Norethisterone

Norethisterone is used as a hormonal contraceptive in combination with estrogen - usually ethinyl estradiol - in combined oral contraceptives and alone in pill form. In addition to its use as a contraceptive, norethisterone can be used to treat premenstrual syndrome , dysmenorrhea , menorrhagia, irregular menstruation , menopausal symptoms (in combination with estrogen), or delay menstruation . It is also widely used to prevent uterine bleeding in complex non-surgical or non-surgical gynecological diseases and in the treatment of cyclic mastalgia .

Androgenic

Despite the weak androgenic activity, norethisterone can manifest such androgenic side effects as acne , hirsutism , and mild voice changes in some women when taking large doses (for example, from 10 to 40 mg / day). ^[10] this does not apply to combined oral contraceptives that contain norethisterone and ethinyl estradiol , however. Such drugs contain low doses of norethisterone (0.35 to 1 mg / day) in combination with estrogen and are practically used to relieve acne symptoms. ^[11] In fact, they are FDA approved for the treatment of acne in women in the United States. ^{[12] an} improvement occurs due to a two-, three-fold increase in the blood content of sex hormone-binding globulin and, as a result, a decrease in the amount of free testosterone caused by ethinyl estradiol, which leads to a general decrease in androgen signaling in the body. ^[13]

The sebaceous glands are very sensitive to androgens and their size and activity is a potential marker of androgenic effects. ^[14] A higher dosage of norethisterone or its acetate 20 mg / day significantly stimulates the sebaceous glands, while lower doses of 5 mg / day and 2.5 mg / day norethisterone and its acetate, respectively, do not significantly stimulate the production of sebum. and therefore do not lead to virilization . When taking norethisterone from 0.5 to 3 mg / day, a dose-dependent decrease in the level of sex hormone-binding globulin was established (and, therefore, suppression of the liver production of sex hormone-binding globulin), which is another very sensitive marker of virilization.

A large clinical study of a high and very high oral dose of norethisterone (10 to 40 mg / day) over a long period of time (4 to 35 weeks) to prevent miscarriage in pregnant women showed that 5.5% of the women showed minor androgenic side effects effects, such as a slight change in voice (hoarseness), acne and hirsutism , and that 18.3% of girls born had minor genital virilization . Maternal androgenic symptoms are most common in women who received doses of 30 mg / day or more for 15 weeks or longer. In newborn girls who experienced masculinization of the genitals, the only manifestation in 86.7% of cases was a slight increase in the clitoris. In the remaining 13.3% of cases, an increase in the clitoris and a partial fusion of the labioscrotal folds were noted . The dose used in these cases was from 20 to 40 mg / day.

In high doses, norethisterone suppresses menstruation in women with severe intellectual disabilities who are unable to regulate their menstruation. ^{[15] [16]} According to a study of 118 nulliparous women who received 5 mg / day for 2 to 30 months, they found that the drug was effective for amenorrhea in 86% of women, while the remaining 14% showed breakthrough bleeding. Side effects such as weight gain, hirsutism , acne , headache , nausea, and vomiting have been reported in most cases. In another study of a dosage of 5 mg / day, in which 132 women participated, androgenic side effects were also not mentioned. ^[17] These results prove a minimal risk of androgenic side effects at a dosage of 5 mg / day.