The side effects of cyproterone acetate (CPA), a steroidal antiandrogen and progestin, including its frequent and rare side effects, have been studied and characterized. It is generally well-tolerated and has a mild side-effect profile, regardless of dosage, when it used as a progestin or antiandrogen in combination with an estrogen such as ethinylestradiol or estradiol valerate in women. Side effects of CPA include hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis; breast changes such as breast tenderness, enlargement, and gynecomastia; emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes. Weight gain can occur with CPA when it is used at high doses. Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to prevent estrogen deficiency. Few quantitative data are available on many of the potential side effects of CPA. Pooled tolerability data for CPA is not available in the literature. At very high doses in aged men with prostate cancer, CPA can cause cardiovascular side effects. Rarely, CPA can produce blood clots, liver damage, excessively high prolactin levels, prolactinomas, and meningiomas. Upon discontinuation from high doses, CPA can produce adrenal insufficiency as a withdrawal effect.
Overview
Low hormone levels Side effects in men resulting from the antiandrogenic and antigonadotropic properties of CPA include physical demasculinization, sexual dysfunction (including loss of libido and erectile dysfunction), absence of ejaculate, impaired spermatogenesis, testicular atrophy, and reversible infertility. CPA has been described as causing "severe" suppression of sex drive and erectile potency in men with prostate cancer, comparable to that seen with surgical castration. Due to suppression of the production of estrogens, long-term use of high-dose CPA without concomitant estrogen therapy can result in the development of osteoporosis in both sexes. CPA can also sometimes cause breast changes in men such as gynecomastia (breast growth), breast tenderness, and galactorrhea (milk outflow). The use of CPA in men has been associated with cellulite, which has been attributed to androgen deficiency as well.
Breast changes CPA can sometimes cause breast changes in men including gynecomastia (breast development) and breast tenderness. Rates of gynecomastia of 4 to 30% have been reported. Galactorrhea (milk outflow) can also occur in men, due to the strong progestogenic effects of CPA.
Depression CPA has occasionally been associated with depressive mood changes in both men and women. Similar depressive changes have been observed with castration, and may be a consequence of androgen deprivation in men. In large studies, the incidence of depression has been 1 to 10% in both women taking high-dose CPA in combination with an estrogen for androgen-dependent skin and hair conditions and men taking high-dose CPA alone or in conjunction with castration for prostate cancer. In some small studies however, relatively high rates of depression of 20 to 30% have been reported with both low- and high-dose CPA in combination with an estrogen in women. In one large randomized controlled trial that performed a direct head-to-head comparison of high-dose (100 mg/day) versus low-dose CPA (2 mg/day), both in combination with an estrogen, the overall rate of depression was 12.7% and the rates did not differ between the two groups. Despite some association with depression, the incidence of depression in women taking CPA in combination with an estrogen has been described by some researchers as "remarkably low", which they have said may be related to the positive psychological effects of the improvement in androgenic symptoms. 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. 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. In a series of relatively small studies of the combination of low-dose CPA and ethinylestradiol as a birth control pill, depression was reported to have occurred in 1.3 to 4% of cycles. This is similar to the rate of mood changes (<3.5%) observed with birth control pills containing other progestins. A pharmacoepidemiological study using data from the United Kingdom General Practice Research Database found that the incidence of depression with birth control pills containing CPA was identical to that of birth control pills containing other progestins (IRR = 0.99). In clinical studies of the combination of low-dose CPA and estradiol valerate for the treatment of menopausal symptoms, preexisting adverse mood symptoms have been found to be significantly improved. Because of the possible side effect of worsened depressive symptoms, it may be advisable to use CPA with caution in individuals with a history of depression, particularly if severe.
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