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.

To name substances we use the International Nonproprietary Name if allocated and known. To minimize confusion we refer to esters of steroids by their traditional name; these names correspond to archaic names of carboxylic acids. For example we use “estradiol valerate” instead of “estradiol pentanoate”. “valerate” comes from the archaic name of pentanoic acid: “valeric acid”. When naming the acids the systematic name must be used. Thus referring to pentanoic acid as “valeric acid” is unacceptable.

2 Endogenous sex hormones

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; only a brief summary is given next.

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 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.

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 and follicle-stimulating hormone. 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 details on the chemical structure and pharmacodynamics of GnRH, LH and FSH, see Kleine, Rossmanith (2016).

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.

Stricker et al. (2006) investigated the levels of gonadotrpoins, estradiol and progesterone in normal cis women of reproductive age. We assume measurements of estradiol and progesterone refer to total (not free). The highest level of total estradiol observed is during the lutenizing hormone peak. The amount observed at that time of the menstrual cycle is median: 671 pmol/l, 95th percentile: 1 880 pmol/l. The highest level of total progesterone observed is during the mid-lutear phase. The amount observed at that time is median: 36.2 nmol/l, 95th percentile: 54.3 nmol/l. All quantities reproduced in this paragraph were rounded to 3 significant digits from those reported in the paper, round to nearest with ties to even.

3 Hormone replacement treatment

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

Pharmacologically the goals of MTF HRT are:

• Suppress the activation of the nuclear androgen receptor to prevent further masculinization and partially revert its already-present effects.
• Activate the nuclear estrogen receptors to cause feminization.
• Optionally, activate the progesterone receptors. This is speculated to result in increased feminization. As of 2020 the effects of progesterone on feminization are not well characterized.

There are 2 usual ways to achieve this:

• With a high dose of an estrogen and nothing else. This causes enough activation of the estrogen receptors to decreased production of gonadotropins.
• With a moderate dose of an estrogen and a separate anti-androgen. (see § Anti-androgens below).

Idrus, Hymans (2014) reported about the HRT regimes and effects of transsex people in Indonesia which self-medicate.

3.1 Effects

3.1.1 Sexual function

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.

A common side effect of HRT is lowered libido after starting lasting for week to months. Depending on the user this may be a desirable or undesirable effect. In the experience of the author and other transsex people that shared their experience through personal communication, libido rises after some weeks to months on HRT. If the user wishes to increase libido, bupropion can be used. Crenshaw et al. (1987) found bupropion to be effective in raising libido in cis males and cis females. Wibowo, Wassersug (2013) found that estrogens increase sexual interest in biological males.

Schneider et al. (2017) and Jindarak et al. (2019) examined the effects of HRT on testicular tissue and function.

3.1.2 Breast growth

Breast growth in MTF transsex people tends to be different than in cis women. MTFs tend to grow breasts conical in shape that are smaller and firmer than typical breasts of cis women. In the author’s opinion, the typical MTF breasts are more aesthethic and more desirable than the bigger and less firm hemispherical brestas typical of cis women.

Vandenberg (2006) found a non-monotonic response of size of breasts developed as a function of the dose of exogenous estrogen administered to ovariectomized female mice. Size of breasts was smaller in mice administered the highest dose of estradiol than mice administered an intermediate dose. The optimum dose for breast growth in humans can not be extrapolated from this study because metabolization of pharmaceuticals does not scale linearily with body mass and the growth of the human body is slower than that of mice. This result suggests the hypothesis that to maximize breast growth in transsex people it can be appropriate to use a lower dose of the estrogen or increase the dose slowly. However many HRT regimes rely on the estrogen to suppress endogenous androgens; therefore, starting with low dose of an estrogen potentially risks some degree of continued masculinization and sub-optimal feminization.

3.1.3 Immune response

Estrogens appear to increase the strength of the immune system to disease and progestogens to decrease it. Davis et al. (2017) found that estradiol delays onset of influenza and fastens recovery in mice compared to placebo and progesterone has the opposite effect.

3.1.4 Other

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.

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

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.

3.2 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.

3.2.1 Oral ethynylestradiol

Take 2 pills of Diane-35 per day. Take the pills preferentially always at the same time of the day, every 12 hours; timing within a day is not critical. 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).

3.3 Anti-androgens

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.

In cases other than when using androgen receptor inhibitor the suppression of androgenicity can be evaluated by total testosterone levels. We recommend to aim at a level of free testosterone ≤ 1.0 nmol/l. This is lower than the upper reference value for cis women and achieveable with the regimes mentioned in this aricle. When an androgen receptor inhibitor is used the level of circulating testosterone is not indicative of androgenic activity.

3.3.1 Algestone acetophenide

Algestone acetophenide (a.k.a. dihydroxyprogesterone acetophenide, DHPA) is a progestogen. Like other progestogens it is an anti-androgen through suppression of synthesis of endogenous androgens. The first description of algestone acetophenide seems to be in Fried (1960) where it is referred to as “acetophenone derivative of 16α,17α-dihydroxyprogesterone”. According to Recio et al. (1986), the first to employ algestone acetophenide as an human anticonceptive was Taymor et al. (1964).

Lerner et al. (1961) examined the effect of of algestone acetophenide administered orally and parenterally in rats. They found it to be a strong progestogen without androgenic, estrogenic nor corticoid activity. They found that it has a long duration of action, continued up to 25 days after injection. This study did not invetigate pharmacokinetic parameters. A possible point of confussion is that this paper states that no anti-androgenic activity was found. By this it is meant that algestone acetophenide did not inhibit the direct action of androgens in target tissue, not that it is not an anti-androgen in the sense used in this article.

Newton (1994) reviewed the high-level clinical aspects of algestone acetophenide and other progestogens used as anti-conceptives in cis women.

3.3.2 Cyproterone acetate

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. 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).

CPA must be combined with an estrogen for effective suppression of testosterone. Toorians et al. (2003) found that 100 mg/d of CPA without an estrogen was not enough to suppress testosterone in biological males (average level in group that received 100 mg/d of CPA only: 8.1 nmol/l). Tack et al. (2017) found that after 1 year of treatment with 50 mg/d of CPA without an estrogen the level of free testosterone was not properly suppressed (average: 7.84 nmol/l). In a group with dose of oral estradiol increasing up to 1 mg/d they also found insufficient suppression of testosterone after 1 year at which this was the estrogen dose (average: 5.82 nmol/l). Fung et al. (2017) found that a dose of 25 mg/d along with oral estrogens is sufficient to suppress testosterone in MTF transsexuals to below cis female levels. In a group that received 25 mg/d of CPA with different oral estrogen dose (average ~3 mg/d) the free testosterone concentration was 0.9 nmol/l.

3.3.3 Medroxyprogesterone acetate

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.

3.3.4 Spironolactone (not suitable)

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.

3.4 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).

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.

3.4.1 Ethynylestradiol

Ethynylestradiol is an estrogen obtained by subtituting an hydrogen atom at the 17α position of estradiol with an ethynyl group. The name “ethinyl estradiol” can also be found in the literature to refer to the same compound; we regard that name as incorrect becuase the name of the functional group is “ethynyl”, not “ethinyl” and functional groups in subtitutive nomenclature are written without a separating space (example: “chlorobenzene”, not “chloro benzene”).

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 indicative that the substance is more effective, only that a lower dose will be required for a similar effect.

Oral ethynylestradiol is effective in suppressing testosterone. Lübbert et al. (1992) found ethynylestradiol only 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. Shearer (1973) found that 100 mg/d of ethynylestradiol only, split in 2 doses per day lowered total testosterone to around 2.6 nmol/l in prostate cancer patients; no number is given, this is an estimate of the mean of the data in the graph.

Jain et al. (2006) report K_d(ethynylestradiol-human ERα) = 2.0 nmol/L, K_d(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”. Toorians et al. (2003) compared head to head the effects of CPA alone, CPA with transdermal estradiol and CPA with oral ethynylestradiol on circulating estradiol, testosterone, coagulation factors and gonadotropins.

3.4.2 Estradiol esters

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.

3.5 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.

3.6 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.

4 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”.

5 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.

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 not a direct equivalence, because the pharmacokinetics are different. This data is not directly applicable to oral delivery because different substances can have different availability.

6 Hypodermic needles

Gauges of hypodermic needles used for intravenous injections, intramuscular injections, subcutaneous injections, blood extraction and local anesthesia infiltration are listed below. Outer diameters and colors are from Indian Standard IS 16004 which is equivalent to ISO 6004. Thicker gauges are standardized but not commonly used for these purposes; consult the standard for the full list.

7 References

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