By Aly W. | First published March 30, 2019 | Last modified June 10, 2021
I’ve carefully reviewed the literature on cyproterone acetate and depression. I used a query like this in Google Scholar and went through all of the results. I found that there was surprisingly tenuous data to support a considerable risk of depression with cyproterone acetate. The results of my literature review can be found here on Wikipedia. Here is a summary of the findings I wrote:
Low-dose (e.g., 2 mg/day) cyproterone acetate, for instance in birth control pills, has no risk of depression. Moreover, the risk of depression with higher doses of CPA may be considerably less than previously thought. This is on the basis of clinical studies that were in some cases rigorous and well-designed, checking carefully for changes in mood. The severity of depression with CPA may also be much less than previously thought. The risk of depression with CPA may be isolated mainly to when it is used without an estrogen, such as in men with prostate cancer. Only small, uncontrolled, and poor quality clinical studies have observed high incidences of depression with CPA. But many of these studies were in women with severe hirsutism, who had high baseline rates of emotional disturbances due to the nature of their condition. And in at least some cases these studies lumped “depression” and “fatigue” into a single “mood changes” group—fatigue at high doses notably being a more well-established side effect of CPA. Other research has likewise found very low rates of mood changes with medroxyprogesterone acetate, a progestin that is closely related to CPA (Wiki).
It is possible that a nocebo effect (i.e., a psychogenic effect based on pre-existing knowledge and expectations) may be occurring with transfeminine people when it comes to CPA and depression. It is notable that about 75% of the mood-lifting effect of antidepressants is estimated to be due to the placebo effect (Mora, Nestoriuc, & Rief, 2011), so this is well within the realm of possibility. (Another possibility is misattribution, as transgender people have high baseline rates of depression.) A nocebo effect for depression with finasteride has likewise been suggested (Kuhl & Wiegratz, 2017).
The best-quality study I found was this one (from the first link):
A randomized controlled trial comparing the cognitive and emotional effects of GnRH agonists and CPA in 82 men with prostate cancer found no significant differences in scores on the Depression Anxiety Stress Scale-21 (DASS-21) after 6 months of treatment. However, a 12-month follow-up of 62 of the men found a significant increase in emotional distress as measured by the DASS-21 in the CPA and watchful waiting groups relative to the GnRH-agonist groups. Nonetheless, the mean levels of emotional distress remained within the normal range.
Here are some data in transfeminine people (also from the first link):
A retrospective study reported that the rate of depression was greater with CPA (8.3%) than with GnRH analogues (2.2%) when both were used in combination with an estrogen in transgender women, although this study did not control for mood-related confounds. Another retrospective study in transgender women, which used the Beck Depression Inventory‐II and other scales, found no significant differences in psychological well‐being or satisfaction with the combination of an estrogen and CPA or a GnRH agonist. Hormone therapy in transgender women, including studies that used CPA, has been found to result in a significant decrease in depressive symptoms.
On another note, low doses (5–12.5 mg/day) of cyproterone acetate are likely to exert maximal suppression of testosterone levels, especially in combination with an estrogen (Aly W., 2019). If cyproterone acetate does have a risk of depression that can be attributed more than just androgen deprivation (which is only relevant to people who do not also take an estrogen), then lower doses may minimize the risk. If 2 mg/day cyproterone acetate has no risk of depression, then 5 or 6.25 mg/day may not either.
J Clin Endocrinol Metab. 2012 Dec;97(12):4422–4428. doi: 10.1210/jc.2012-2030:
With regard to the use of antiandrogens, the major side effect was an increased rate of depression compared with that seen in those treated with GnRH analogs (7.6 vs. 2.2%, P 0.029) (see Table 4). It should be remembered that this is in the context of a background rate of depression reported in 35.6 and 34.1% of clients, respectively, before treatment. Of the antiandrogens studied, only cyproterone acetate was significantly associated with depression (8.3%, P 0.05) (see Table 4).
Cyproterone acetate use is statistically more likely to cause depression than the other antiandrogen types used in this study. These results are consistent with previous studies using cyproterone acetate to treat hirsutism (11–13). It is, however, the first time this has been reported in transwomen. The incidence of depression was much lower in those using GnRH analogs, which is consistent with the findings of Dittrich et al. in 2005 (14), who found that depression was not a significant problem in transwomen treated with GnRH analogs.
Because cyproterone acetate was associated with an increased incidence of depression compared with GnRH analogs, it could be argued that GnRH analogs are better for testosterone reduction.
European Journal of Endocrinology (2011) 164 635–642:
Depressive mood changes have been reported in cyproterone acetate use but these are usually transient occurring during the first 6 months of use.
Basson RJ. Towards optimal hormonal treatment of male to female gender identity disorder. J Sex Reprod Med 2001;1:45–51:
[…] a high incidence of depression with its associated increased risk of suicide, for which persons with GID are already at increased risk, is reported by Asscheman et al (7) who routinely use CPA.
Metabolism. 1989 Sep;38(9):869–873:
Combined treatment with estrogen and cyproterone acetate in 303 male-to-female transsexuals was associated with (…) depressive mood changes (15-fold).
Acta Endocrinol (Copenh). 1979 Jul;91(3):545–552:
One daily dose of either 5 mg or 10 mg cyproterone acetate (CA) was administered to 2 groups of 4 fertile men for 6 months.
Three subjects who began the study were withdrawn because of depressive mood changes (2) and weakness combined with dizziness (1).
Lancet Diabetes Endocrinol. 2017 Apr;5(4):291–300:
Cyproterone seems to have a stronger anti-androgenic action than spironolactone,14 but depression is a potential side-effect.15
Curr Opin Endocrinol Diabetes Obes. 2013 Dec;20(6):565–569:
Cyproterone acetate (CPA) is probably the most widely used molecule outside the USA (where it is not available), but this may induce liver toxicity and higher incidence of depression has been reported .
Lancet Diabetes Endocrinol. 2017 Apr;5(4):243–246:
CPA, a progesterone derivative with some glucocorticoid-like activity, is also a highly effective antiandrogen, albeit potentially associated with hepatic dysfunction, depression, meningioma development, and weight gain.5
Clin Endocrinol (Oxf). 1991 Jul;35(1):5–10:
The hirsute women were allocated at random into three treatment groups: (i) Dianette which contains 35 pg ethinyl oestradiol and 2 mg CPA, (ii) Dianette with 20 mg CPA and (iii) Dianette with 100 mg CPA. Individual dose regimens were blinded to both subjects and investigator. The supplementary CPA was given on days 1–10 of the birth control pill cycle as described by Hammerstein et al. (1975). A treatment period of 12 months was chosen to reduce any error introduced by seasonal variation in hair growth (Casey et al., 1964) and to allow the full therapeutic effect to develop.
Six women withdrew because of side-effects (depression, four; […]
The adverse effects of CPA therapy were evenly distributed throughout the three dose groups (Table 3). Twelve women became depressed: three within the first month and nine after 6 months therapy, and four subjects withdrew due to depression. (…) Weight gains were experienced by 23/36 women who completed the 12 months trial period.
The profile of side-effects of cyproterone acetate demonstrated in this study is similar to previous reports. The prevalence of depression in 19% subjects may appear high as it includes symptoms reported in previous studies as lassitude and tiredness. The incidence of weight gain (64%) and breast tenderness (22%) are considerably greater than other reports (Hammerstein et al., 1983; Belisle & Love, 1986).
Dianette only: 4 cases of depression (1 withdrawal), onset 3–6 months (3 at 3 months)
Dianette + 20 mg CPA: 4 cases, 2 withdrawal, onset after 6 months
Dianette + 100 mg CPA: 4 cases, 1 withdrawal, onset after 6 months
Acta Obstet Gynecol Scand. 1981;60(3):295–300:
Ten women with essential hirsutism were treated for one year with cyclic administration of cyproterone acetate and ethinyl estradiol. Biochemical and clinical control took place after 1, 3, 6 and 12 months of treatment.
Side effects included (…) mental depression in 3 (30%).
Therapy was then initiated according to Hammerstein et al. (14) with 100 mg CA/day from day 5 to 14 of the menstrual cycle, and EE 50 pg/day from day 5 until day 25.
The treatment is, however, rather frequently afflicted with side effects, among which decreased libido and mental depression were the most troublesome both in our patients and in those reported by the above mentioned authors. They may be so severe as to necessitate cessation of treatment.
I’ll go through papers/excerpts one by one.
J Clin Endocrinol Metab. 2012 Dec;97(12):4422–4428. doi: 10.1210/jc.2012-2030.
Seal et al. (2012). Retrospective case-controlled study of transgender women treated with estrogens and antiandrogens. Low-quality clinical data. Prospective randomized controlled trials are better.
Some excerpts from the paper:
The most commonly reported adverse effect of estrogen treatment was depression (4.5%), with no statistical difference in depression between the types of estrogen used (see Table 4). There was a self-reported depression rate of 32.2% in individuals untreated with estrogens and/or antiandrogens (data not shown).
With regard to the use of antiandrogens, the major side effect was an increased rate of depression compared with that seen in those treated with GnRH analogs (7.6 vs. 2.2%, P < 0.029) (see Table 4). It should be remembered that this is in the context of a background rate of depression reported in 35.6 and 34.1% of clients, respectively, before treatment. Of the antiandrogens studied, only cyproterone acetate was significantly associated with depression (8.3%, P < 0.05) (see Table 4).
There is a high incidence of depression in our series, with approximately 30% of individuals reporting depression at baseline. Our data suggested that the depression rate in treated individuals was much lower at 4.5%, with no difference in rate between the estrogen types used. Although we did not control for mood-related confounds specifically, this suggests that hormonal treatment per se decreases depression in transwomen, which is in line with a number of studies that have found that treatment for gender dysphoria positively affects mood (10).
The use of antiandrogens was also associated with an increase in self-reported depression, compared with GnRH analogs. Cyproterone acetate use is statistically more likely to cause depression than the other antiandrogen types used in this study. These results are consistent with previous studies using cyproterone acetate to treat hirsutism (11–13). It is, however, the first time this has been reported in transwomen. The incidence of depression was much lower in those using GnRH analogs, which is consistent with the findings of Dittrich et al. in 2005 (14), who found that depression was not a significant problem in transwomen treated with GnRH analogs.
The rates of reported depression with spironolactone (9.1%) and dutasteride (12.5%) were higher than with CPA (8.3%), while the rates of reported depression with finasteride (6.3%) and GnRH analogues (2.2%) were lower than with CPA. Antiandrogens as a group vs. GnRH analogues and CPA vs. GnRH analogues were significant for difference in depression rates, while other comparisons were not.
Overall, considering the retrospective nature of this study along with the high baseline rate of depression and various possible uncontrolled confounding variables, I think we should take this data with a grain of salt.
Let’s also look at References 11, 12, and 13. Reference 11 was this study. I don’t have access to the full text PDF at this time, but the abstract says the following:
175 women of reproductive age, with hirsutism of differing degrees and different pathogenetic causes (ovarian, adrenal, iatrogenic) or idiopathic, and acne were treated with two different combinations of Cyprotrone acetate and ethinyl estradiol (SH 8.1041 and SH B209AB). 90 patients were given SH 8.1041 and 10 were given SH B209AB. 75 received both preparations. The total number of treatment cycles was 1534. […] Some patients on SH 8.1041 complained of transient frigidity, mild depression, breast discomfort and nausea.
Reference 12 was this study of 10 women treated with EE + CPA, 3 of whom were reported to have developed depression. I discuss it below (look for “Acta Obstet Gynecol Scand. 1981;60(3):295–300” quote).
Reference 13 was this study. Prospective study of EE + CPA in 23 women with hirsutism for 6 months. No control or comparison group, randomization, blinding, etc. Low-quality data. Some excerpts from the paper:
Side effects which were thought to be due to the medication were common. Nausea occurred in 10, headache in 9, decreased libido in 9, tiredness in 7, and depression in 6 patients. In one patient a superficial thrombophlebitis was diagnosed. Six women discontinued the treatment because of the side effects.
CA at a dose of 100 mg daily caused frequent side effects in our trial as in previous investigations (2, 3). These side effects resemble those seen during the use of contraceptive pills, but they occur more frequently. Nausea, headache, loss of libido and depression were commonly complained. It was disappointing that 26 per cent of the patients withdrew from CA intake because of side effects, although the treatment lasted only six months. It must be stressed, however, that the dose of CA used in this study was high (100 mg daily).
Various side effects, such as nausea, headache, loss of libido and depression, were reported very frequently, which undoubtedly limits the large scale use of this treatment, at least with the doses used in this study.
Six out of 23 is a rate of depression of 26%, which is indeed high. But, as I said, this is low-quality data.
From the above excerpts, Reference 2 is Hammerstein et al. (1975), which is discussed below, and Reference 3 is this study, which I don’t have access of the full text for but the abstract of which says the following:
Treatment of virilization symptoms in 230 patients is reported. 68 patients were treated with Planovin (4 mg megestrol acetate and .05 mg ethinyl estradiol), 77 with SH81041 (100 mg Cyproterone acetate for 10 days and .05 mg ethinyl estradiol for 21 days), and 85 were treated first and Planovin and then with SH81041. […] Side effects included breakthrough bleeding and sweating.
European Journal of Endocrinology (2011) 164 635–642
Basson RJ. Towards optimal hormonal treatment of male to female gender identity disorder. J Sex Reprod Med 2001;1:45–51.
Metabolism. 1989 Sep;38(9):869–873.
The cited source in all of these papers, Asscheman (1997), was a retrospective non-case-controlled study. From Asscheman (1997) itself:
This study is a retrospective and not a case-control study. Therefore, no definitive conclusions about the relative risks of cross-gender hormone treatment can be drawn. The conclusion of this study could have been more firm if a control group had been included. It did not appear feasible to match our group, which was heterogeneous in age and duration of hormone treatment, with a control group. In the latter group there should have been a similar follow-up with regular clinic visits and laboratory tests. To compensate for this drawback, we compared our findings with the expected number of deaths and morbidity calculated from health statics, adjusted for age and sex, of the general population. This approach still poses a problem because our group was selected in two ways: (1) in our clinical population serious preexistent morbidity was excluded (eg, serious cardiovascular disease), and (2) the patients were treated on the basis of their transsexualism, which might be associated with a greater proneness to some pathologies (eg, suicide).
Temporary mood changes were spontaneously reported by a considerable number of male-to-female transsexual patients in the first six months of treatment but subsequently waned. In particular, cyproterone acetate has been reported to be associated with a lack of energy and depressive mood changes.30 The reason for these mental changes may not only be the hormone effect but also the psychologic pressure of living in the new gender role.
From Reference 30 (a 1974 German study on EE/CPA for androgen-dependent skin/hair conditions in 241 women) cited in the Asscheman (1974) paper (translated):
In the foreground in the first three months of treatment are the subjective symptoms of mastodynia and nausea, of which only mastodynia still occur in the further months of treatment. The increased occurrence of weight gain is also limited to the first treatment period. Bleeding disorders in the sense of increased menstrual bleeding and pre- and post-menstrual bleeding did not occur after SH 81041 treatment after the first treatment cycles. The fatigue indicated by several patients can be explained pharmacologically as a central sedative effect of the progestogenic activity of cyproterone acetate. Also, the depressive moods mentioned by some patients suggest a connection with altered state of well-being under the medication. Headache occurred only to a small extent and only passing. Among the other side effects is only the libido loss to emphasize, which forced only in a few cases to discontinue the medication.
As well as the following table (only relevant side effects included) from the paper:
|Side effect||3 months||6 months||9 months||12 months||>12 months|
|Loss of libido||3||3||–||1||–|
|Total patients treated||241||155||76||37||24|
In other words, only 0 to 1.2% of the women actually reported incidence of depression…
Acta Endocrinol (Copenh). 1979 Jul;91(3):545–552.
Small and low-quality study of 5 to 10 mg/day CPA monotherapy in men age 25 to 40 years. Seven men completed treatment, two withdrew prior to completion of treatment due to self-reported depressive symptoms. Several others also withdrew for personal/unrelated reasons. No control group. Testosterone levels were suppressed. Depressive symptoms may have been nocebo-based, coincidental, and/or related to testosterone suppression. Properly controlled studies with adequate sample sizes are better.
Lancet Diabetes Endocrinol. 2017 Apr;5(4):291–300.
Nothing in the source cited by the paper (Reference 15; a review on transgender hormone therapy) about depression, mood changes, or anything similar with CPA. (See for yourself.)
Curr Opin Endocrinol Diabetes Obes. 2013 Dec;20(6):565–569.
Lancet Diabetes Endocrinol. 2017 Apr;5(4):243–246.
Source cited by these papers was Seal et al. (2012), which was already discussed above.
Clin Endocrinol (Oxf). 1991 Jul;35(1):5–10.
Prospective study with no placebo group. Randomization to and comparison between different EE + CPA dosages only. Rates of “depression” were equivalent between the three different CPA treatment groups (about 4 women in 20, or 20% for all three groups): EE + 2 mg/day CPA, EE + 22 mg/day CPA, and EE + 102 mg/day CPA. However, from your own included excerpt from the paper:
The profile of side-effects of cyproterone acetate demonstrated in this study is similar to previous reports. The prevalence of depression in 19% subjects may appear high as it includes symptoms reported in previous studies as lassitude and tiredness.
Fatigue is a more well-supported side effect of CPA based on the studies I’ve seen.
Due to relatively small sample size, lack of true placebo group, and lumping of depression, lassitude, and tiredness together as “depression”, few conclusions can be drawn.
Acta Obstet Gynecol Scand. 1981;60(3):295–300.
Prospective study with no control or comparison groups. Sample size was small; 10 women. Of these, 3 (30%) were reported to have developed depression. Low-quality data.
In reference to this excerpt from the paper specifically:
Several hundred women have until now been treated with a drug regimen similar to that employed in our study, and improvement of hirsutism has been reported in 60–80% (4, 7, 10, 14, 15). […] The treatment is, however, rather frequently afflicted with side effects, among which decreased libido and mental depression were the most troublesome both in our patients and in those reported by the above mentioned authors. They may be so severe as to necessitate cessation of treatment.
Reference 4 is the 1974 German study I discussed above in which a rate of depression of 0 to 1.2% was reported in 241 women.
Reference 7 is a prospective study with no control or comparison groups of 14 women treated with EE + CPA for hirsutism. One woman reported emotional lability and one other woman reported depression.
Reference 10 is a prospective study of EE + CPA for hirsutism. No access to the full text at this time, but the abstract contains the following:
In 44 hirsute women treated with antiandrogens, sequential administration of cyproterone acetate and ethinylestradiol produced a success rate of 87%. The mean duration of treatment was 9 months, and side effects were rare.
Reference 14 was a review of a large prospective study of 602 women across five different German treatment centers given CPA + EE for hirsutism and other androgen-dependent indications. It contains this table:
|Loss of libido||60/602||10.0%|
There is no other discussion of mood changes or depression. In another paper around the same time by the same lead author (Hammerstein) however, the following is stated:
Zielske (Berlin) reported on the clinical results of antiandrogen treatment with CPA in 602 women and more than 5,000 treatment cycles on the basis of cooperative surveys at the University Women’s Hospital in Berlin, Diisseldorf, Hamburg, Ulm and Frankfurt. […] A decrease in libido was reported by every 10th woman. The side effects are similar in frequency and intensity to those in hormonal contraception. Only 4.5% of women abstained from continuing treatment for the same accompanying symptoms.
Reference 15 was a prospective study of 5 women treated with EE + CPA. There was no mention or discussion of depression or related symptoms.
Taken together, most of the studies are low-quality (e.g., retrospective, small sample sizes, no control/comparison groups, no randomization/blinding, etc.), while the highest-quality studies (e.g., prospective, large sample sizes, etc.) report low rates of depression. I don’t think I saw a single true randomized controlled trial in any of the citations though.
My literature review of CPA and depression includes large prospective studies, multiple randomized controlled trials, and population-based pharmacoepidemiological data, which is much better quality than most of the above studies.
All in all, considering the best-quality evidence, the risk of depression with CPA appears to be minimal, especially when combined with an estrogen and hence when there is no sex hormone deficiency.
Thank you for posting all of these sources and excerpts though. I hadn’t seen some of them before and hence missed a number of them in my review.