Pharmacology of transsexualism 2018-12-04T03:41:38Z A compilation of notes and references to the scientific literature relevant to male-to-female transition.

Pharmacology of trans­sexualism

1. Terminology and concepts

We define “transsex” as the people who undergo a treatment to change their sexually dimoprhic features to resemble the other sex. The word “transsexual” is widespread for the same meaning; we prefer the term “transsex” to emphasize that it is about sexual dimorphism, not sexuality. We use the word “transsexualism” to refer to this phenomenon. We refer to people who are not transsex as “cissex” or just “cis”. This text concerns exclusively male to female transsex people. Male to female transsex people (MTFs) are also called trans women.

2. Hormone replacement treatment

For an overview at the endocrinological level of the signaling pathway responsible for progestogens, androgens and estrogens, see Golan et al. (2017) chapter 30 “Pharmacology of Reproduction”; this is required knowledge for any transsexual.

The main source of endogenous androgens in biological males are the testis. Additionally, in both sexes the adrenal glands secrete androgens. The main androgen produced by testis is testosterone. The enzymes 5α-reductases converts testosterone into 4,5-dihydrotestosterone (common abbreviation: DHT). DHT is a more potent androgen than testosterone, thus the effect of 5α-reductases is to amplify the action of testosterone selectively in the cells where it is expressed and unselectively by increasing circulating DHT. 5α-reductases are highly expressed in cells of the male reproductive system. There are 2 known types of 5α-reductases in humans. 5α-reductase type I (gene SRD5A1) is expressed in the liver and nongenital skin (among other tissues) and 5α-reductase type II (gene SRD5A2) is expressed in the prostate and genital skin (among other tissues). There are other genes classified under the SRD5A family that appear to not to participate in steroid metabolism (Stiles 2010); in specific Chávez (2015) found that the so-called “5α-reductase type III” (gene SRD5A3) does not act as a 5α-reductase in humans, i.e.: does not convert testosterone into DHT.

The synthesis of androgens in the testicles requires the presence of circulating lutenizing hormone (LH). Lutenizing hormone is a protein secreted by the hypophysis. Lutenizing hormone (LH) and follicle stimulating hormone (FSH) are collectively referred to as the gonadotropins. The production of adrenal androgens is not dependant on gonadoptropins.

Tebbens et al. (2019) examined quantitatively changes in facial dimensions on HRT with measurements taken over the skin; they found that HRT changes sexually dimoprhic dimensions towards female (see the paper for quantitative data).

Kranz et al. (2014) found that HRT decreases expression of the serotonin transporter in MTF transsexuals. Thus it is inferred, HRT has a similar effect to a serotonin reuptake inhibitor and increases the concentration of available serotonin.

In a review about multiple orgasms in biological males Wibowo, Wassersug (2016) mention that ejaculation and exposure to androgens may be at least in part responsible for the post-ejaculatory refractory period and thus the inability to have multiple orgasms in one sexual session in cis men. Kinsey (mentioned in Wibowo, Wassersug 2016) reported that among young males, capacity for multiple penile orgasms are more prevalent in kids and teens. Warkentin et al. (2016) reported a case of a prostate cancer patient who became penile-multi-orgasmic on anti-androgen treatment.

Leinung et al. (2018) studied the effect of estradiol alone, with spironolactone, and with finasteride on estradiol and testosterone levels. They found that oral estradiol slightly suppresses androgens. However, they found that administering estradiol together with either spironolactone or finasteride increases the level of testosterone compared to the same dose of oral estradiol alone.

Reviews of the pharmaceuticals used for HRT and its effects include Tangpricha, den Heijer (2016).

Ulrich et al. (1994) found that high-dose treatment with estrogen and progestogen depot injections quickly improved bone density.

2.1. Concrete HRT regimes

The following is a non-exhaustive collection of HRT regimes that the author considers useful. It is up to the reader to decide whether any of these regimes are suitable for her particular case.

Oral administration regime: Begin with 1 Diane-35 pill every day. After 30 days, raise the dose to 1.5 pills per day (that is, alternate between 2 pills one day and 1 pill the following one). Take the pills preferentially always at the same time of the day. Each pill of Diane-35 contains 35 μg of ethynylestradiol and 2 mg of cyproterone acetate. Any brand of pills with the same active ingredients as Diane-35 is suitable; known alternatives include Mileva-35 and Ginette-35. Missed doses: If the user remembers within the same day, take the pill(s) immediately. If it is more than a day, continue the regime as usual. Do not use this regime for people ≥ 35 years old or with a propensity for thrombosis. References: Lübbert et al. (1992), personal exprience of the author and reports of other transsexuals (through private communication with the author).

2.2. Anti-androgens

This section assumes basic knowledge of the hypothalamus-hypophysis-gonads axis from the reader, only a very succint review is given next. In a physiologically normal human, the hypthalamus secretes gonadotrpoin releasing hormone (GnRH) in slow pulses. The pulses of GnRH causes the hypophysis to secrete lutenizing hormone (LH) and follicle-stimulating hormone (FSH). In both sexes LH and FSH are necessary for the normal functioning of the reproductive system and for fertility. LH stimulates synthesis of testosterone in ovaries and testicles. For a more detailed summary see chapters previously mentioned in the book of Golan et al. (2017). For details on the chemical structure and pharmacodynamics of GnRH, LH and FSH, see Kleine, Rossmanith (2016).

Anti-androgens work by interfering with at least one step of the hypothalamus-hypophysis-gonads system or by preventing androgens from acting on the androgen receptor by competitive inhibition (silent antagonist). More specifically their mechanism of action may be classified as follow (categories are not mutually exclusive):

  • Progestogens and estrogens suppress release of gonadotropins by the hypophysis exploiting the natural negative feedback that sex hormones excert upon the hypophysis.
  • GnRH analogues activate GnRH receptors continuously (in contrast to endogenous GnRH which is released intermittently). Initially this causes a surge of testosterone but after approximately 7 days levels reach the same as pre-treatment and thereafter continue to decrease until testosterone is effectively supressed (van Poppel, Nilsson 2008).
  • GnRH receptor antagonists suppress activation of GnRH receptors by endogenous GnRH. Unlike GnRH analogues, GnRH receptor antagonists do not create an initial testosterone flare.
  • Androgen receptor inhibitors inhibit the action of all androgens by binding to the androgen receptors without activating them, thus preventing androgens from binding and activating those receptors. Examples include bicalutamide, flutamide and nilutamide.

Cyproterone acetate (common abbreviation: CPA) is the anti-androgen par excellence for male to female hormone replacement therapy (MTF HRT). CPA is a progestogen. Like other progestogens, it suppresses secretion of gonadotropins and thus of gonadal androgens. Additionally it acts as a partial agonist of the androgen receptor. Fung et al. (2017) found that a dose of 25 mg/d is sufficient to suppress testosterone in MTF transsexuals to below cis female levels. See Neuman (1994) for an account of the development and pharmacology of cyproterone acetate and of progestogens in general. Another review of the pharmacology of progestogens is Schindler et al. (2013).

Medroxyprogesterone acetate (common abbreviation: MPA) is an anti-androgen of the progestogen class. It is commonly available as solutions for depot injections and oral tablets. Johanson et al. (1986) investigated the pharmacokinetics of MPA on humans via oral intake. They found a half-life of 40 h to 60 h.

Spironolactone should not be used as an anti-androgen and is mentioned here only as an advertence. Spironolactone is a mineralocorticoid duiretic with weak progestogen activity which has been misused as an anti-androgen, especially in the United States. Liang et al. (2018) found that a HRT regime of oral estradiol and spironolactone failed to supress testosterone in the top quartile of biological males per pre-treatment level of testosterone. Leinung et al. (2018) found that estradiol alone suppresses testosterone better than if combined with spironolactone.

2.3. Estrogens

The main estrogens in cis women are estradiol, estrone and estriol, of which estradiol is the most potent. The commonly used estrogens for MTF transsex people are estradiol (17β-estradiol), 17β-esters of estradiol and ethynylestradiol. The reader interested the in pharmacodynamics, pharmacokinetics and structure-activity relationship of estrogens is recommended to consult Oettel et al. (1999a, 1999b).

17β-esters and occasionally 3-esters of estradiol are the common active compounds used for depot injection; these are pro-drugs that are convereted to estradiol within the body. The longer the ester chain, the slower the pharmacokinetics (longer time to peak dose and longer half life). Oriowo et al. (1980) compared the pharmacokinetics of 3 esters of estradiol administered as intramuscular depot injections with arachis oil as the carrier. They found the time to peak blood concentration as follows: estradiol benzoate: 1.8 d, estradiol valerate: 2.2 d, estradiol cypionate: 3.9 d. Garza-Flores (2014) compared the pharmacokinetics of 3 esters of estradiol again administered as depot injections. He found the time to peak blood concentration of estradiol to be as follows: estradiol valerate: 2 d, estradiol cypionate: 4 d, estradiol enanthate: 6.5 d, 8.1 d (the 2 numbers are for different medical centers).

In chapter 35 “Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens” of Oettel et al. (1999b) were reviewed the pharmacokinetics of estradiol via oral administration. The chapter cites a half-life of 1.7 h and 5.5 % bioavailability in young cis women for estradiol administered orally.

Kuhl (2005) found that ethynylestradiol is 120 times as potent as estradiol compared on a mass basis, oral administration. Note that an higher potency is not an indicative that the substance is more effective, only that a lower dose will be required for a similar effect. Lübbert et al. (1992) found ethynylestradiol to be effective in reducing gonadotropins and testosterone to below-castrate levels in an experiment done in a single healthy male. This suggests that when an high-enough dose is used for MTF HRT no additional anti-androgen is needed. Jain et al. (2006) report Kd(ethynylestradiol-human ERα) = 2.0 nmol/L, Kd(ethynylestradiol-human ERβ) = 8.1 nmol/L. In chapter 35 “Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens” of Oettel et al. (1999b) cite a mean oral availability for ethynylestradiol of 45 % and a half-life after intravenous administration between 6.8 h and 26.1 h varying among the primary studies included. The pharmacokinetics after oral administration are complicated; the chapter says “The time course of EE plasma levels following oral administration can be described, in most cases, by a two-compartment model. A rapid distribution phase is followed by a terminal disposition phase that is characterized by a half-life in the range of about 5 h-30 h”.

Wibowo, Wassersug (2013) found that estrogens increase sexual interest in biological males.

Schneider et al. (2017) examined the effects of HRT on testicular tissue and function.

Harrison et al. (2014) found that 17α-estradiol (an isomer of 17β-estradiol with diminished estrogenic potency) prolonges lifespan in a study with mice.

Estrogens are known to be responsible for the cessation of grow in height in both males and females. Therefore, transsexuals should not use estrogens until they reach their desired height or until ephyphyseal plates have ossified (because after ossification, there is no prospect of natural vertical growth). See Chagin, Sävendahl (2007). Transsex people and other people who desire a higher height but have already ossified growth disks can opt for limb lengthening by the method of distraction osteogenesis. This method was pioneered in the USSR by Gavriil Ilizarov. For small increments in height, the procedure can involve exclusively lengthening the femur. For higher increases, the femur, tibia, and peroné are lengthened, and optionally the arms for the sake of proportions. A full discussion of limb lengthening is beyond the scope of this text.

Giltay, Gooren (2000) studied the effect of HRT in production of body hair and skin oil (sebum). They found that “The hair diameter fell sharply within 4 months and remained rather constant thereafter, whereas the median growth rate and density on the cheek and upper abdomen dropped only slowly but progressively”. In other words, HRT will not make beard and mustache disappear; for that, temporary or permanent hair removal procedures like waxing, plucking, laser, intense pulsed light or electrolysis should be used. The same study found that production of skin oil decreased and was already very little after 4 months of HRT.

A common side effect of HRT is lowered libido. Depending on the user this may be a desirable or undesirable effect. If the user wishes to increase libido to pre-HRT levels or higher, bupropion can be used. Crenshaw et al. (1987) found bupropion to be effective in raising libido in cis males and cis females.

2.4. Selective estrogen receptor modulators

In a study on old post-menopausal women (56 to 66 years old) Francucci et al. (2005) found that raloxifene causes a change towards a female pattern of fat distribution.

2.5. Prolactin

Prolactin is an endogenous protein secreted by the hypophysis. Prolactin promotes the secretion of milk. Dopamine receptor agonists like cabergoline, bromocriptine and pramipexole can be used to reduce prolactin.

3. Melanogenesis inhibitors (skin, hair and eye whitening agents)

Statistically, women tend to have a lighter skin color than men. Given that skin color is sexually dimorphic to some degree, and a ligher skin color is more aesthetically desirable, skin whitening is a complement –not a substitute– for manipulaion of one’s primary sex hormones. Anecdotally, many transsexuals (including the author) with light skin report to have experienced further lightening concurrent with starting HRT. It can be conjectured that HRT has overall a skin whitening effect, but it could also be attributed to confounders (i.e.: spending more time indoors and under shadow). See the companion article “Pharmacological control of skin, hair and eye pigmentation”.

4. Conversion factors

There are 2 systems in widespread use to express concentration of substance in biological systems. One is mass concentration, expressed in units of mass per unit of volume. The other is amount of substance concentration, expressed in units of amount of substance per unit of volume.

Conversion factors for select sex steroids measured in blood tests
SubstanceMolar massEquivalence
Estradiol272.4 g/mol1 pg/ml ↔ 3.671 pmol/l
Progesterone314.5 g/mol1 ng/ml ↔ 3.180 pmol/l
Testosterone288.4 g/mol1 ng/dl ↔ 0.034 67 nmol/l

When estradiol or estradiol esteres are administered as depot injections, we assume 100 % bioavailability and complete cleavage of the ester group in estradiol esters. The relative potency is the total mass of estradiol released divided between the mass of the substance injected. For example, injectiong 10 mg of estradiol results in 10 mg of estradiol being released. Injecting 10 mg of estradiol enanthate results in 7.08 mg of estradiol being released. Note that this is no a direct equivalence, because the pharmacokinetics are different. This data is not directly applicable to oral delivery because different substances can have different availability.

Comparative potency of estradiol and esters used for depot injections
SubstanceRelative potency
Estradiol1.000
Estradiol cypionate0.687
Estradiol enanthate0.708
Estradiol valerate0.764

5. References

  • A. S. Chagin, L. Sävendahl (2007) “Oestrogen receptors and linear bone growth”. DOI: 10.1111/j.1651-2227.2007.00415.x.
  • B. Chávez et al. (2015) “Hamster SRD5A3 lacks steroid 5α-reductase activity in vitro”. DOI: 10.1016/j.steroids.2014.11.005.
  • T. L. Crenshaw et al. (1987) “Pharmacologic modification of psychosexual dysfunction”. DOI: 10.1080/00926238708403896.
  • C. M. Francucci et al. (2005) “Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women”. DOI: 10.1007/BF03347261.
  • R. Fung et al. (2017) “Is a lower dose of cyproterone acetate as effective at testosterone suppression in transgender women as higher doses?”. DOI: 10.1080/15532739.2017.1290566.
  • E. J. Giltay, L. J. G. Gooren (2000) “Effects of Sex Steroid Deprivation/Administration on Hair Growth and Skin Sebum Production in Transsexual Males and Females”. DOI: 10.1210/jcem.85.8.6710.
  • D. E. Golan et al. (2017) “Principles of Pharmacology: The Patophysiologic Basis of Drug Therapy”, 4th ed. ISBN: 9781451191004.
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  • D. E. Harrison et al (2014) “Acarbose, 17α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males”. DOI: 10.1111/acel.12170.
  • N. Jain et al. (2006) “Novel Chromene-Derived Selective Estrogen Receptor Modulators Useful for Alleviating Hot Flushes and Vaginal Dryness”. DOI: 10.1021/jm060353u, (supporting information).
  • E. D. B. Johansson et al. (1986) “Medroxyprogesterone Acetate Pharmacokinetics Following Oral High-Dose Administration in Humans: A Bioavailability Evaluation of a New MPA Tablet Formulation”. DOI: 10.1111/j.1600-0773.1986.tb00115.x.
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  • H. Lübbert et al. (1992) “Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal male”. DOI: 10.1016/s0015-0282(16)55271-6.
  • M. Tebbens et al. (2019) “Gender-Affirming Hormone Treatment Induces Facial Feminization in Transwomen and Masculinization in Transmen: Quantification by 3D Scanning and Patient-Reported Outcome Measures”. DOI: 10.1016/j.jsxm.2019.02.011.
  • F. Neuman (1994) “The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research”. DOI: 10.1055/s-0029-1211261.
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  • E. Wibowo, R. Wassersug (2016) “Multiple Orgasms in Men—What We Know So Far”. DOI: 10.1016/j.sxmr.2015.12.004.
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