The side effects of<unk>  are sex-dependent. In men, a variety of side effects related to androgen deprivation may occur, the most common being gynecomastia and breast tenderness. Others include hot<unk> ashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression, and sexual dysfunction including reduced libido and erectile dysfunction. In women,<unk>  is, generally, relatively well tolerated, and does not interfere with ovulation. The only common side effect of<unk>  in women is dry skin (75%), which can be attributed to a reduction of androgen-mediated sebum production. General side effects that may occur in either sex include dizziness, lack of appetite, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine, and hepatic changes. Because<unk>  is a pure antiandrogen, unlike steroidal antiandrogens like cyproterone acetate and megestrol acetate (which additionally possess progestogenic activity), it does not appear to have a risk of cardiovascular side effects (e.g., thromboembolism) or<unk> uid retention. Gynecomastia<unk> , as a monotherapy, causes gynecomastia in 30 to 79% of men, and also produces breast tenderness. However, more than 90% of cases of gynecomastia with NSAAs including<unk>  are mild to moderate. Tamoxifen, a selective estrogen receptor modulator (SERM) with predominantly antiestrogenic actions, can counteract<unk> -induced gynecomastia and breast pain in men. Diarrhea Diarrhea is more common and sometimes more severe with<unk>  than with other NSAAs. In a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for<unk>  and 12% for bicalutamide. Moreover, 6% of<unk> -treated patients discontinued the medication due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so. In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5 to 20% for<unk> , 2 to 5% for bicalutamide, and 2 to 4% for nilutamide. In contrast to diarrhea, the rates of nausea and vomiting are similar among the three medications. Rare reactions Liver toxicity Although rare,<unk>  has been associated with severe hepatotoxicity and death. By 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities. There have been continued case reports since, including liver transplants and death. A 2021 review of the literature found 15 cases of serious hepatotoxicity in women treated with<unk> , including 7 liver transplantations and 2 deaths. Based on the number of prescriptions written and the number of cases reported in the MedWatch database, the rate of serious hepatotoxicity associated with<unk>  treatment was estimated in 1996 as approximately 0.03% (3 per 10,000). However, other research has suggested that the true incidence of significant hepatotoxicity with<unk>  may be much greater, as high as 0.18 to 10%.<unk>  is also associated with liver enzyme elevations in up to 42 to 62% of patients, although marked elevations in liver enzymes (above 5 times upper normal limit) occur only in 3 to 5%. The risk of hepatotoxicity with<unk>  is much higher than with nilutamide or bicalutamide. Lower doses of the medication appear to have a possibly reduced but still significant risk. Liver function should be monitored regularly with liver function tests during<unk>  treatment. In addition, due to the high risk of serious hepatotoxicity,<unk>  should not be used in the absence of a serious indication. The mechanism of action of<unk> -induced hepatotoxicity is thought to be due to mitochondrial toxicity. Specifically,<unk>  and particularly its major metabolite hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes I (NADH ubiquinone oxidoreductase), II (succinate dehydrogenase), and V (ATP synthase), and thereby reduce cellular respiration via ATP depletion and hence decrease cell survival. Inhibition of taurocholate (a bile acid) efflux has also been implicated in<unk> -induced hepatotoxicity. In contrast to<unk>  and hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. It is thought that the nitroaromatic group of<unk>  and hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity. The hepatotoxicity of<unk>  appears to depend on hydrolysis of<unk>  catalyzed by an arylacetamide deacetalyse enzyme. This is analogous to the hepatotoxicity that occurs with the withdrawn paracetamol (acetominophen)-related medication phenacetin. In accordance, the combination of paracetamol (acetaminophen) and<unk>  appears to result in additive to synergistic hepatotoxicity, indicating a potential drug interaction. Others<unk>  has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). The incidence of interstitial pneumonitis with<unk>  was found to be 0.04% (4 per 10,000) in a large clinical cohort of 41,700 prostate cancer patients. A variety of case reports have associated<unk>  with photosensitivity.<unk>  has been associated with several case reports of methemoglobinemia. Bicalutamide does not share this risk with<unk> .<unk>  has also been associated with reports of sulfhemoglobinemia and neutropenia. Birth defects Out of the available endocrine-disrupting compounds looked at,<unk>  has a notable effect on anogenital distance in rats.)
Flutamide
Darolutamide
Bicalutamide
Nilutamide
Topilutamide
Apalutamide
Acetothiolutamide
Enzalutamide