In accordance, they are in fact approved by the FDA 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 norethisterone or NETA has been found to significantly stimulate the sebaceous glands, whereas lower dosages of 5 mg/day and 2.5 mg/day norethisterone and NETA, respectively, did not significantly stimulate sebum production and were consequently regarded as devoid of significant androgenicity. Conversely, dosages of norethisterone 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 norethisterone (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 norethisterone 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 NETA 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 norethisterone for up to six months.High-dosage norethisterone 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 norethisterone 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.