At contraceptive and hormone replacement dosages (0.35 to 1 mg/day),<unk>  has essentially progestogenic side effects only. In most clinical studies of<unk>  for contraception or menopausal hormone therapy, the drug has been combined with an estrogen, and for this reason, it is difficult to determine which of the side effects were caused by<unk>  and which of them were caused by estrogen in such research. However,<unk> TE, an intramuscularly administered prodrug of<unk>  which is used as a long-acting contraceptive, is used without an estrogen, and hence can be employed as a surrogate for<unk>  in terms of understanding its effects and tolerability. In clinical studies, the most common side effect with<unk> TE has been menstrual disturbances, including prolonged bleeding or spotting and amenorrhea. Other side effects have included periodic abdominal bloating and breast tenderness, both of which are thought to be due to water retention and can be relieved with diuretics. There has been no association with weight gain, and blood pressure, blood clotting, and glucose tolerance have all remained normal. However, a decrease in cholesterol has been observed. At high doses (5 to 60 mg/day), for instance those used in the treatment of gynecological disorders,<unk>  can cause hypogonadism due to its antigonadotropic effects and can have estrogenic and weak androgenic side effects. High doses of<unk> TA (10 mg/day) have been associated with abnormal liver function tests, including significant elevations in liver enzymes. These liver enzymes included lactate dehydrogenase and glutamate pyruvate transaminase. Although they were described as having no clinical relevance, the elevated liver enzymes associated with<unk> TA may have precluded its further development for male hormonal contraception. Androgenic Due to its weak androgenic activity,<unk>  can produce androgenic side effects such as acne, hirsutism, and voice changes of slight severity in some women at high dosages (e.g., 10 to 40 mg/day). This is notably not the case with combined oral contraceptives that contain<unk>  and EE, however. Such formulations contain low dosages of<unk>  (0.35 to 1 mg/day) in combination with estrogen and are actually associated with improvement in acne symptoms. In accordance, they are in fact approved by the for the treatment of acne in women in the United States. The improvement in acne symptoms is believed to be due to a 2- to 3-fold increase in sex hormone-binding globulin (SHBG) levels and a consequent decrease in free testosterone levels caused by EE, which results in an overall decrease in androgenic signaling in the body. The sebaceous glands are highly androgen-sensitive and their size and activity are potential markers of androgenic effect. A high dosage of 20 mg/day<unk>  or<unk> TA has been found to significantly stimulate the sebaceous glands, whereas lower dosages of 5 mg/day and 2.5 mg/day<unk>  and<unk> TA, respectively, did not significantly stimulate sebum production and were consequently regarded as devoid of significant androgenicity. Conversely, dosages of<unk>  of 0.5 to 3 mg/day have been found to dose-dependently decrease SHBG levels (and hence to suppress hepatic SHBG production), which is another highly sensitive marker of androgenicity. A large clinical study of high to very high oral dosages of<unk>  (10 to 40 mg/day) administered for prolonged periods of time (4 to 35 weeks) to prevent miscarriage in pregnant women found that 5.5% of the women experienced mild androgenic side effects such as mild voice changes (hoarseness), acne, and hirsutism and that 18.3% of female infants born to the mothers showed, in most cases only slight, virilization of the genitals. Maternal androgenic symptoms occurred most often in women who received a dosage of<unk>  of 30 mg/day or more for a period of 15 weeks or longer. In the female infants who experienced virilization of the genitals, the sole manifestation in 86.7% of the cases was varied but almost always slight enlargement of the clitoris. In the remaining 13.3% of the affected cases, marked clitoral enlargement and partial fusion of the labioscrotal folds occurred. The dosages used in these cases were 20 to 40 mg/day. In a letter to the editor on the topic of virilization caused by high dosages of<unk> TA in women, a physician expressed that they had not observed the "slightest evidence of virilization" and that there had "certainly been no hirsutism nor any voice changes" in 55 women with advanced breast cancer that they had treated with 30 to 60 mg/day<unk>  for up to six months. High-dosage<unk>  has been used to suppress menstruation in women with severe intellectual disability who were incapable of handling their own menses. A study of 118 nulliparous women treated with 5 mg/day<unk>  for a period of 2 to 30 months found that the drug was effective in producing amenorrhea in 86% of the women, with breakthrough bleeding occurring in the remaining 14%. Side effects including weight gain, hirsutism, acne, headache, nausea, and vomiting all did not appear to increase in incidence and no "disturbing side effects" were noted in any of the women. Another study of 5 mg/day<unk>  in 132 women also made no mention of androgenic side effects. These findings suggest little to no risk of androgenic side effects with<unk>  at a dosage of 5 mg/day. A study of 194 women treated with 5 to 15 mg/day<unk> TA for a median duration of 13 months of therapy to suppress symptoms of endometriosis observed no side effects in 55.2% of patients, weight gain in 16.1%, acne in 9.9%, mood lability in 8.9%, hot flashes in 8.3%, and voice deepening in two women (1.0%). Estrogenic<unk>  is weakly estrogenic (via conversion into its metabolite EE), and for this reason, it has been found at high dosages to be associated with high rates of estrogenic side effects such as breast enlargement in women and gynecomastia in men, but also with improvement of menopausal symptoms in postmenopausal women. It has been suggested that very high dosages (e.g., 40 mg/day, which are sometimes used in clinical practice for various indications) of<unk> TA (and by extension<unk>  may result in an increased risk of venous thromboembolism (VTE) analogously to high dosages (above 50 μg/day) of EE, and that even doses of<unk> TA of 10 to 20 mg, which correspond to EE doses of approximately 20 to 30 μg/day, may in certain women be associated with increased risk. A study also found that ethinylestradiol and<unk>  had a greater influence on coagulation factors when the dose of<unk>  was 3 or 4 mg than when it was 1 mg. This might have been due to additional ethinylestradiol generated by higher doses of<unk> .
Norethisterone
Cloxotestosterone acetate
Androstanolone benzoate
Norvinisterone
Norethandrolone
Oxandrolone
Nandrolone propionate
Ethisterone