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.
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
- Induce female secondary changes
- Minimize male secondary changes as much as possible
- Optimize the safety of the woman undergoing the treatment
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:
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.
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
The serum levels of estrogens in premenopausol and post-pubertal cis women and men follow (see ER5):
|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|
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.
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 :
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.
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):
|Cis women postpubertal and premenopausal||0.2-1 ng/mL|
|Cis men (> 16 years old)||0.27-0.9 ng/mL|
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.
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).
Many evidence suggest that the use of progesterone instead of progestins is better for cis women. Please see PR14, PR15, PR16 and PR17.
What are androgens?
Androgens are the molecules that can bind to the androgen receptors (AR) and induce an effect.
There are two main androgens: testosterone (T) and dihydrotestosterone (DHT), also called androstanolone.
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 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.
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 is a much more potent agonist of the AR than testosterone (see T4).
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).
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.
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:
|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).
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).
Some positive effects were observed during the take of estrogens:
Some negatives effets have been observed while undergoing an estrogens treatment:
There also have been case reports of :
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.
Various recommandations exist for transgender women undergoing an SHT (see ER29 and SHT1):
|Initial visit||PSA (prostate-specific antigen) as per official recommandation|
|liver functions tests|
|Every 3-6 months||testosterone levels until stable|
|estradiol blood level|
|ratio estradiol over total estrogens e.g. E2/(E1 + E2 + E3)|
|encourage breast exams|
|Every 6 months to 1 year pre-operative||visual fields to asses for prolactinoma|
|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).
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.
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.
Here are some recommandations (see SHT1):
|Progesterone||200 mg (nightly)|
Many studies suggest that progestrone is well-tolerated and provokes quite no side effects (see PR18). However, side effets may include:
|Every 3-6 months||progesterone levels|
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).
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:
Due to its potassium sparing action, it may cause hyperkalemia. Doses may up to 200mg daily to achieve anti-androgenic effects. (see SHT1)
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):
|Finasteride||1-5 mg daily|
Some side effets of finasteride (depression, suicidal ideation, loss of libido, erectile dysfunction, muscle atrophy…) have been described (see SHT1).
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.
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|
|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|
|ER1||Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility (ISBN 978-1-4511-4847-3). Philadelphia, PA: Lippincott Williams & Wilkins; 2011.|
|ME1||Labhart A. Clinical Endocrinology: Theory and Practice. Springer Science & Business Media pp. 548– (ISBN 978-3-642-96158-8). 2012.|
|ER2||Marieb E. Anatomy & physiology. Benjamin-Cummings. p. 903 (ISBN 978-0-321-88760-3). 2013.|
|ER3||Hemsell DL, Grodin JM, Brenner PF, Siiteri PK, MacDonald PC. "Plasma precursors of estrogen. II. Correlation of the extent of conversion of plasma androstenedione to estrone with age". The Journal of Clinical Endocrinology and Metabolism. 38 (3): 476–9. (doi:10.1210/jcem-38-3-476). 1974.|
|ER4||Häggström Ml, Richfield D. "Diagram of the pathways of human steroidogenesis". WikiJournal of Medicine. 1 (1). (doi:10.15347/wjm/2014.005. ISSN 2002-4436). 2014.|
Kenneth LB. Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 889, 1059–1060, 2153 (ISBN 978-0-7817-1750-2). 2001
|SHT1||Randolph J, "Gender Affirming Hormone Therapy for Transgender Females". Clinical Obstetrics and Gynecology. 61 (4) p 705–721 (doi: 10.1097/GRF.0000000000000396). 2018|
|PR1||Clark MA, Harvey RA, Finkel R, Rey JA, Whalen K. Pharmacology. Lippincott Williams & Wilkins. p. 322. (ISBN 978-1-4511-1314-3). 2011|
Progesterone Reference Ranges, Performed at the Clinical Center at the National Institutes of Health, Bethesda MD, 03Feb09
|PR3||Prior JC, "Progesterone as a Bone-Trophic Hormone", Endocrine Review 11(2). 1990|
|PR4||Lee JR, "Osteoporosis reversla; the role of progestorone" International Clinical Nutrition Review 10(3) p. 384-91 (1990)|
|PR5||Lydeking-Olsen E, Beck-Jensen JE, Setchell KDR, Holm-Jensen T, "Soymilk or progesterone for prevention of bone loss - A 2 year randomizel, placebo-controlled trial" European Journal of Nutrition 43, p. 246-257, 2004.|
Prior JC, Vigna YM, Schechter MT, Burgess AE "Spinal bone loss and ovulatory disturbances". N Engl J Med 323(18):S1221–S1227. 1990
Prior JC, Vigna YM, Alojado N. Progesterone and the prevention of osteoporosis. Can J Ob/Gyn & Women’s Health Care 3(4):S178–S184. 1991
Macias H, Hinck L. "Mammary gland development". Wiley Interdisciplinary Reviews: Developmental Biology. 1 (4): 533–57.2012
Aupperlee MD, Leipprandt JR, Bennett JM, Schwartz RC, Haslam SZ. "Amphiregulin mediates progesterone-induced mammary ductal development during puberty". Breast Cancer Research. 15 (3): R44.2013
Wierckx K, Gooren L, T'Sjoen G. "Clinical review: Breast development in trans women receiving cross-sex hormones". J Sex Med. 11 (5): 1240–7. 2014
Cowan LD, Gordis L, Tonascia JA, et al. Breast cancer incidence in women with a history of progesterone deficiency. American Journal of Epidemiology 1981; 114:209.
Desreux J, Kebers F, Noel A, Francart D, Van Cauwenberge H, Heinen V, Thomas JL, Bernard AM, Paris J, Delansorne R, Foidart JM. Progesterone receptor activation- an alternative to SERMs in breast cancer. Eur JCancer 2000 Sep;36 Suppl 4:S90-1.
Horita K, Inase N, Miyake S, Formby B, Toyoda H, Yoshizawa Y. Progesterone induces apoptosis in malignant mesothelioma cells. Anticancer Res 2001 Nov-Dec;21(6A):3871-
Cummings JA, Brizendine L. Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women. Menopause 2002 Jul-Aug;9(4):253-63
|PR15||De Lignieres B. Oral micronized progesterone. Clin Ther 1999; 21(1):41-60.|
|PR16||Martorano JT, Ahlgrimm M, Meyers D. Differentiating be tween natural progesterone and synthetic progestogens: clinical implications for PMS management. Comprehensive Therapy 1993; 19(3):96-8.|
|PR17||Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000 Oct-Nov;65(10-11):651-8.|
|T1||Mooradian AD, Morley JE, Korenman SG (Feb 1987). "Biological actions of androgens". Endocrine Reviews. 8 (1): 1–28|
|T2||Chernecky CC, Berger BJ (31 October 2012). Laboratory Tests and Diagnostic Procedures - E-Book. Elsevier Health Sciences. pp. 1059–1062.|
|T3||Travison TG, Vesper HW, Orwoll E, Wu F, Kaufman JM, Wang Y, Lapauw B, Fiers T, Matsumoto AM, Bhasin S (April 2017). "Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe". The Journal of Clinical Endocrinology and Metabolism. 102 (4): 1161–1173.|
|T4||Mozayani A, Raymon L (18 September 2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science & Business Media. pp. 656–|
|ER6||The Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the women’s health initiative randomized controlled trial. JAMA. 2004;291:1701–1712.|
|ER7||Gooren L. Hormone treatment of the adult transsexual patient. Horm Res. 2005;64(suppl 2):31–36.|
|ER8||Moore E, Wisniewski A, Dobs A. Endocrine treatment of transsexual people: a review of treatment regimens, outcomes, and adverse effects. J Clin Endocrinol Metabol. 2003;88:3467–3473.|
|ER9||Gooren LJ, Giltay EJ, Bunck MC. Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience. J Clin Endocrinol Metabol. 2008;93:19–25. Getahun D, Nash R, Flanders WD,|
|ER10||Katrien Wierckx, Eva Van Caenegem, Thomas Schreiner, Ira Haraldsen, Alessandra Fisher, Kaatje Toye, Jean Marc Kaufman, and Guy T’Sjoen, Cross-Sex Hormone Therapy in Trans Persons Is Safe and Effective at Short-Time Follow-Up: Results from the European Network for the Investigation of Gender Incongruence, 1999 (doi:10.1111/jsm.12571)|
|ER11||Bitzer J, Simon JA. Current issues and available options in combined hormonal contraception. Contraception. 2011;84:342–356.|
|ER12||Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA. 2002;288:321–333.|
|ER13||Van Kesteren PJ, Asscheman H, Megens JA, Gooren LJ. Mortality and morbidity in trans subjects treated with cross-sex hormones. Clin Endocrinol 1997;47:337–42|
|ER14||Kanhai R, Hage J, Asscheman H, Mulder J 1999 Augmentation mammaplasty in male-to-female transsexual people. Plast Reconstr Surg 104 :542–549|
Schlatterer K, Von Werder K, Stalla G 1996 Multistep treatment concept of transsexual patients. Exp Clin Endocrinol Diabetes 104:413-419
Reutrakul S, Ongphiphadhanakul B, Piaseu N, Krittiyawong S, Chanprasertyothin S, Bunnag P, Rajatanavin R 1998 The effects of oestrogen exposure on bone mass in male to female transsexual people. Clin Endocrinol (Oxf) 49 811–814
Meyer W , Webb A, Stuart C, Finkelstein J, Lawrence B, Walker P 1986 Physical and hormonal evaluation of transsexual patients: a longitudinal study. Arch Sex Behav 15:121–138
Leiter E, Futterweit W, Brown G 1993 Gender reassignment: psychiatric, endocrinologic, and surgical management. In: Webster G, Kirby R, King L, Goldwasser B, eds. Reconstructive urology. Boston: Blackwell Scientific Publications; 23:921–932
Giltay E, Lambert J, Gooren L, Elbers J, Steyn M, Stehouwer C 1999 Sex steroids, insulin, and arterial stiffness in women and men. Hypertension 34:590–597
Van Kesteren P, Asscheman H, Megens J, Gooren L 1997 Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 47:337–342
Asscheman H, Gooren L , Eklund P 1989 Mortality and morbidity in transsexual patients with cross-gender hormone treatment. Metabolism 38:869–873
Schlatterer K, Yassouridis A, von Werder K, Poland D, Kemper J, Stalla G 1998 A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients. Arch Sex Behav 27:475–492
Polderman K,Gorren L, Asscheman H, Bakker A, Heine R 1994 Induction of insulin resistance by androgens and estrogens. J Clin Endocrinol Metab 79:265–271
van Kesteren P, Lips P, Deville W, Popp-Snijders C, Asscheman H, Megens J, Gooren L 1996 The effects of one-year cross-sex hormone treatment on bone metabolism and serum insulin-like growth factor-1 in transsexual people. J Clin Endocrinol Metab 81:2227--2232
Gooren L, Assies J, Asscheman H, de Slegte R, van Kessel H 1988 Estrogen-induced prolactinoma in a man. J Clin Endocrinol Metab 66:444–446
Michel A, Mormont C, Legros J 2001 A psycho-endocrinological overview of transsexualism. Eur J Endocrinol 145:365–376
Pritchard T, Pankowsky D, Crowe J, Abdul-Karim F 1988 Breast cancer in a male-to-female transsexual: a case report. JAMA 259:2278–2280
van Haarst E, Newling D, Gooren L, Asscheman H, Prenger D 1998 Metastatic prostatic carcinoma in a male-to-female transsexual. Br J Urol 81:776
Stadel BV 1981 Oral contraceptives and cardiovascular disease. N Engl J Med 305:612–618; 672–677
Adlercreutz H, Tenhunen R 1970 Some aspects of the interaction between natural and synthetic female sex hormones and the liver. Am J Med 49:630–648
“Emerging potential of parenteral estrogen as androgen deprivation therapy for prostate cancer”, Shah S, South Asian J Cancer. 2015 Apr-Jun; 4(2): 95–97.
“Molecular and kinetic basis for the mixed agonist/antagonist activity of estriol.”, Mol Endocrinol. 1997 Nov;11(12):1868-78.
“Pharmacology of Estrogens and Progestogens — Influence of Different Methods of Administration” by Kuhl, from Climacteric, 2005;8 Suppl 1:3-63
Goletiani NV, Keith DR, Gorsky SJ (2007). "Progesterone: review of safety for clinical studies". Exp Clin Psychopharmacol. 15 (5): 427–44