Excerpts: Perspectives and Opinions of Clinicians and Researchers Concerning the Use of Progestogens in Transfeminine Hormone Therapy
By Sam | First published April 18, 2020 | Last modified October 5, 2020
Oriel, K. A. (2000). Clinical update: Medical care of transsexual patients. Journal of the Gay and Lesbian Medical Association, 4(4), 185–194. [DOI:10.1023/a:1026563806480]:
The use of progesterone to augment breast development is controversial in physicians treating MTF transsexuals. When deciding on a hormone regimen, prescribers should remember that it is estrogen that causes the serious side effects, so the lowest effective dose should be used.
[…] Progesterone is the third and optional component of the MTF regimen. Although some physicians working with transgendered patients do not prescribe progesterone, others argue feminization involves the actions of both estrogen and progesterone (31). Medroxyprogesterone is a weak antiandrogen, and testosterone suppression may be accomplished with lower doses of estrogen. Medroxyprogesterone is less androgenic than norethindrone and norgestrel. Progesterone is important for breast development (24). Unlike estrogen, progesterone does not carry the risk of thromboembolism, prolactinoma, and myocardial infarction. Although it has been noted that doses of 20–40 mg per day are required to suppress luteinizing hormone (20), medroxyprogesterone acetate may become androgenic at higher doses, so others (5) recommend 10 mg a day. Micronized progesterone (Prometrium) is advantageous because it has a more favorable side effect profile (anxiety and irritability) than medroxyprogesterone. It is also less androgenic when higher progesterone doses are needed, but is more costly.
Dittrich, R., Binder, H., Cupisti, S., Hoffmann, I., Beckmann, M. W., & Mueller, A. (2005). Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist. Experimental and Clinical Endocrinology & Diabetes, 113(10), 586–592. [DOI:10.1055/s-2005-865900]:
Ethinyl oestradiol was no more effective in comparison with the oestradiol-17β valerate administered in the regimen studied here. Similar efficacy in terms of feminisation, e. g., increases in breast size, were achieved in the present study group compared to prior reported treatment regimes using cyproterone acetate and ethinyl oestradiol. The use of a progestin as part of the endocrine treatment regime of male-to-female transsexuals is still controversial; however, advantages in only a couple of patients with abnormal psychological irritability and mammary tenderness could be observed (Michel et al., 2001).
Gooren, L. J., Giltay, E. J., & Bunck, M. C. (2008). Long-term treatment of transsexuals with cross-sex hormones: extensive personal experience. The Journal of Clinical Endocrinology & Metabolism, 93(1), 19–25. [DOI:10.1210/jc.2007-1809]:
There is no evidence that progestagens add to the feminization process of M2F. In female reproductive endocrinology, progesterone prepares the uterus for conception and the breasts for lactation. Some patients strongly believe that progestagens are a necessary addition to estrogens in their feminization process. But this is not the case, and progestagens may have side effects, such as salt/water retention leading to elevated blood pressure or venous varicosis. In the large-scale study of postmenopausal hormone use in women, the combination of estrogens and progestagens appeared to be associated with a higher incidence of breast cancer (4) and cardiovascular disease.
Gooren, L. J. (2011). Care of transsexual persons. New England Journal of Medicine, 364(13), 1251–1257. [DOI:10.1056/nejmcp1008161]:
Although progestins suppress androgen production, they have no role in the feminization of the body and may have harmful metabolic effects; consequently, progestins should be discontinued after orchiectomy.24 In postmenopausal women, progestins combined with estrogens increase the risk of breast cancer.25
Wierckx, K., Gooren, L., & T’Sjoen, G. (2014). Clinical review: breast development in trans women receiving cross-sex hormones. The Journal of Sexual Medicine, 11(5), 1240–1247. [DOI: 10.1111/jsm.12487]:
With regard to the hormonal impact on female breast development, the classic view is that estrogens induce proliferation, whereas progestins cause differentiation in female breast development [2,3]. It is widely assumed that progestins have no significant role in the formation of the volume of the breasts, the reason why it is not included in endocrine treatment of girls with Turner and juvenile trans women persons .
[…] Although there is undeniably a role of progesterone in breast development and lactation, it is uncertain whether the treatment of progestogens adds much to the volume of the breasts, the concern of trans women. […] In the medical profession and even more in the transsexual community, there has been an ongoing debate for many years on the potential benefit of adding progestogens to estrogen use in trans women’s hormonal treatment, especially concerning its role in the volume/size breast development and maintenance. Progestagen treatment is also often requested by trans women themselves as it is their perception that their treatment should closely mimic hormonal treatment of hypogonadal women requiring hormone treatment. However, for the latter group, addition of progestogens has a different relevance, specifically the modifying estrogen effects on the uterus potentially inducing cancerous development.
[…] Few studies have investigated the effects of cross-sex hormone treatment on breast volume. Meyer et al.  investigated breast growth in 52 trans women during cross-sex hormone treatment. Notably, 41 trans women received cross-sex hormone treatment with a median of 26.4 months before inclusion in the study. Different estrogen regimes (ethinyl estradiol [EE], conjugated estrogen, or both) were analyzed, and 15 trans women of their sample (28%) additionally received a progestational agent. No difference in breast size was observed between trans women who received progestogens compared with the others.
[…] The available evidence does not provide support for better effects on breast size of adding progestogens to cross-sex hormone administration in trans women as suggested by some authors [14,18,48–51]. However, it should be said that the quality and amount of available evidence are extremely poor and hamper any firm conclusion at this moment.
[…] Our knowledge concerning the natural history and effects of different cross-sex hormone therapies including progestogens on breast development in trans women is extremely sparse and based on low quality of evidence. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.
Deutsch, M. B. (2016). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People. Center of Excellence for Transgender Health, Department of Family and Community Medicine, University of California at San Francisco. [URL:https://transcare.ucsf.edu/guidelines] [PDF]:
There have been no well-designed studies of the role of progestagens in feminizing hormone regimens. Many transgender women and providers alike report an anecdotal improved breast and/or areolar development, mood, or libido with the use of progestagens.[17,18] There is no evidence to suggest that using progestagens in the setting of transgender care are harmful. In reality some patients may respond favorably to progestagens while others may find negative effects on mood. While progestagens have some anti-androgen effect through central blockade of gonadotropins, there is also a theoretical risk of a direct androgenizing effect of progestagens. This class includes micronized bioidentical progesterone (Prometrium) as well as a number of synthetic progestins. The most commonly used synthetic progestin in the context of transgender care is the oral medroxyprogesterone acetate (Provera).
While concerns exist from the Women’s Health Initiative (WHI) regarding risks of cardiovascular disease and breast cancer in the setting of medroxyprogesterone use, these concerns likely do not apply in the context of transgender care for several reasons. First, the transgender women may be at lower risk of breast cancer than non-transgender women. Second, this arm of the WHI involved the use of conjugated equine estrogens in combination with medroxyprogesterone in a sample of menopausal women, some of whom were as long as 10 years post-menopausal at the time of hormone initiation. Third, while statistically significant, the clinical significance of the findings in the WHI was subtle at best. The study aimed to evaluate the role of menopausal hormone therapy in the prevention of chronic disease. The actual findings in the conjugated equine estrogen plus medroxyprogesterone group were an excess absolute risk per 10 000 person-years of 7 more cardiac events events, 8 more strokes, 8 more pulmonary emboli, and 8 more invasive breast cancers, with no change in overall mortality. As such this arm of the WHI was stopped early, and it was concluded that combined menopausal hormone therapy is not indicated for prevention of chronic disease.
In the setting of gender-affirming care, there are numerous differences to the findings of the WHI: populations tend to be younger, equine estrogens are not used, and the emphasis is on genderaffirming interventions which have numerous benefits on mental health and quality of life, rather than prevention. Considering these differences in demographics and goals of therapy, extremely modest increase in overall risk, and lack of difference in mortality, as well as more recent reassuring data with other forms of estrogen, the risks of using progestagens in transgender women are likely minimal or even absent (Grading: NT O M). Injected depomedroxyprogesterone acetate (Depo-Provera®) is less commonly used in transgender women. Other synthetic progestins may be used as necessitated by formulary limitations; some evidence suggests that norpregnane derived progestins (norethindrone, norgestrel) may have an increased risk of venous thromboembolism.
Tangpricha, V., & den Heijer, M. (2017). Oestrogen and anti-androgen therapy for transgender women. The Lancet Diabetes & Endocrinology, 5(4), 291–300. [DOI:10.1016/S2213-8587(16)30319-9]:
Some patients request progesterone for enhanced breast growth. However, there have not been any well designed studies to assess the eff ectiveness of progesterone to improve breast development. Results of studies of progesterone combined with oestrogen in postmenopausal cis-gender women—ie, women who are not transgender—suggest that progesterone combined with oestrogen might be associated with an increased risk of cardiovascular disease . 21 In fact, in a population-based study of premenopausal cis-gender women, taking oral contraceptives including progesterone with or without oestrogen was associated with increased risk of thromboembolism.22
Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., … & T’Sjoen, G. G. (2017). Endocrine treatment of gender-dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 102(11), 3869–3903. [DOI:10.1210/jc.2017-01658]:
In the future, we need more rigorous evaluations of the effectiveness and safety of endocrine and surgical protocols. Specifically, endocrine treatment protocols for GD/gender incongruence should include the careful assessment of the following: (1) the effects of prolonged delay of puberty in adolescents on bone health, gonadal function, and the brain (including effects on cognitive, emotional, social, and sexual development); (2) the effects of treatment in adults on sex hormone levels; (3) the requirement for and the effects of progestins and other agents used to suppress endogenous sex steroids during treatment; and (4) the risks and benefits of gender-affirming hormone treatment in older transgender people.
[…] Although the time course of breast development in transgender females has been studied (150), precise information about other changes induced by sex hormones is lacking (141). There is a great deal of variability among individuals, as evidenced during pubertal development. We all know that a major concern for transgender females is breast development. If we work with estrogens, the result will be often not what the transgender female expects. Alternatively, there are transgender females who report an anecdotal improved breast development, mood, or sexual desire with the use of progestogens. However, there have been no well-designed studies of the role of progestogens in feminizing hormone regimens, so the question is still open. Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in transgender females is extremely sparse and based on the low quality of evidence. Current evidence does not indicate that progestogens enhance breast development in transgender females, nor does evidence prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions (162).
Coxon, J., & Seal, L. (2018). Hormone management of trans women. Trends in Urology & Men’s Health, 9(6), 10–14. [DOI:10.1002/tre.663]:
Progesterone is recommended by some gender clinics internationally, but rarely in the UK. Some trans women strongly believe that it should be added, to enhance breast development. A meta-analysis found no additional benefit for breast development when comparing progesterone plus oestrogen to oestrogen alone.17 We advise patients that oestrogen-only hormone therapy is the best and safest option, as progesterone is not produced during the breast development phase of physiological female puberty, and trans women do not have endometria to protect. At a cellular level, progesterone reverses oestrogen induced cell proliferation and, more importantly, evidence in cis women has shown that adding progesterone to oestrogen therapy is associated with increased risk of cardiovascular disease and breast cancer.18
Prior, J. C. (2019). Progesterone is important for transgender women’s therapy—applying evidence for the benefits of progesterone in ciswomen. The Journal of Clinical Endocrinology & Metabolism, 104(4), 1181–1186. [DOI:10.1210/jc.2018-01777]:
Oral micronized progesterone, a fundamental ovarian steroid, molecularly identical to the natural hormone, should be added to E2 for transgender women based on physiology and emerging evidence of the importance of progesterone with E2 for ciswomen’s bone and likely cardiovascular health. Progesterone will probably prevent at least some of the negative cardiovascular system and bone health effects reported in transgender women on current long-term, E/E2-only, or E/E2 antiandrogen CHT. Progesterone will also aid antiandrogen effects through different pathways than spironolactone or cyproterone acetate and may promote feminine physiological breast maturation, while also aiding disturbed sleep and perhaps decreasing anxiety. It may also facilitate transgender women’s acceptance of physiological (rather than high) E2 doses ideally delivered transdermally. Evidence is mounting that ciswomen’s lifelong health is enhanced by sufficient P4 (normally ovulatory) within regular estradiol-sufficient monthly menstrual cycles. I believe it is time that we now follow current guidelines and provide transgender women with these P4 or progesterone benefits in their CHT.
Iwamoto, S. J., T’Sjoen, G., Safer, J. D., Davidge-Pitts, C. J., Wierman, M. E., Glodowski, M. B., & Rothman, M. S. (2019). Letter to the Editor: “Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”. The Journal of Clinical Endocrinology & Metabolism, 104(8), 3127–3128. [DOI:10.1210/jc.2019-00249]:
We respect Dr. Jerilynn C. Prior’s many contributions to endocrinology and transgender (trans) health. Yet, we have multiple concerns about her Perspective(1) which is limited to her clinical experience, assumptions taken from in vitro and animal data, and selected data from cisgender (cis) women, whose female gender identity aligns with their natal sex.
[…] Prior asserts that P4 with estradiol (E2) will optimize breast maturation and size, but P4 causes ductal differentiation in puberty and has not been shown to enhance breast development in trans women(2). Prior argues that bone mineral density (BMD) improves with P4. However, selected studies from her meta-analysis were limited by significant heterogeneity of hormone dose, race and range of years after menopause(3). Although Prior states that low BMD is a major risk for trans women “on long-term” hormones, the major concerns are low baseline BMD before pharmacologic gender-affirming hormone therapy (GAHT) and monitoring after gonadectomy and cessation of GAHT(4). Recent ten-year GAHT data (without P4) showed gains in lumbar spine Z-scores of trans women(4).
We also object to Prior’s assumption that P4 will decrease breast cancer risk in trans women based on the French E3N self-administered questionnaire study in cis women. Randomized controlled trial (RCT) data from the Women’s Health Initiative (WHI) demonstrated increased invasive breast cancer during the intervention, postintervention and cumulative follow-up in the conjugated equine estrogen (CEE)+medroxyprogesterone (MPA) group compared to CEE alone(5).
Lastly, Prior’s statement of cardiovascular benefits with progestins conflicts with WHI data which revealed increased coronary heart disease in women ≥20 years past menopause onset and higher risk of stroke and blood clots in the CEE+MPA group during cumulative follow-up(5). Recent data raise concerns for higher risks of blood clots and stroke among trans women on GAHT compared to reference women and men(6).
[…] To conclude that oral micronized P4 will be positive for bone and cardiovascular health based on selected data in menopausal cis women is premature and potentially dangerous. Further, we know that clinical assumptions based on observational data, murine studies, cell models and personal experience can lead to risks to patients. Our transgender patients deserve the benefits of rigorous RCT data so we can provide evidence-based recommendations regarding the risks and benefits of GAHT.
Cheung, A. S., Wynne, K., Erasmus, J., Murray, S., & Zajac, J. D. (2019). Position statement on the hormonal management of adult transgender and gender diverse individuals. Medical Journal of Australia, 211(3), 127–133. [DOI:10.5694/mja2.50259]:
Despite anecdotal reports that progestins increase breast growth, no data support their use. Healthy postmenopausal women who received estradiol with progestins had increased risk of coronary heart disease compared with placebo34 (not reported with estradiol alone42). Progestins can also increase risk of thrombosis, bloating, nausea and weight gain and are not recommended.10 Cyproterone acetate, a commonly used anti-androgen agent, has progestogenic effects.
Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 2042018819871166. [DOI: 10.1177/2042018819871166]:
Alternative anti-androgen therapies exist that have not yet been substantiated for routine use by supporting research. Progesterone is discussed in the breast development section, but we do not recommend its routine use in TW until more rigorous studies demonstrate potential benefits outweigh any risks.40
[…] The impact of various combinations of different oestrogens, anti-androgens and progestogens on breast development was previously reviewed by Wierckx and colleagues,67 who concluded that current evidence did not support or refute any enhancement of breast development with progestogens. Pubertal data in people assigned female at birth (AFAB) (e.g. girls with Turner syndrome) argue for delaying progesterone as it causes ductal differentiation and may interfere with optimal breast development.68 Due to unsatisfactory effects of GAHT alone on breast growth and development, 60–70% of all TW sought additional surgical breast augmentation.67 Articles on breast development in TW report inconclusive results, possibly due to differences in methodology and the lack of prospective RCTs. Prior69 recently published on the potential benefits of progesterone use on breast development (among other conclusions) in TW but the perspective was limited to clinical experience, assumptions taken from in vitro and animal data, and selected data from cis women.40 It would be worthwhile for future studies to use volume measurements for examining hormonally induced breast development in TW over a longer follow-up period in a large cohort, which may result in the identification of predictive markers for breast development.62 Additionally, rigorous prospective RCTs of oestrogen and oestrogen plus progesterone may provide more conclusive data to guide routine use of progesterone for breast development.
T’Sjoen, G., Arcelus, J., De Vries, A. L., Fisher, A. D., Nieder, T. O., Özer, M., & Motmans, J. (2020). European Society for Sexual Medicine Position Statement “Assessment and Hormonal Management in Adolescent and Adult Trans People, With Attention for Sexual Function and Satisfaction”. The Journal of Sexual Medicine. [DOI:10.1016/j.jsxm.2020.01.012]:
To induce (more) feminine secondary sex characteristics and/or to reduce the masculine ones, estrogens and/or antiandrogens can be used. The debate on the use of progesterone is ongoing, caused by a lack of data.3 A wide range of estrogenic compounds exists, of which 17beta-estradiol (oral 2–6 mg/d or transdermal) represents the treatment of choice. Estrogen dosage should be adjusted to maintain serum estradiol at the level for premenopausal women (100–200 pg/mL), although timing of treatment intake may affect blood concentrations. The most commonly used antiandrogen drug in Europe is cyproterone acetate (oral 10–50 mg, once daily), a progestin with antiandrogenic properties. GnRHa are also effective in reducing testosterone levels with a low risk of adverse effects.3
Reisman, T. (2020). Breast imaging in transgender individuals. In Legato, M. J. The Plasticity of Sex: The Molecular Biology and Clinical Features of Genomic Sex, Gender Identity and Sexual Behavior (pp. 187–205). Academic Press. [DOI:10.1016/B978-0-12-815968-2.00016-5]:
While the role of estrogen in breast growth has been most clearly established, other hormones have also been implicated in breast development. In his 1958 study, Lyon demonstrated in oophorectomized, adrenalectomized, and hypophysectomized rodents that estrogen, growth hormone, and corticosteroids are all required for ductal develoment.10 Progesterone does not appear to be important for either early pubertal duct development or breast growth. However, with increasing levels throughout pregnancy, progesterone is reported to mediate the lobular alveolar development facilitating lactation.