Rationale
The practice of sex-reassignment for trans-sexual persons offers a rare possibility to study the effects of physiological substances (in this case, hormones) in a non-physiological situation. In this report our attention is devoted to the effect of a male sex hormone in adult biological females, that is persons who have not been exposed to high blood concentration of testosterone in the developmental age and puberty, and have therefore not undergone the body change that can be observed in biological males. Some of these effect can also be studied through the observation of hypo-gonadal syndrome and its therapy with testosterone administration in adult biological males.
Through testosterone replacement therapy, biological females undergo both irreversible and reversible body and metabolism changes, that's why the hormone has to be supplied all life long, with different administration tools.
There are also some side effects, even if some recent long term studies proved HRT for FtM to be quite safe (1,2,3).
Overview of Testosterone in the human body
First we take a look on the molecular and cellular pathways of testosterone, so that we can later understand better its effect on the level of whole sex-differentiated adult organisms.
Biosynthesis and related pathways:
From the KEGG map (Fig. 1), we can see that the main (with possibility for alternatives) pit stops in the pathways from cholesterol to testosterone (mainly implemented in the gonads and adrenal glands) goes through: 20alfa,22beta-dihydroxycholesterol, pregnenolone (an important divergent point between male and female sex hormones), and dehydroepiandrosterone (considered as a very important hormones in puberty and other pathways).
Still we can observe how testosterone is transformed in the tissues in its active form, 5alfa-dihydro-testosterone and other molecules. An important following pathway is the one bringing from testosterone to estradiol, this is the pathways used in the ovary to produce female hormones, but also in the body of biological males to produce certain effects, in particular the ones related to bone metabolism.
We just mention here (it's not our aim to go further deeply into this) the obvious fact that testosterone is biologically stimulated in the male gonads by the hypophyseal release of LH, which is under the control of the hypothalamic release of GnRH, and that it inhibits in a negative feedback both these hormones. Something similar, on a smaller scale, happens in the line CRH, ACTH, testosterone from the adrenal gland, reticular stratum.
Cellular effects:
Primarily, even if it has some effects also as testosterone per se, the hormone, as liposoluble, can enter the cell membrane, and in the cytoplasm it is transformed in 5alfa-dihydro-testosterone. As such it interacts with cytoplasmic receptor, provoking its conformational change and the release of proteins of the family of Heat Shock Proteins, and its transport to the nucleus and dimerisation. Here, it binds the Androgen Responsive Elements on the DNA sequence. In different cells, through this mechanism, the production of several proteins is enhanced, whose effect we can then observe at the macroscopical level. Among other it activates the IGH-1, as a common intermediate messenger with GH, and sharing thereby some of its effects.
Figure 1
Effects on FtM trans-sexuals
In the review by Moore et al. (4), the most important effects and the evidence for those is reported, and summed up here in Tabel 2, where the effects until “Increased muscle mass” are desired effects, and the following ones are unwanted side effects.
Table 2
Moore and colleagues, though, don't describe the mechanisms leading to such effects, we want here, where possible with the help of the literature, to advance some hypotheses about such mechanisms, and/or learn something about the general functions of the human organism and its gender differentiation.
Laryngeal prominence and deepened voice. This effect simply witnesses for the persistence of testosterone receptors in the laryngeal cartilage. We know that in puberty of biological males this cartilage is stimulated in its growth and thereby transforms the voice of the young male, while in females the lack of this stimulation let the larynx stay similar to that of children. The effect on FtM trans-sexuals tells us that this effect is totally under the control of testosterone, and that the possibility for this development is saved all life long, without “critical period”, that is it can be triggered whenever in life. The change is an irreversible one, as it can also be seen in post-puberty testosterone deprivation in hypogonadism or MtF trans-sexuals: larynx and voice cannot be changed.
Cessation of menses. This occurs also in those FtM trans-sexuals who are not ovariectomised, and thereby save a certain amount of female hormones. It is easy to advance the hypothesis that this effect is due to feedback interferences of a constant administration of testosterone on the hypothalamic-hypophyseal axis, leading to a lack of ovarian stimulation and possibly atrophy, as it can also happen with testicular atrophy in testosterone supplementation in body builders. This could also exert an effect on ovarian cancer.
Hirsutism, clitoral growth, redistribution of fat, increased muscle mass. As for laryngeal growth, these body changes show that particular tissues don't have a critical period for their testosterone triggered growth. Body hair bulbs can be transformed in a male pattern whenever and irreversibly throughout life. Also the clitoral tissue save some growth possibility, even if the transformation of this tissue in a penis can only happen through foetal stimulation, both this stimulation are then irreversible.
On the contrary redistribution of fat and increased muscle mass require a constant testosterone stimulation, and can be reversed if the administration is interrupted. Muscular and adipose cells are the ones that constantly undergo most changes, following different levels of activity and energetic balance in the body, so it is easy to understand that they are in every moment affected by the present state and concentration of different hormones and growth factors in the body. Other tissues, such as laryngeal and genital ones, don't require a constant determination in the shape they take, so it's determined once and forever.
Increased libido (and other psychological effects). This effect is accompanied by an increase in frequency of masturbation, sexual arousal, and ability to achieve orgasm (5). We enter here the grey field of psychological effect of hormones (others are also mentioned in Table 2, such as increased aggressiveness). We know that testosterone concentration in the foetal period can determine some brain differences in male and female (e.g. hypothalamic dimorphic nuclei), but the effect of testosterone in adulthood seems to tell us that such differences are not important in the differences in sexual behaviours. To achieve these effects, in fact, the hormone has to be administered constantly, and so we can see that its concentration, and not the shape of the brain, is responsible for this kind of effect. A further support of this view is that testosterone deprivation in biological male brings to a decrease in libido and ability to reach orgasm (6).
An interesting possible link is suggested by Giltay & coll. (7): they found that testosterone increases blood concentration of tryptophan, advancing the hypothesis that this can be required for an increase in the synthesis of neurotransmitters. As we know Trp is the precursor of 5-HT, and this is correlated with mood and libido. This gives us important (even if not conclusive) indications that most actions of testosterone also on psychological gender differences goes not through foetal influences on brain shape, but through continuous modification of neurotransmitters profile.
Psychological effects are anyway far more complex than the state of our science can explain, testosterone also affects cognitive differences between males and females (8): “Testosterone appears to activate a distributed cortical network, the ventral processing stream, during spatial cognition tasks, and addition of testosterone improves spatial cognition in younger and older hypogonadal men”. Also in this case we see that constant stimulation is more important than brain shape.
The same articles also describes effects on mood, that can also be better explained using the correlation with 5-HT already described, since it is an important mood modulator and depression inhibitor. On this issue, it was also described during the course, how different brain isoforms of 5alfa-reductase bring to a higher concentration of stimulator of NMDA and GABA receptors, with an improvement in mood and calm. Reduction of testosterone can, on the opposite, lead to hyper-activation and epileptic crisis.
The effect on mood is anyway very different in different persons, as also (6) reports, Zitzmann (8) suggests it is due to the fact that there are different genotype determined isoforms of androgen receptors, leading to possibly different effects.
Acne. This can be of course due to the stimulation of male patterns in sebo production, as in adolescent biological males, also this effect does not present, therefore, critical periods.
Increased hematocrit. We know that testosterone stimulates eritropoietin. The effect is also observed in hypo-gonadal men (6).
Poor lipid profile. This is mostly related with high level of cholesterol. Looking at the pathways of testosterone biosynthesis, and as it's generally known, cholesterol is the first precursor of all steroid hormones, so we can naturally suppose that external administration of one of them shifts “to the left” all reaction equilibria on this pathway, leading to an accumulation of the first precursor. That such a mechanism can explain the whole of cholesterol increase, has anyway to be further enquired.
Decreased insulin sensitivity. As it is generally known, part of the effects of testosterone, as for GH, are mediated through stimulation of IGF-1, similarly to GH testosterone can thereby have an effect on insulin sensitivity.
Effects on bones. Moore and coll. report lower bone density, but anyway the effect on bones is not really simple and can present different aspects. The effect of testosterone on bones can be direct, but mostly it acts through its aromatisation to estradiol. As Turner and colleagues (9) also report, the influence of sex hormones on bone density is exerted through concentration of osteoprotegerine (OPG) and soluble RANKL, affecting that way the re-absorption of bones matter. The effects can be also different in different parts of the body, leading to possible artefactual conclusion in different articles, due to different measurements. Turner and coll. write in fact: “supra-physiologic testosterone therapy increases BMD (Bone Mineral Density) at the hip while maintaining BMD at the spine in female-to-male transsexuals. The effects of testosterone may be the result of testosterone hormone directly acting on the bone or indirectly through aromatization to oestradiol. Lower RANKL levels coupled with unchanged OPG levels results in an increased OPG/RANKL ratio, which may be beneficial to the bone by inhibiting osteoclastogenesis”.
Cardiovascular effects and inflammatory processes. The initially hypothesised relation of testosterone and cardiovascular disease has not really been proved, and the results are quite different in different studies. An interesting study we would like to quote also brings no clearcut conclusions, but it explores a pathway involving the effect on COX2, whose obvious effects on inflammation and arteriosclerosis are not to be highlighted here: “Thus we conclude that DHT differentially influences COX-2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells. This effect of DHT on COX-2 involves androgen receptor-dependent and independent mechanisms, depending on the physiological state of the cell” (10).
References
1. Asscheman et al. 2011, A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones, European J. of Endocrinology, 164(4):635-42.
2. Traish & Gooren 2010, Safety of physiological testosterone therapy in women: lessons from female-to-male transsexuals (FMT) treated with pharmacological testosterone therapy, J. of sexual medicine, 7(11):3758-64.
3. Mueller et al. 2010, Effects of intramuscular testosterone undecanoate on body composition and bone mineral density in female-to-male transsexuals, J. of sexual medicine, 7(9):3190-8.
4. Moore et al. 2003, Endocrine Treatment of Transsexual People: A Review of Treatment Regimens, Outcomes, and Adverse Effects, The Journal of Clinical Endocrinology & Metabolism 88(8):3467–3473.
5. Wierckx et al. 2011, Quality of life and sexual health after sex reassignment surgery in transsexual men, J. of sexual medicine, 8(12):3379-88.
6. Bassil et al. 2009, The benefits and risks of testosterone replacement therapy: a review, Therapeutics and Clinical Risk Management, 5:427–448.
7. Giltay et al. 2008, Effects of sex steroids on the neurotransmitter-specific aromatic amino acids phenylalanine, tyrosine, and tryptophan in transsexual subjects, Neuroendocrinology, 88(2):103-10.
8. Zitzmann 2006, Testosterone and the brain, Aging male, 9(4):195-9.
9. Turner et al. 2004, Testosterone increases bone mineral density in female-to-male transsexuals: a case series of 15 subjects, Clinical endocrinology, 61(5): 560–566.
10. Osterlund et al. 2010, Dihydrotestosterone alters cyclooxygenase-2 levels in human coronary artery smooth muscle cells, Am J Physiol Endocrinol Metab. 298(4):E838-45.
