Supplement: Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People
By Aly W. | First published July 1, 2019 | Last modified October 5, 2020
This page is a supplement to the Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People article. It’s a collection of literature excerpts and personal communications evidencing the clinical adoption of lower doses of cyproterone acetate.
Raymond Fung and colleagues conducted a study showing that, in combination with estradiol, 25 and 50 mg/day CPA did not differ in terms of testosterone suppression in transgender women (Fung, Hellstern-Layefsky, & Lega, 2017). I emailed Dr. Fung and presented the case for lower dosages of CPA in transgender women, such as 6.25 to 12.5 mg/day, than the 25 mg/day dosage he used in his study. He responded as follows:
A 2019 Australian position statement and the first clinical guidelines for transgender hormone therapy in Australian recommended a dosage range of CPA of 12.5 to 25 mg/day (Cheung et al., 2019). I emailed the lead author, Ada Cheung, to make the case for lower dosages of CPA. She responded as follows:
Rainbow Health Ontario, part of Sherbourne Health, stated the following in December 2019 in the 4th edition of their guidelines for transgender hormone therapy (Bourns, 2019):
Historically at our clinic, spironolactone was chosen preferentially as it was believed to have a superior safety profile. This practice has changed somewhat over time, as adequate anti-androgenic effects and testosterone suppression into the female range have been shown to be attainable at lower doses of cyproterone (i.e., 12.5–25 mg daily), at which adverse effects are much less likely.4
Cyproterone can be initiated at 12.5 mg and increased by 12.5 mg every 2–4 or more weeks (to a rare maximum of 50 mg) if required. Lower doses and/or less frequent dosing (e.g., one-quarter of a 25 mg tablet twice weekly, one-eighth of a 25 mg tablet every other day, etc.) have been used with success for patients who wish to maintain sexual function or minimize other side effects.
Table 2 Options and recommended doses of anti-androgens in feminizing therapy: Cyproterone [acetate] (oral): Starting/low dose: 12.5 mg (¼ 50 mg tab) q2d-daily. Usual dose: 12.5 mg (¼ 50 mg tab) –25 mg (½ 50 mg tab) daily. Maximum dose: 50 mg dailya. a = Rarely required or used. Maximal effect does not necessarily require maximal dosing. Use clinical judgement in selecting optimal individual dosing.
Our data indicate that small doses of 10-25 mg cyproteronacetate, less as recommended in the current clinical guidelines, are sufficient to suppress androgens in a majority of transwomen.
Louis Gooren, a lead member of one of the most well-known and -esteemed groups in transgender hormone therapy research and standards, has recently recommended dosages of CPA of 10 to 50 mg/day in transgender women (Nota, den Heijer, & Gooren, 2019). This is in significant contrast to their past extensive use and recommendation of 100 mg/day CPA (Asscheman & Gooren, 1993; Gooren, Giltay, & Bunck, 2008). Moreover, they have also recently made notable cautionary statements on the use of CPA in general (Nota, den Heijer, & Gooren, 2019):
Possibly, venous and arterial cardiovascular side-effects become more prominent past the age of 40-50 years, and in people with cardiovascular risk factors. While strong evidence is currently lacking, transdermal estradiol might be preferred over oral estrogens in these transwomen (9,42,43). In addition, one should be aware that progestogenic antiandrogens (e.g. cyproterone acetate) may further increase one’s risk for venous thromboembolism (44), and should therefore be continued no longer than necessary.
Estrogen in combination with antiandrogen therapy in transwomen stimulate the development of breast lobules, ducts, and acini which are histologically identical to those of ciswomen (56). While for a long time it was believed that the risk of breast cancer in transwomen receiving hormonal therapy was not higher than those of men (57,58), most recent evidence show that transwomen receiving hormonal therapy do have a 46-fold higher risk for breast cancer compared to men (59). As became clear in the Women’s Health Initiative study, addition of progestin to estrogen leads to an increase of the risk of breast cancer in women (60). Although evidence regarding breast cancer and the usage of the progestogenic cyproterone acetate is lacking, the above described data suggest that cyproterone acetate should be continued no longer than necessary.
Serum prolactin concentrations usually rise slightly in response to estrogen administration and more so by cyproterone acetate (65,66). Based on case reports, it was initially believed that prolactin concentrations in transwomen had to be regularly monitored because of their increased risk for prolactinomas. Surprisingly, a very recent cohort study suggests that the occurrence of prolactinomas in transwomen using hormonal therapy is not higher than that in ciswomen, and that regular prolactin checks are not necessary (67). However, cyproterone acetate should be continued no longer than necessary.
Several meningiomas have been reported in transwomen. The current estimated incidence rate of this type of tumor is 33 per 100,000 person-years. This incidence rate is 4 times higher than the incidence rate in ciswomen and 12 times higher than the incidence rate in cismen (67,68). It has been suggested that the occurrence of meningiomas in transwomen is mainly related to cyproterone acetate usage as progesterone receptors are abundantly expressed in human meningiomas (67). Since the occurrence of meningiomas is still rare in transwomen, regular screening for this type of tumor seems not necessary. It is recommended to continue cyproterone acetate no longer than necessary.
As described by other authors, such as Mahfouda and colleagues below however, it is likely that lower and more physiologically reasonable dosages of CPA will have reduced and potentially acceptable risks. Continuing therapy with cyproterone acetate only as long as necessary (e.g., until SRS or orchiectomy) is certainly advisable though.
Mahfouda and colleagues has advocated for lower CPA dosages (Mahfouda et al., 2018):
Other adjuncts that can support oestrogen therapy in transgender females include cyproterone acetate, which has progestational and antiandrogenic properties. Although widely used in Europe and Australia, it is not approved in the USA because of concerns over acute hepatic dysfunction, and rarely, occurrence of meningiomas. Use of smaller doses (12-5 mg) has substantially reduced the risk of these side effects.
In the last two decades, recommendations for hormone preparations and formulations used in GAHT have changed considerably. Reasons are alterations in preparations and formulations available and, particularly, a rising awareness of side effects. While twenty years ago, ethinyl estradiol was used regularly for treatment of transwomen, it is no longer recommended because of its increased risk of thromboembolic events. The currently recommended dosage of the antiandrogenic drug cyproterone acetat of 10-50 mg daily is less than half the dosage used ten years ago.
Antiandrogenic medication was established with cyproteronacetate in 71.5 % (dosage: 10-50 mg/d, median of 25 mg/d). Based on own clinical experience, since 2014 mainly low dosages between 10 and 25 mg per day were used. Spironolactone was used in 5.6 % (dosage 50-100 mg/d, median of 100 mg/d) and combinations of both in 5.6 %. 17.4 % of transwomen refused to use antiandrogens. Antiandrogen medication was discontinued at the time of gonadectomy.
In our cohort, we could not find any significant differences between testosterone level or FAI 3–4 months after onset of GAHT and different starting doses of cyproteronacetate, neither comparing dosages of 25 vs 50 mg/day (testosterone: median difference (MD): 8.05, 95% CI: 14.06 to 30.16, P = 0.468; fAI: MD: 0.12, 95% CI: 1.95 to 2.19, P = 0.498), 10 vs 25 mg/day (testosterone: MD: 13.63, 95% CI : 33.75 to 6.5, P = 0.180; fAI: MD: 1.13, 95% CI: 2.75 to 0.5, P = 0.170), nor 10 vs 50 mg/day (testosterone: MD: 5.57, 95% CI: 19.54 to 8.39, P = 0.427; fAI: MD: 1, 95% CI: 2.69 to 0.69, P = 0.239).
Various German clinics have started using low-dose CPA in transgender women:
“Androcur® initial 1 × 50 mg, je nach Testosteronspiegel schnelle Reduktion auf 25–10–5 mg tgl.” → “Androcur® initial 1 × 50 mg, depending on the testosterone level rapid reduction to 25–10–5 mg daily” (Athanasoulia-Kaspar & Stalla, 2019)
“Cyproteronacetat (z. B. Andro-Diane® 10 mg/Tag p.o., Androcur® 10–100 mg/Tag p.o.” →”Cyproterone acetate (e.g. Andro-Diane® 10 mg/day p.o., Androcur® 10–100 mg/day p.o.” (Winkler-Crepaz et al., 2017)
“Mann-zu-Frau-Standardtherapie. Östradiol 2–6 mg/Tag. Kombination mit einem Antiandrogen (Cyproteronacetat, CPA: z. B. Androcur® 10–20 mg/Tag).” → “Male-to-female standard therapy. Estradiol 2–6 mg/day. Combination with an antiandrogen (cyproterone acetate, CPA: e.g. Androcur® 10–20 mg/day).” (Jacobeit, 2019)
“Zusätzlich wird von den meisten Zentren als Antiandrogen Cyproteronacetat (Androcur) rezeptiert, in der Regel sind Dosierungen von 10 mg pro Tag ausreichend.” → “In addition, most centers use an antiandrogen cyproterone acetate (Androcur), with dosages of 10 mg per day being generally sufficient.” (Lederbogen, 2009)
“Table 1. General characteristics at baseline. […] Transwomen (N = 10) […] Cyproterone acetate use. N=10. % = 90. […] Cyproterone acetate dosage (mg). Median (min-max): 7.2 (2.0-25.0).” (Fuss et al., 2019)
Guy T’Sjoen of the Ghent University Hospital in Belgium and his colleagues recently recommended 10 to 50 mg/day cyproterone acetate (T’Sjoen et al., 2020):
The most commonly used antiandrogen drug in Europe is cyproterone acetate (oral 10–50 mg, once daily), a progestin with antiandrogenic properties.
Table. 1. Hormone treatment in AMAB people. […] Antiandrogens […] Mode of administration: Oral […] Type: Cyproterone acetate. Total dose: 10–50 mg.
If GnRH analogs are not being taken or are not funded, then a testosterone or androgen blocker, for example spironolactone 50 to 200 mg daily or cyproterone acetate 12.5 to 50 mg daily, should be used in conjunction with the estrogen therapy.
Cyproterone acetate is commonly used at low doses of 12.5 to 25 mg daily for trans women and, like spironolactone, is effective and safe.