Norethisterone
Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen. It is used by mouth or, as norethisterone enanthate, by injection into muscle.
Side effects of norethisterone include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth. Norethisterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak androgenic and estrogenic activity, mostly at high dosages, and no other important hormonal activity.
Norethisterone was discovered in 1951 and was one of the first progestins to be developed. It was first introduced for medical use on its own in 1957 and was introduced in combination with an estrogen for use as a birth control pill in 1963. It is sometimes referred to as a "first-generation" progestin. Like desogestrel and Norgestrel, Norethisterone is available as a progestogen-only "mini pill" for birth control. Norethisterone is marketed widely throughout the world. It is available as a generic medication. In 2023, it was the 136th most commonly prescribed medication in the United States, with more than 4million prescriptions. It is on the World Health Organization's List of Essential Medicines.
Medical uses
Norethisterone is used as a hormonal contraceptive in combination with an estrogen – usually ethinylestradiol – in combined oral contraceptive pills and alone in progestogen-only pills.Another medical use of norethisterone is to alleviate endometriosis related pain. In fact, 50% of patients who received medical or surgical treatment for endometriosis-related pelvic pain have benefited from progestin therapy. This could be due to the fact that norethisterone induces endometrial proliferation during secretory phase, which has been shown to alleviate endometrial pain complaints. Another way in which norethisterone may be acting to reduce endometrial pain is via inhibition of ovulation. Endometriosis pain and discomfort is worse during ovulation.
Contraindications
High-dose norethisterone has been associated with hepatic veno-occlusive disease, and because of this adverse effect, norethisterone should not be given to patients undergoing allogeneic bone marrow transplantation, as it has been associated with substantially lower one-year survival post-transplantation.Side effects
At contraceptive and hormone replacement dosages, norethisterone has essentially progestogenic side effects only. In most clinical studies of norethisterone 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 norethisterone and which of them were caused by estrogen in such research. However, norethisterone enanthate, an intramuscularly administered prodrug of norethisterone which is used as a long-acting contraceptive, is used without an estrogen, and hence can be employed as a surrogate for norethisterone in terms of understanding its effects and tolerability. In clinical studies, the most common side effect with norethisterone enanthate 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, for instance those used in the treatment of gynecological disorders, norethisterone can cause hypogonadism due to its antigonadotropic effects and can have estrogenic and weak androgenic side effects.
High doses of norethisterone acetate 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 norethisterone acetate may have precluded its further development for male hormonal contraception.
Androgenic
Due to its weak androgenic activity, norethisterone can produce androgenic side effects such as acne, hirsutism, and voice changes of slight severity in some women at high dosages. This is notably not the case with combined oral contraceptives that contain norethisterone and EE, however. Such formulations contain low dosages of norethisterone 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 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 norethisterone acetate has been found to significantly stimulate the sebaceous glands, whereas lower dosages of 5 mg/day and 2.5 mg/day norethisterone and norethisterone acetate, 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, which is another highly sensitive marker of androgenicity.
A large clinical study of high to very high oral dosages of norethisterone administered for prolonged periods of time to prevent miscarriage in pregnant women found that 5.5% of the women experienced mild androgenic side effects such as mild voice changes, 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 norethisterone acetate 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. Another study of 5 mg/day norethisterone in 132 women also made no mention of androgenic side effects. These findings suggest little to no risk of androgenic side effects with norethisterone at a dosage of 5 mg/day. A study of 194 women treated with 5 to 15 mg/day norethisterone acetate 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.