone in order to return to living her life in the male gender role (more about that below), I became suspicious of testosterone being the hormone that causes gender dysphoria in some genetic males. Obviously this is not true for the vast majority of males, they do just fine on normal levels of testosterone (300-999 ng/dl). However, a subset of genetic males appear to respond to testosterone in a manner that evokes an overwhelming desire to express feelings of femininity. I know that sounds counterintuitive but hear me out.

When we take into account that all perinatal males experience defeminization of the brain (Wallen and Baum (2002), thereby leaving them incapable of female behavior and sensibility, by testosterone that is converted to estradiol by a process of aromatase, it is not too hard to imagine, that for some reason, yet to become clear to science, that that process could easily have been disrupted leading to incomplete masculinization of some male brains. In addition, to account for the periodic need to cross dress in certain males, I predict that eventually we will find that as testosterone levels rise above some threshold in the daily lives of these males (Ahokoski et al 1998), that the enzyme aromatase becomes active and temporarily converts testosterone into estradiol forcing a strong desire to dress and live, even if only temporarily, as a woman.

Here are some observations:

It is well known that the body works very hard to maintain hormonal homeostasis. Both sexes naturally produce both androgenic and estrogenic compounds. Males produce levels of androgens, primarily from the testes, significantly high enough to not only maintain male secondary sex characteristics and male demeanor but also to limit the effect endogenous estrogens, also produced from the testes, from inducing feminizing effects on their body. The opposite is true for genetic females. Females produce sufficiently high levels of estrogens, primarily from the ovaries, to not only maintain their female secondary characteristics but to also limit any masculinizing effect the low levels of endogenous testosterone produced in the adrenals may have on their body. Essentially masculine homeostasis in males is maintained by a “balanced” high testosterone to low estradiol ratio and feminine homeostasis in genetic females is maintained by a “balanced” high estradiol to androgens ratio. This A/E relationship is dynamic over the life span. As estrogen levels decrease (women experiencing menopause), testosterone levels automatically increase to maintain homeostasis. The opposite is true, when testosterone levels in older males decrease, estrogen levels automatically increase in response. The result is softer skin and minor breast development.

What is significant about this paradigm is that the androgen/estrogen hormonal relationship can be manipulated artificially. With the exogenous administration of cross sex hormones, the A/E ratio can be completely reversed leading to significant physical and emotional alteration to an individual’s appearance and demeanor.

It is well known that large doses of exogenous estrogens administered to some genetic males, dramatically reduces the anxiety of gender dysphoria. The same outcome is true when gender dysphoric genetic females take testosterone. (i.e. Testosterone increases-->Estrogen decreases = feelings of well being). In this later case, it is reasonable to believe that what would otherwise be normal levels of estrogen in most women, can have an anxiety invoking effect in others.

It is also known that the administration of cross sex hormones MUST be maintained to sustain the anxiolytic effect. It is not unusual for some patients, feeling better after starting hormones, to believe they are cured and no longer need to continue the medication. Unfortunately what they experience is a quick return of their gender dysphoria. If there is any physical test to determine who should seriously consider partial or full transition, taking cross sex hormones is it.

Case study 1.: In 2005 a genetic male who had transitioned to the female gender role (Sex Reassignment Surgery in the mid 1980s) and had been living happily--or at least contently--as a woman for 20 years, presented to me with relationship issues. What is significant about this case is that the individual made the appointment using her legal female name (S.) but presented as an individual with a male appearance and a subdued but obvious male demeanor.

On further discovery, it was learned that two years earlier, while S. was still living in the female gender role, she met a woman and fell in love. They started dating and eventually cohabiting. As is common with most MTFs, her libido was low to nonexistent. To please her girlfriend, she returned to the doctor who originally prescribed her estrogen, and asked to be put on testosterone to increase her libido.

However, along with the increase in libido, the testosterone caused a re-masculinization of her body. To complicate matters, the girlfriend not only enjoyed her partner's increased libido, she also enjoyed the masculinization and encouraged S. to take increasingly massive doses of testosterone. In time S. had in effect retransitioned back to looking and presenting as a male.

To S's surprise, a strong unrelenting desire to be a woman returned to pre-transition levels. Still owning a large female wardrobe, she started to cross dress to relieve the anxiety. The problem now was that the girl friend was upset over seeing her, now male looking lover, wearing women's clothes and was threatening to leave her unless she stopped. Totally distraught over her situation, S. came to me in the hope that I could help to save the relationship. In the end S. realized that in order to find peace, she needed to give up the relationship, stop taking the testosterone and resumed an estrogen regimen. She is now happily--or at least contently--once again living in the female gender role.

Case Study 2.: In a similar vein, I recently received an email message from a genetic male who had transitioned, complete with SRS, to living in the female gender role in the early 1980s. Over the last several years the individual, expressing regret for having transitioned, reported that he had been very active over the internet as an anti-transition advocate. Having read my previous report on what role I believe testosterone plays in exciting feelings of femineity in some males, he contacted me telling me that in an attempt to remasculinize, he made three attempts at taking testosterone, all with the same result. Puzzled by it all, he writes:

"That's the third time I've taken testosterone and every time I've had overwhelming desires to present myself as a female."


Another factor to consider is the oft reported unrelenting, persistent nature of untreated gender dysphoria chronic across the entire life span. In order for that to be, there must be an ongoing, disconnect between androgen/estrogen levels produced by the body and what receptors in the brain have been wired to expect. Evidence of sexual differentiation of the brain has been documented by research. Here I copy, in full, a passage from my essay "Current Thinking Regarding the Etiology of Gender Dysphoria" written in 2002

"Zhou J.-N, et al. (1997) 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 as a result of an interaction between the developing brain and sex hormones".

In a follow-up study KRUIJVER et al. (2000) 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 in relation 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.”

Conclusions: It is beyond dispute that there are both androgen and estrogen receptors in the brain. Genetic males normally have more active androgen receptors than women and women have more active estrogen receptors then men. That this “normal” distribution of estrogen and androgen receptor cells can be different in some individuals appears to be a possibility. It therefore follows that androgenic and estrogenic compounds will result in a modified-to-counter expected behavior in affected individuals. For reasons beyond the scope of this Note and as counterintuitive as it may seem, it can only be assumed that testosterone plays a crucial role in forcing certain male individuals to crossdress and experience femininity to the maximum degree possibly.


Kruijver, Frank P. M., Zhou Jiang-Ning, Pool Chris W., Hofman Michel A., Gooren Louis J. G. and Swaab Dick F. (2000), Male-to-female transsexuals have female neuron numbers in a limbic nucleus, J Clin Endocrinol Metab 85: 2034&endash;2041.

Vitale A., (2002), Current Thinking Regarding the Etiology of Gender Dysphoria http://www.avitale.com/etiologicalreview.htm

Zhou J.-N, Hofman M.A, Gooren L.J, Swaab D.F (1997), A sex difference in the human brain and its relation to transsexuality, Int J Transgenderism 1,1, http://www.symposion.com/ijt/ijtc0106.htm.

Handa R. J., Andersen M.E., Teeguarden J, and Conolly R. B. ( 2005), Non-Linear Dose Response Relationships for Developmental Responses: An Example with Defeminization by Estrogenic Xenobiotics Colorado State University; CIIT Centers for Health Research; Environ Corporation.

Wallen K. and Baum M.J. (2002), Masculinization and Defeminization in Altricial and Precocial Mammals: Comparative Aspects of Steroid Hormone Action. Hormones Brain and Behavior Volume four.

Ahokoski O; Virtanen A; Huupponen R; Scheinin H; Salminen E; Kairisto V; Irjala K (1998) Biological day-to-day variation and daytime changes of testosterone, follitropin, lutropin and oestradiol-17beta in healthy men. Clin Chem Lab Med. 1998; 36(7):485-91 (ISSN: 1434-6621)

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