side effects of cyproterone acetate side effects of cyproterone acetate 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 side effects of high-dose cyproterone acetate frequencysystem organ classside effect very common (≥10%)general disorders and administration site conditionsheadachetiredness psychiatric disordersdecreased libido (men)erectile dysfunction (men)reduced ejaculate volume (men) reproductive system and breast disordersreversible inhibition of spermatogenesis (men)inhibition of ovulation and reversible infertility (women) hepatobiliary disorderselevated liver enzymes common (≥1% and <10%)metabolism and nutrition disordersweight gain or loss (can be associated with fluid retention) psychiatric disordersdepressed moodrestlessness reproductive system and breast disordersgynecomastia (men)breast pain/tendernessirregular menstruation general disorders and administration site conditionsfatiguehot flashessweating respiratory, thoracic, and mediastinal disordersshortness of breath gastrointestinal disordersnauseagastrointestinal complaints uncommon (≥0.1% and <1%)psychiatric disordersdecreased libido (women) skin and subcutaneous tissue disordersrash rare (≥0.01% and <0.1%)immune system disordershypersensitivity reactions (rash, itching, shortness of breath) psychiatric disordersincreased libido (women) very rare (<0.01%)neoplasms benign and malignantbenign and malignant liver tumors musculoskeletal and connective tissue disordersosteoporosis cardiovascular disordersthromboembolic eventstachycardia reproductive system and breast disordersgalactorrhea general disorders and administration site conditionssleep disturbances unspecifiedunsortedanemiameningiomahyperprolactinemiaprolactinomaintra-abdominal hemorrhagebreast tensionmenstrual spotting lowdysmenorrheavaginal dischargeskin discolorationstretch marks rareliver toxicity (including jaundice, hepatitis, liver failure) notes: side effects are for dosages of cyproterone acetate (androcur) of 10 to 300 mg/day. sources: see template. side effects of cyproterone acetate in the sexual-hormonal surveillance study (sehost) side effectmales (136 mg/day)(n = 1248) (%)females (18 mg/day)(n = 1258) (%)total (77 mg/day)(n = 2506) (%) elevated liver enzymes12.53.69.6 gynecomastia, breast pain4.91.02.9 overweightness, weight gain0.94.12.5 headache, migraine–3.41.7 depression, anxiety, nightmares, mood swings1.01.81.4 gastrointestinal dysfunction0.22.31.2 thyroid dysfunction0.21.81.0 skin changes (pigmentation, chloasma, others)0.31.40.8 edema–1.10.6 adrenal insufficiency or hyperplasia0.20.80.5 tiredness, lethargy, apathy0.60.60.6 alopecia, hair growth0.20.20.2 increased asthma attack rates–0.30.2 osteoporosis0.20.080.2 more frequently prone to attacks0.20.20.2 diabetes mellitus0.080.080.08 total (excluding elevated liver enzymes)9.019.114.0 notes: data from the sexual-hormonal surveillance study (sehost), a long-term pharmacoepidemiologic active surveillance study. the sample included males and females age 3 to 75 years with precocious puberty, hyperandrogenism, sexual deviance, and/or transgenderism; prostate cancer was not included. sources: see template. side effects of estradiol undecylate versus cyproterone acetate in men side effectestradiol undecylate100 mg/month i.m. (n = 96)cyproterone acetate100 mg/day oral (n = 95) n %n % gynecomastia*7477.1%1212.6% breast tenderness*8487.5%66.3% sexual impotence"occurred in essentially all patients of both groups" leg edema*1717.7%44.2% thrombosis44.2%55.3% cardiovascular mortality22.1%22.1% other mortality1a1.0%00% notes: for 6 months in 191 men age 51 to 88 years with prostate cancer. footnotes: * = differences in incidences between groups were statistically significant. a = due to unknown causes. sources: see template. 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. bone loss androgen deprivation therapy, with medications such as cpa or gnrh modulators or with orchiectomy, results in profound deficiency of both androgens and estrogens in men. these hormones, particularly estrogens, are known to be importantly involved in maintaining bone mineral density, both in men and women. as a result, androgen deprivation therapy causes a rapid decrease in bone mineral density in men and can result in osteopenia or osteoporosis with long-term therapy. the bone loss that happens with androgen deprivation therapy typically occurs in the spine, hip, and forearm, but can also occur in other areas of the appendicular skeleton such as the femoral neck. it can be seen within one year of treatment, and continues thereafter. lumbar spine bone density has been found to decrease at a rate of 3 to 7% per year with androgen deprivation therapy in men. androgen deprivation therapy also decreases muscle mass, and this may increase the risk of falls that can result in bone fractures as well as directly decrease bone mass. the risk of bone fractures in men with prostate cancer given androgen deprivation therapy has been estimated to be increased by 45%. the incidence of osteoporosis increases in men with prostate cancer from 36% to 80% after 10 years of androgen deprivation therapy, and following that, it can be expected that all treated men will develop osteopenia or osteoporosis. the bone loss that occurs with androgen deprivation therapy in men is similar to that which occurs in postmenopausal women. although androgen deprivation therapy is known to cause osteoporosis, it is thought that cpa may have a lower risk of osteoporosis than gnrh modulators or orchiectomy. this is believed to be due to the progestogenic activity of cpa, which may help to inhibit bone resorption caused by sex-hormone deficiency. however, the notion that progestogenic activity has beneficial effects on bone health is controversial. regardless of whether the notion is correct or not, case reports and case series of osteoporosis with cpa therapy in men have been published. changes in biomarkers suggestive of bone loss have also been reported for high-dose cpa monotherapy. in addition, the use of progestogen-only birth control in women, with progestins similar to cpa like medroxyprogesterone acetate, has been found to result in decreased bone mineral density in premenopausal women. calcium and vitamin d supplementation may help to reduce the risk of osteoporosis with androgen deprivation therapy in men. bisphosphonates can be used to reduce bone loss and fractures due to androgen deprivation therapy. estrogen replacement and selective estrogen receptor modulators may also be employed, although estrogens can produce gynecomastia in men and may increase the risk of male breast cancer. selective estrogen receptor modulators have been found to decrease the rate of bone loss due to androgen deprivation therapy in men by 50% after 2 years of therapy. however, selective estrogen receptor modulators are described as substantially less effective for this indication than estrogens, which are the most effective medications for this purpose available. high progestogenic exposure high prolactin levels cpa increases prolactin levels and can produce hyperprolactinemia (high prolactin levels) due to its progestogenic activity and consequent stimulation of pituitary lactotrophs. increases in prolactin levels can occur at low, medium, and high doses of cpa, with or without an estrogen. elevation of prolactin levels may be greater and hyperprolactinemia more likely to occur when cpa is combined with an estrogen, as combinations of estrogens and progestogens show synergistic increases in prolactin levels in non-human primates. although hyperprolactinemia can develop with cpa, prolactin levels only rarely exceed the normal physiological range, and increased prolactin levels with cpa are said to be seldom of clinical significance. at a dosage of 10 mg/day in men, cpa has been found to increase prolactin levels by 75%. in another study, a combination of 2 or 20 mg/day cpa with testosterone undecanoate resulted in modest increases in prolactin levels (+96%) in men similarly. the increase in prolactin levels in men with 100 mg/day oral cpa (+118%) has been found to be less than that with 100 mg/month intramuscular estradiol undecylate (+192%). the combination of high-dose (100 μg/day) ethinylestradiol and high-dose (100 mg/day) oral cpa in transgender women has been reported to increase the risk of hyperprolactinemia by 425-fold (20% incidence) relative to cisgender men. however, other studies using the same regimen have found lower incidences of hyperprolactinemia (e.g., 4–7% per year). in one study, prolactin levels were 18 ng/ml at the start of