Posted by: maria | in Biology, Hormones | 1 year, 9 months ago | 0 comments

I'd like to draw your attention that I'm in no way an expert in sexual hormones, however I do have a degree in Biology and Health and a strong and lasting interest in SHT available for trans women. This is the result of a review of different articles that I read in order to enhance my knowledge and to be a decent ally and a ressource person for transgender women around me.

Who can do the medical monitoring of transgender women and what is the goal of SHT?

Usually the medical monitoring of transgender women is provided by endocrinologists but it may be provided by gynecologists. Indeed, gynecologists are powered to initiate some medical investigations such as breast examination which can be critical for transgender women (we'll come back to this later). Morevoer, the hormonal treatment used by transgender women tends to be very similar to the one given to postmenopausal women, with an adjustment of the doses, making gynecologists a good candidate for the medical monitoring of transgender women.

The medical monitoring can also be done by a well-informed general practitioner.

The goals of SHT (Substitutive Hormonal Therapy) are usually those listed in the Table below:

Goals of SHT in transgender women

1. Induce female secondary changes
2. Minimize male secondary changes as much as possible
3. Optimize the safety of the woman undergoing the treatment

A bit about Estrogens

What are estrogens?

Any molecule that binds to either or both of the two human estrogen receptor ER \( \alpha \) and ER \( \beta \) and induces a response can be considered as an estrogen (see ER1)

There are 4 major endogenous estrogens in cis women, whose structure can be found in the Figure below:

1. estrone (E1)
2. estradiol (E2)
3. estriol (E3)
4. estetrol (E4)

Estradiol is the predominent endogenous estrogen during the reproductive years of cis women, both in terms of serum levels and estrogenic activity. When a cis woman experiences menopause, the major endogenous estrogen, in terms of serum levels, shifts to estrone; and when a cis woman experiences pregnancy, the major circulating estrogen is estriol.

A study was carried about the potency of the different estrogens in mice and here are the results: estradiol is 10 times more potent than estrone and a hundred times more potent than estriol (see ME1).

Estretrol is only produced in cis women during pregancy.

Biosynthesis in cis women

The main location of estrogens production in cis women are the ovaries. During pregancy, the placenta also qualifies as a main source of estrogens production (ER2).

Estrogens are also produced in other areas of the body such as: liver, pancreas, bone, skin, brain and adipose tissue (see ER3). Those are the main sources of estrogens in postmenopausal cis women.

Estrogens are produced from cholesterol through various enzymes that produce testosterone and androstenedione. Thanks to the aromatase enzyme, estradiol and estrone are produced as you can see in the Figure below (see ER4).

Häggström M, Richfield D (2014). "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). doi:10.15347/wjm/2014.005. ISSN 2002-443

Usual levels of main estrogens

The serum levels of estrogens in premenopausol and post-pubertal cis women and men follow (see ER5):

Phase	E1	E2	Ratio
Early follicular phase (Day 1-4)	40-60 pg/mL	40-60 pg/mL	0.5-1
Mid follicular phase (Day 5-9)	No data	60-100 pg/mL	No data
Late follicular phase (Day 10-14)	170-200 pg/mL	200-400 pg/mL	1-2
Luteal Phase (Day15-28)	100-150 pg/mL	190 pg/mL	1.5
Men	20-90 pg/mL	20-55 pg/mL	0.4-0.6

Circulation of estrogens in the blood

Since estrogens are hydrophobic steroids, they cannot go into solution in the blood, requiring a carrier protein such as albumin or sex hormone-binding globulin.

This is of primarly importance in order to decide which estrogen to prescribe and the route of administration. It seems that 17 \( \beta \) estradiol crosses mucous membrane and skin more efficiently than gut membrane (see SHT1), therefore transdermic estrogens solutions tend to be good candidates for SHT.

A bit about progestogens

What are progestogens?

Progestogens are a class of steroid hormones that bind and activate the progesterone receptor (PR) (see PR1).

The most famous and important progestogens is progesterone (P4). Other endogenous progestogens exist, they are all metabolites of progestorone, products of progesterone.

Here you can find the structure of P4 :

Biosynthesis in cis women

P4 is produced either in the ovaries, either in the placenta (during pregnancy). It is a derivative of pregnenolone thanks to the 3 \( \beta \) HSD enzyme.

Usual levels of P4

The usual levels of progesterone (P4) serum levels in cis individuals can be found in the Table below (see PR2 and converted from mass values using molar mass of 314.46 g/mol​):

Phase	P4
Cis women postpubertal and premenopausal	0.2-1 ng/mL
	0.6-3 nmol/L
Cis men (> 16 years old)	0.27-0.9 ng/mL
	0.86-2.9 nmol/L

Progesterone and positive effect on osteoporosis

It is known that progesterone is a bone-trophic hormone (see PR3) and therefore its anti-osteoporosis effects have been studied.

A 1990 study (see PR4) suggests a partial osteoporosis reversal through the use of progesterone.

Morevorer a 2004 study suggests that progesterone is key for prevention of bone loss in cis women (see PR5). They show a positive effect of progesterone on bone mass, e.g. bone-remodelling and that progesterone slowed bone loss, through the application skin cream with a dosage of approximatively 30g per 3 weeks.

More studies show the bone-trophic effect of progesteron, please see PR6 and PR7.

Progesterone and effect on breast development

P4 has both an effect on labuloalveolar development (see PR8) and ductal development (see PR9). No spectacular effects of the use of progesterone on transgender women's breast development have been shown (see PR10).

However, P4 seems to have quite an effect on breast cancer (please see PR11, PR12, and PR13 as examples).

Progesterone (natural) versus progestins

Many evidence suggest that the use of progesterone instead of progestins is better for cis women. Please see PR14, PR15, PR16 and PR17.

A bit about androgens

What are androgens?

Androgens are the molecules that can bind to the androgen receptors (AR) and induce an effect.

Testosterone (T)

There are two main androgens: testosterone (T) and dihydrotestosterone (DHT), also called androstanolone.

Dihydrotestosterone (DHT)

Biosynthesis in cis men

Like the other hormones we described, testosterone and dihydrotestosterone are both steroid hormones that derive from cholesterol.

The main source of testosterone in cis men are the testes, approximatively 95% (see T1).

DHT is derived from testosterone through the 5 \( \alpha \) reductase.

Usual levels of androgens

Usual levels of androgens in cis people can be found below (see T2):

Compound	Group	Level (ng/mL)	Level (mmol/L)
Total testosterone	Adult cis men	350-1080	12.15-37.48
	Adult cis women (premenopausal)	10-54	0.347-1.873
	Adult cis women (postmenopausal)	5-50	0.243-1.388

The levels of DHT in the serum are about 10% of the testosterone levels (see T3). Levels in the prostate are 5 to 10 times higher than in the rest of the body, thus making DHT the major androgen of the prostate gland.

Circulation of androgens in the blood

Like estrogens, androgens are hydrophobic steroid hormones that need binding to circulate in the blood. They mainly bind to the sexual hormone binding globulin (SHBG) and to albumin.

DHT versus testosterone

DHT is a much more potent agonist of the AR than testosterone (see T4).

Administration of estrogens in trans women

There exist a multiple of therapeutic options for trans women when it comes to estrogens. As for cis women, human 17 \( \beta \) estradiol (E2) has to be prioritized since it's more potent than E1.

Indeed, equine estrogens increase the risk of stroke and does not indicate benefits (see ER6).

Administration routes for 17 \( \beta \) estradiol

They are most variable: oral, across buccal, vaginal, rectal mucous membranes, transdermally, transnasally, or through intramuscular or subcutaneous injections. Not all of this routes are available world-wide.

Doses

The dose of estrogens required for transgender women is a difficult subject, with little to no scientific background. Here's a table (see ER7-9) that sums up the results that seem equivalent in the litterature:

Estrogen	Route	Doses
17 \( \beta \) estradiol	oral	2-10 mg daily
	sublingual	1-5 mg daily
	transdermal patch	0.1-0.4 mg daily
	transdermal gel, lotion,spray	unknown
Estradiol valerate, estradiol cypionate	intramuscular, subcutaneous	2-10 mg weekly

However, in a study, when patch were not tolerated, 100 \( \mu \)g per 24h patch were replaced by 2 mg of 17 \( \beta \) estradiol gel twice daily (see E10).

Risks of the use of estrogens

The main and immediate risk inheritent to the use of estrogens in the increase of venous thromboembolic events (VTE), associated with the risk of cardiac attacks, strokes and pulmonary emboli (see ER6, ER11 and ER12).

The risk for VTE seems to be decreased in older transgender women by the use of transdermal estrogens (see ER13).

Effects of the take of estrogens (or estrogens and anti-androgens)

Positive effects

Some positive effects were observed during the take of estrogens:

• breast development and growth (see ER14)
• enlarged areola and nipple (see ER15)
• softened skin (see ER15)
• reduced testicular volume (see ER16)
• decreased spontaneous erections (see ER17)
• decreased libido (see ER15)
• redistribution of fat (see ER18)
• testosterone levels to cis women levels (see ER19)

Negative effets

Some negatives effets have been observed while undergoing an estrogens treatment:

• venous thrombosis (see ER20)
• choletithiasis (see ER20)
• hyperprolactinemia (see ER20)
• elevated liver enzyme (see ER20)
• depression (see ER21)
• decrease in hemoglobin (see ER22)
• decrease in insulin sentitivity (see ER23)
• decrease IGF (see ER24)

There also have been case reports of :

• prolactinoma (see ER25 and ER26)
• breast cancer (see ER27)
• prostatic carcinoma after orchiectomy (see ER28)

Risks are very likely to be dose-dependant since estrogen intake for reproductive age cis women has a dose-dependant risk factor for thromboembolytic diseases, pulmonary emboli, stroke (see ER29) and adverse liver effets (see ER30).

Therefore, it seems crucial to find the minimal efficient dose of estrogens intake for the woman involved and to take appropriate actions (quit smoking, exercize…), like for cis women who are routinely prescribed 1-6 mg transdermally.

Surveillance recommandation for women on estrogens

Various recommandations exist for transgender women undergoing an SHT (see ER29 and SHT1):

Schedule	Recommandation
Initial visit	PSA (prostate-specific antigen) as per official recommandation
	lipid profile
	liver functions tests
	metabolic profile
Every 3-6 months	testosterone levels until stable
	estradiol blood level
	ratio estradiol over total estrogens e.g. E2/(E1 + E2 + E3)
	liver function
	lipid profile
	encourage breast exams
Every 6 months to 1 year pre-operative	visual fields to asses for prolactinoma
	serum prolactin
	liver profile
	metabolic profile
	Over 50 years-old: PSA, consider mammogram
Every 6 month to 1 year post-operative	Decrease SHT doses
	Scan to assess ostoporosis

It has been shown (see ER31 and ER32) that the ration estradiol over total estrogens has to be as high as possible to maximize feminization, therefore it should be tested. This can be achieved through the use of injection, pellet or transdermal use of estrogens, by order of preference (see ER33).

Administration of progesterone in trans women

As said earlier, progestins are not a good option for trans and cis women alike, so we'll focus here on the administration of progesterone.

Administrations routes of progesterone

Progesterone is available in a wide variety of forms, such as oral capsules, vaginal capsules, sublingual tablets and tablets, gels, suppositories, and rings, oil solutions for intramuscular injection; and aqueous solutions for subcutaneous injection.

Doses

Here are some recommandations (see SHT1):

Compound	Dose
Progesterone	200 mg (nightly)

Risks due to the use of progesterone

Many studies suggest that progestrone is well-tolerated and provokes quite no side effects (see PR18). However, side effets may include:

• nausea
• abdominal cramps
• breast tenderness
• constipation
• dizziness
• vaginal bleeding
• hypotension
• irritability
• depression

Surveillance recommandations for women on progesterone

Schedule	Exam
Every 3-6 months	progesterone levels

Antiandrogens for trans women

A wide variety of anti-androgens of several types exist.

However, they do not seem mandatory while taking a treatment based on estrogens and progesterone (see SHL1).

Spironolactone

It is a well-known anti-androgen. However, it is known, thanks to its antimineralocorticoid action, to interfere with a lot of steroid receptors. It is:

• predominent antagonist of AR
• selective modulator of the ER
• weak agonist of the PR
• antagonist of the glucocorticoid receptor
• inhibitor of the production of androgens
• modest inhibitor of the 5 \( \alpha \) reductase (the enzyme that converts T to DHT)

Due to its potassium sparing action, it may cause hyperkalemia. Doses may up to 200mg daily to achieve anti-androgenic effects. (see SHT1)

5 \( \alpha \) reductase inhibitors: finasteride and dutasteride

Both those molecules suppress the activity of the enzyme that converts testosterone to DHT, which is primarly known for its effects on terminal hair growth and sebum production in hair follicles. It is usually prescribed for androgenic alopecia and prostatic dysfunctions (hypertrophy or cancer).

The doses are given below (see SHT1):

Compound	Dose
Finasteride	1-5 mg daily
Dutasteride	0.5 mg

Some side effets of finasteride (depression, suicidal ideation, loss of libido, erectile dysfunction, muscle atrophy…) have been described (see SHT1).

Androgen receptors blockers: flutamide and bicalutamide

Flutamide is no longer used due to extreme liver failures and deaths.

Bicalutamide is a safer option that is approved for treatment of prostate cancer at a 50 mg per day dose. Its side effets include feminization of the body, reduced penile length, hot flashes, erectile dysfunction, elevated liver enzymes, breast tenderness. »SHT1)

Studies of the effects of bicalutamide in transgender women are quite limited.

GnRH agonists and antagonists

Those molecule either down regulate GnRH receptors (agonists) or competitively block those receptors (antagonists).

They are known to be very efficient in suppressing testosterone effects.

Routes of administration are quite difficult (injection) and the treatment in costly.

Doses recommended are available below (see SHT1):

Compound	Route of administration	Dose
Leuroprolide	intramuscular/subcutaneous	3.75 mg monthly (or 11.25 every three month)
Nafarelin	nasal spray	2 puffs daily 2 times a day
Goserelin	subcutaneous implant	3.6 mg monthly (or 10.8 every three month)
Triptolerin	intramuscular	3.75 monthly (or 11.25 every three month or 22.5 every six month)
Buserelin	nasal spray	2 puffs 3 times a day
Histrelin	subcutaneous implant	50 mg daily

Main physical changes due to SHT

See SHT1.

Estrogen-induced

• induction of breast development
• alteration of body composition by increasing the volume of fat and redistribution

Anti-androgen induced

• erectile dysfunction (erections can still be induced and orgasm can still be reached)
• change in muscle mass
• change in terminal hair growth (approximatively 3-5 years, can be helped by laser)
• decrease in sperm production (complete azoospermia is not reachable)

Schedule

Effect	Onset	Completion
Decreased spontaneous erections	1-3 month	persistent
Decreased sexual sexdrive	1-3 month	persistent
Breast growth	2-6 month	1-2 years
Body fat redistribution	2-6 month	1-2 years
Muscle mass loss	3-6 month	1-2 years
Softer, less oily skin	3-6 month	1-2 years
Decreased testicular volume	2-6 month	2-3 years
Decreased sperm production	uncertain	persistent
Decreased terminal hair growth	3-12 month	3-5 years
Cessation of scalp hair loss	3-12 month	persistent
Recovery of scalp hair loss	quite variable	variable

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