Aminoglutethimide

Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. It has also been used by bodybuilders, athletes, and other men for muscle-building and performance- and physique-enhancing purposes. AG is taken by mouth three or four times per day. Side effects of AG include lethargy, somnolence, dizziness, headache, appetite loss, skin rash, hypertension, liver damage, and adrenal insufficiency, among others. AG is both an anticonvulsant and a steroidogenesis inhibitor. In terms of the latter property, it inhibits enzymes such as cholesterol side-chain cleavage enzyme (CYP11A1, P450scc) and aromatase (CYP19A1), thereby inhibiting the conversion of cholesterol into steroid hormones and blocking the production of androgens, estrogens, and glucocorticoids, among other endogenous steroids. As such, AG is an aromatase inhibitor and adrenal steroidogenesis inhibitor, including both an androgen synthesis inhibitor and a corticosteroid synthesis inhibitor. AG was introduced for medical use, as an anticonvulsant, in 1960. It was withdrawn in 1966 due to toxicity. Its steroidogenesis-inhibiting properties were discovered serendipitously and it was subsequently repurposed for use in the treatment of Cushing's syndrome, breast cancer, and prostate cancer from 1969 and thereafter. However, although used in the past, it has mostly been superseded by newer agents with better efficacy and lower toxicity such as ketoconazole, abiraterone acetate, and other aromatase inhibitors. It remains marketed only in a few countries. AG is used as an anticonvulsant in the treatment of petit mal epilepsy and as a steroidogenesis inhibitor in the treatment of Cushing's syndrome, postmenopausal breast cancer, and prostate cancer. It is also used to treat secondary hyperaldosteronism, edema, adrenocortical carcinoma, and ectopic adrenocorticotropic hormone (ACTH) producing tumors. When used as a steroidogenesis inhibitor to treat breast cancer and prostate cancer, AG is given in combination with hydrocortisone, prednisone, or an equivalent corticosteroid to prevent adrenal insufficiency. AG is a second- or third-line choice in the treatment of hormone-sensitive metastatic breast cancer. While effective in the treatment of breast cancer in postmenopausal women, it is not effective in premenopausal women and is not an effective ovarian steroidogenesis inhibitor, probably because it is not a potent enough aromatase inhibitor. The medication is effective in the treatment of prostate cancer, but its effectiveness is low and inconsistent, likely due to its relatively weak steroidogenesis inhibition and poor pharmacokinetics. Nonetheless, AG was found to be non-significantly different in effectiveness from surgical adrenalectomy in terms of prostate cancer tumor regression. In any case, AG is not recommended as a first-line therapy in prostate cancer, but instead only as a second-line therapy. It has only rarely been used in the treatment of prostate cancer. AG is used for adrenal steroidogenesis inhibition by mouth at a dosage of 250 mg three times per day (750 mg/day total) for the first 3 weeks of therapy and then increased to 250 mg four times per day (1,000 mg/day total) thereafter. It can be used at a dosage of up to 500 mg four times per day (2,000 mg/day). It is used as an aromatase inhibitor to inhibit peripheral estrogen production by mouth at a dosage of 125 mg twice per day (250 mg/day total), without significant suppression of adrenal steroidogenesis at this dosage. Maximal aromatase inhibition is said to occur between dosages of 250 to 500 mg per day. The side effects of AG are less frequent and severe at this dosage. However, they are still less when AG is combined with hydrocortisone, and so AG is generally combined with a corticosteroid even at this lower dosage. AG should only be used under close medical supervision and with laboratory tests including thyroid function, baseline hematological, serum glutamic-oxaloacetic transaminase, alkaline phosphatase, and bilirubin. Ketoconazole can achieve similar decreases in steroid hormone levels as AG but is more effective in promoting tumor regression and is moderately less toxic in comparison. AG can still be a useful alternative in those who have failed or are unable to tolerate ketoconazole and other therapies however. AG is provided most commonly in the form of 250 mg tablets. AG is used by bodybuilders, athletes, and other men to lower circulating levels of cortisol in the body and thereby prevent muscle loss. Cortisol is catabolic to protein in muscle and effective suppression of cortisol by AG at high doses can prevent muscle loss. It is usually used in combination with an anabolic steroid to avoid androgen deficiency. However, the usefulness of AG for such purposes has been questioned, with few users reportedly having positive comments about it, and the risks of AG are said to be high. In any case, AG is also used by bodybuilders and other men for its actions as an aromatase inhibitor in order to decrease estrogen levels. It is said to be useful for inhibiting the estrogenic side effects of certain anabolic steroids such as gynecomastia, increased water retention, and fat gain.