treatment, 23 ng/ml after 3 months of 100 mg/day cpa, and 19 to 28 ng/ml after 6 to 15 months of 100 μg/day ethinylestradiol and 100 mg/day oral cpa in transgender women. the major symptom of hyperprolactinemia as a condition is hypogonadism, which is caused by the antigonadotropic effects of prolactin. symptoms consequent to hypogonadism include amenorrhea, menopausal symptoms like hot flashes and vaginal dryness, sexual dysfunction, infertility, reduced muscle mass, and decreased bone mineral density. however, due to its progestogenic actions and the potent antigonadotropic effects produced by this activity, cpa can produce such symptoms as side effects regardless of the presence or absence of hyperprolactinemia. prolactin additionally appears to have a direct inhibitory effect on sexual desire in men that is independent of hypogonadism. in men with hyperprolactinemia and hypogonadism, sexual desire is not restored by testosterone replacement therapy, but is restored by prolactin-suppressing medications. conversely, erectile dysfunction in men with hyperprolactinemia is considered to be due to hypogonadism rather than due to direct actions of prolactin itself. on the other hand, it is thought that prolactin may be responsible for the normal sexual refractory period in men, and may directly inhibit the capacity for orgasm. in addition to symptoms of hypogonadism and sexual dysfunction, hyperprolactinemia can cause breast changes such as breast pain, breast enlargement, gynecomastia, and galactorrhea. galactorrhea secondary to hyperprolactinemia is very common in premenopausal women (80%) but more uncommon in individuals with low estrogen levels such as postmenopausal women and men. gynecomastia likewise occurs at a relatively low rate in men with hyperprolactinemia (23%). studies in transgender women have found low but significant incidences of galactorrhea with the combination of estrogen and cpa. prolactin increases levels of adrenal androgens like dehydroepiandrosterone and dehydroepiandrosterone sulfate by increasing their production and secretion from the adrenal glands. for this reason, hyperprolactinemia can cause symptoms of hyperandrogenism such as acne and hirsutism in women. however, such symptoms are not described with cpa, which instead treats these conditions; this can be attributed to the antiandrogenic and glucocorticoid activity of cpa. through such activities, cpa directly blocks the actions of androgens and can suppress dehydroepiandrosterone sulfate secretion from the adrenal glands. brain tumors the combination of an estrogen and cpa has been associated, albeit rarely, with the incidence and/or aggravation of a few different types of usually benign (non-cancerous) brain tumors, most notably prolactinomas and meningiomas. prolactinomas are benign tumors of the pituitary gland that secrete prolactin, and are one of several types of secreting pituitary adenomas. they can produce hyperprolactinemia (abnormally high prolactin levels) as a symptom, which often leads to their diagnosis. meningiomas are usually-benign tumors of the meninges, the membranes that envelop the brain and spinal cord. due to its association with meningiomas, cpa is considered to be contraindicated in people with meningioma or a history of meningioma. benign brain tumors associated with an estrogen and/or cpa can cause visual disturbances or in severe cases complete blindness due to compression of the optic nerve and/or chiasm. meningiomas are 2 to 3 times as prevalent in women than in men, and acceleration of meningioma growth has been observed during pregnancy and in the luteal phase of the menstrual cycle, indicating a possible hormonal link. there is expression of the pr in the anterior pituitary and high expression of the pr in the meninges, suggesting that activation of the pr by cpa is involved in the pathogenesis of the benign brain tumors associated with it. estrogen receptors are also expressed in the anterior pituitary, and are known to increase the expression of the pr in this area. in accordance, estrogens and progestogens, including cpa, are known to increase prolactin levels, particularly at high concentrations (e.g., pregnancy). while most cases of benign brain tumors associated with cpa have been in combination with an estrogen and have occurred in transgender women, there have been cases associated with high-dose cpa alone in both cisgender women and men as well. benign brain tumors such as meningiomas have also been associated with high doses of other progestogens, such as chlormadinone acetate, megestrol acetate, medroxyprogesterone acetate, and nomegestrol acetate, as well as with pregnancy. a number of case reports of prolactinomas (as well as a non-secreting pituitary adenoma), meningiomas, and vestibular schwannomas associated with estrogen and cpa therapy in transgender women have been published. a large retrospective chart study of 2,555 transgender women treated most frequently with an estrogen and cpa and followed for 23,935 person-years reported occurrences of 8 meningiomas (0.31% or 1 in 320 incidence; sir = 4.1 relative to cisgender females, sir = 11.9 relative to cisgender males), 9 prolactinomas (0.35% or 1 in 284 incidence; sir = 4.3 relative to cisgender females, sir = 26.5 relative to cisgender males), one non-secreting pituitary adenoma, and two vestibular schwannomas. a retrospective study of 303 transgender women treated with high-dose estrogen and cpa and followed for a median 4.4 years (range 6 months to 6 months to 14 years) reported occurrences of 46 cases of hyperprolactinemia (serum prolactin >1,000 mu/l) (15% incidence; 400-fold increased risk relative to cisgender males). of 23 persistent cases, 15 of which returned for follow up, 5 of the cases showed an enlarged pituitary gland on ct scanning with contrast enhancement. dosages of cpa in combination with an estrogen that have been associated with benign brain tumors have been 10 mg/day and above. in contrast to the combination of an estrogen and cpa, estrogen alone has been associated only with single case reports of prolactinomas in transgender women. a nationwide population study in denmark found no significant association of cpa or other antiandrogens with meningioma in men. however, studies in spain and the united kingdom have found positive associations of cpa therapy with meningioma. a hemangioblastoma mimicking a meningioma has been reported in a man treated with cpa. published case reports of cyproterone acetate-associated prolactinoma #agesexmedicationstreatment durationreflink 126 yearsmtfcpa 100 mg/day, ee 100 μg/day, eu 100 mg/2x week~10 monthsgooren et al. (1988) 232 yearsmtfcpa 150 mg/day, ee 1.5 mg/day4 yearsserri et al. (1996) 352 yearsmtfcpa 100 mg/day, ee 100 μg/day15 yearsbunck et al. (2009) 433 yearsmtfcpa 200 mg/day, cees 2.5 mg/day6 monthsgarcía-malpartida et al. (2010) 541 yearsmtfcpa 2 mg/day, ee 35 μg/day, e2-en 10 mg/2 weeks i.m.18 yearscunha et al. (2015) 632 yearsmtfcpa 100 mg/day, e2 injections 100 mg/2 weeks i.m.53 monthsnota et al. (2018) 739 yearsmtfcpa 100 mg/day, cees 2.5 mg/day172 monthsnota et al. (2018) 827 yearsmtfcpa, e2 injections i.m. (no dosage information)156 monthsnota et al. (2018) 946 yearsmtfcpa 100 mg/day, ee 100 μg/day66 monthsnota et al. (2018) 1024 yearsmtfcpa 100 mg/day (no estrogen mentioned)9 monthsnota et al. (2018) 1147 yearsmtfcpa 100 mg/day, ee 100 μg/day91 monthsnota et al. (2018) 1228 yearsmtfcpa 50 mg/day, ev 2 mg/day oral134 monthsnota et al. (2018) 13a34 yearsmtfcpa 50 mg/day, ev 1 mg/day oral35 monthsnota et al. (2018) abbreviations: cpa = cyproterone acetate. e2 = estradiol. ev = estradiol valerate. e2-en = estradiol enanthate. eu = estradiol undecylate. cees = conjugated estrogens. ee = ethinylestradiol. mtf = male-to-female (transgender woman). i.m. = intramuscular injection. footnotes: a = non-secretive pituitary adenoma. notes: asscheman et al. (1988) also described 5 mtf cases of pituitary enlargement and possible prolactinoma. van kesteren et al. (1997) described possible mtf cases of pituitary enlargement as well. five estrogen-only mtf cases (without cpa) have also been reported. futterweit (1998) described an mtf case without information about medications. sources: published case reports of cyproterone acetate-associated meningioma #agesexmedicationstreatment durationreflink 128 yearsmtfcpa 100 mg/day, ee 100 μg/day5 yearsgazzeri et al. (2007) 248 yearsmtfcpa 100 mg/day, ee ("feminizing regimen")10 yearscebula et al. (2010) 346 yearsfemalecpa 50 mg/day, e2 ("substitutive")10 yearsgonçalves et al. (2010) 483 yearsmalecpa ≥50 mg/day2 yearsgil et al. (2011) 571 yearsmalecpa ≥50 mg/day3 yearsgil et al. (2011) 666 yearsfemalecpa ≥50 mg/day3 yearsgil et al. (2011) 743 yearsfemalecpa ≥50 mg/day2 yearsgil et al. (2011) 835 yearsmtfcpa 100 mg/day, e2 100 μg/day patch4 yearsbergoglio et al. (2012) 960 yearsmtfcpa 50 mg/day, e2 8 mg/day oral10 yearsknight et al. (2013) 1056 yearsmtfcpa, ev 2 mg/day oral8 yearsrazavi (2014) 1151 yearsfemalecpa 15 mg/day30 yearsbernat et al. (2015) 1247 yearsfemalecpa 25 mg/day15 yearsbernat et al. (2015) 1343 yearsfemalecpa 50 mg/day12 yearsbernat et al. (2015) 1439 yearsfemalecpa 50 mg/day10 yearsbernat et al. (2015) 1561 yearsfemalecpa 25 mg/day24 yearsbernat et al. (2015) 1638 yearsfemalecpa 25 mg/day10 yearsbernat et al. (2015) 1745 yearsfemalecpa 50 mg/day20 yearsbernat et al. (2015) 1853 yearsfemalecpa 50 mg/day20 yearsbernat et al. (2015) 1956 yearsfemalecpa 50 mg/day8 yearsbernat et al. (2015) 2055 yearsfemalecpa 50 mg/day30 yearsbernat et al. (2015) 2149 yearsfemalecpa 50 mg/day20 yearsbernat et al. (2015) 2249 yearsfemalecpa 50 mg/day25 yearsbernat et al. (2015) 2358 yearsfemalecpa 50 mg/day18 yearsbotella et al. (2015) 2437 yearsfemalecpa 50 mg/day11 yearsbotella et al. (2015) 2542 yearsmalecpa 100 mg/day23 yearssys & kestelyn (2015) 2645 or 46 yearsmtfcpa 10 or 100 mg/day, e2 20 mg/4 months implant5 yearster wengel et al. (2015) 2751 yearsmtfcpa 100 mg/day, ee 100 μg/day25 yearster wengel et al. (2015) 2865 yearsmtfcpa 10 mg/day, cees 1.25 mg/day19 yearster wengel et al. (2015) 2926 yearsfemalecpa 50 mg/day10 yearskalamarides & peyre (2017) 3043 yearsfemalecpa 25 mg/day25 yearskalamarides & peyre (2017) 3183 yearsmalecpa 200 mg/day7 monthskeilani & abada (2017) 3265 yearsfemalecpa 50 mg/day15 yearsbernat et al. (2018) 3377 yearsmtfcpa 50 mg/day, e2 50 μg/day patch24 yearsboer et al. (2018) 3441 yearsmtfcpa 50 mg/day, e2 gel 1–3 mg/day9 yearsmancini et al. (2018) 3560 yearsmtfcpa, cees36 yearsnizar & seal (2018) 3651 yearsmtfcpa 20 mg/week, e2 100 μg/day patch11 yearsnota et al. (2018) 3766 yearsmtfcpa 10 mg/day40 yearsnota et al. (2018) 3858 yearsmtfcpa 50 mg/day, e2 100 μg/day patch6 yearsnota et al. (2018) 3949 yearsmtfcpa, ev 2 mg/day16 yearsnota et al. (2018) 4051 yearsmtfcpa 100 mg/day, ee 100 μg/day patch26 yearsnota et al. (2018) 4150 yearsmtfcpa 50 mg/day, e2 0.6 mg/g cream 2x/day~10 yearsraj et al. (2018) 4248 yearsmtfcpa 50 mg/day, e2 1 mg/g cream 3x/day21 yearsraj et al. (2018) 4343 yearsfemalecpa 25–50 mg/day, ev 2 mg/day, finasteride 5 mg/day, others23 yearschasseur et al. (2019) 4467 yearsmtfcpa, estrogen>14 yearsalalade et al. (2019) 4546 yearsfemalecpa 5 mg/day, subsequently nomac 5 mg/day15 yearschampagne et al. (2019) 4658 yearsfemalecpa 25–100 mg/day for 10 days/cycle34 yearsowens et al. (2019) 47 ?malecpa 300 mg/2 weeks i.m., leuprorelin 11.25 mg/3 months i.m. ?colstrup et al. (2020) abbreviations: cpa = cyproterone acetate. e2 = estradiol. ev = estradiol valerate. cees = conjugated estrogens. ee = ethinylestradiol. mtf = male-to-female (transgender woman). notes: for the bernat et al. (2015) cases, only one was reported to be taking an estrogen (specifically estradiol). froelich et al. (2008) reported an additional 8 female cases (age 33–62 years, mean 46 years; 50 mg/day cpa; 10–20 years exposure) with multiple meningiomas. cea-soriano et al. (2012) also reported 8 cases (4 male (≥50 mg/day, or = 3.28), 4 female (2 mg/day, or = 1.03)) with no individual specifics. peyre et al. reported 38 operated cases. portet et al. (2019) reported 30 operated cases. cases in association with other progestins have been reported as well. deipolyi, han, & parsa (2010) reported a case in an mtf in association with e2 100 μg/day only. sources: blood clots the combination of low-dose (2 mg) cpa in combination with ethinylestradiol (35 μg), as in combined birth control pills, presents an increased risk of venous thromboembolism (vte). women who take contraceptive pills containing cpa have a 6- to 7-fold increased risk of developing vte compared to women not taking a contraceptive pill, and twice the risk of women who take a contraceptive pill containing the androgenic progestin levonorgestrel. the absolute risk of vte with ethinylestradiol and low-dose cpa-containing birth control pills is about 1 to 10 per 10,000 woman-years. at least four publicized cases of fatal vte have been attributed to birth control pills containing ethinylestradiol and low-dose cpa. the progestogenic, antiandrogenic, and glucocorticoid activities of cpa are all thought to be involved in the increased risk of vte with cpa in combination with estrogens. the combination of oral 100 μg/day ethinylestradiol and 100 mg/day cpa was reported to produce a 45-fold increase in the risk of vte in 303 transgender women, with an absolute incidence of 6.3% (19 cases). the risk was highly age-dependent, with a rate of vte of 2.1% in those less than 40 years of age and of 12% in those over 40 years of age. in a subsequent study of 816 transgender women in whom