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.[11][13][15] Side effects of norethisterone include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth.In fact, 50% of patients who received medical or surgical treatment for endometriosis-related pelvic pain have benefited from progestin therapy.In clinical studies, the most common side effect with norethisterone enanthate has been menstrual disturbances, including prolonged bleeding or spotting and amenorrhea.[38]: 253 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.[42] Although they were described as having no clinical relevance,[42] the elevated liver enzymes associated with norethisterone acetate may have precluded its further development for male hormonal contraception.[43][44] In accordance, they are in fact approved by the FDATooltip Food and Drug Administration for the treatment of acne in women in the United States.[47] 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.[17] 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.[17] 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.[17] In the remaining 13.3% of the affected cases, marked clitoral enlargement and partial fusion of the labioscrotal folds occurred.[48] High-dosage norethisterone has been used to suppress menstruation in women with severe intellectual disability who were incapable of handling their own menses.[61][62] Similar findings were observed for ethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone (19-nortestosterone) in rodent bioassays.[11] However, with typical dosages of norethisterone used in oral contraceptives (0.5 to 1 mg), the levels of EE produced are low, and it has been said that they are probably without clinical relevance.[11] However, therapeutic concentrations of norethisterone are in the low nanomolar range, so this action may not be clinically relevant at typical dosages.[68] Since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike norethisterone, 5α-DHNET has been proposed as a potential therapeutic agent in the treatment of ER-positive breast cancer.[11] Norethisterone and some of its 5α-reduced metabolites have been found to produce vasodilating effects in animals that are independent of sex steroid receptors and hence appear to be non-genomic in mechanism.[69] Norethisterone stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).[85][86] In healthy young men, norethisterone acetate alone at a dose of 5 to 10 mg/day orally for 2 weeks suppressed testosterone levels from ~527 ng/dL to ~231 ng/dL (–56%).[12] Some conjugation (including glucuronidation and sulfation)[103][107] of norethisterone and its metabolites occurs in spite of steric hindrance by the ethynyl group at C17α.It has been speculated that the discovery of the necessity of estrogen in addition to progestin for contraceptive efficacy is due to the presence of a small amount of unreduced EME (1) in early batches of 2.After hydrochloride hydrolysis of the formed O-potassium derivative, during which the enol ether is also hydrolyzed, and the remaining double bond is shifted, the desired norethisterone is obtained.Norethisterone was synthesized for the first time by chemists Luis Miramontes, Carl Djerassi, and George Rosenkranz at Syntex in Mexico City in 1951.[21] In 1964, additional contraceptive preparations containing norethisterone in combination with mestranol or EE, such as Norlestrin and Norinyl, were marketed in the United States.[36][28] Norethisterone was previously available alone in 5 mg tablets under the brand name Norlutin in the United States, but this formulation has since been discontinued.
Drugs.comMedlinePlusLicense dataDailyMedRoutes ofadministrationBy mouthDrug classProgestinATC codeG03AC01G03DC02Legal status ℞-only℞-onlyPharmacokineticBioavailabilityProtein bindingAlbuminMetabolismCYP3A45β-reductase3β-HSDaromataseElimination half-lifeIUPAC nameCAS NumberIUPHAR/BPSDrugBankChemSpiderChEMBLCompTox DashboardECHA InfoCardFormulaMolar massMelting pointSMILESbirth control pillsmenopausal hormone therapygynecological disordersestrogennorethisterone enanthateinjection into muscleSide effectsmenstrual irregularitiesheadachesnauseabreast tendernessincreased hair growthsyntheticprogestogenagonistprogesterone receptorbiological targetprogesteroneandrogenicestrogenichormonaldesogestrelNorgestrelprogestogen-only "mini pill"generic medicationWorld Health Organization's List of Essential Medicinesethinylestradiolcombined oral contraceptive pillsprogestogen-only pillsendometriosisovulationProgestogen-only oral contraceptiveProgestogen-only injectable contraceptiveCombined oral contraceptivemestranolestradiolCombined menopausal hormone therapyestradiol valerateCombined injectable contraceptiveNorethisterone acetateleuprorelinhepatic veno-occlusive diseasebone marrow transplantationtolerabilitymenstrual disturbancesprolonged bleeding or spottingamenorrheaabdominal bloatingwater retentiondiureticsweight gainblood pressureblood clottingglucose toleranceHDL cholesterolhypogonadismantigonadotropicliver function testselevations in liver enzymesliver enzymeslactate dehydrogenaseglutamate pyruvate transaminasehirsutismvoice changescombined oral contraceptivessex hormone-binding globulintestosteronesebaceous glandsmiscarriagepregnanthoarsenessvirilizationgenitalslabioscrotal foldsmenstruationintellectual disabilitybreakthrough bleedingheadachevomitingmood labilityhot flashesmetabolitebreast enlargementgynecomastiamenopausalsymptomsvenous thromboembolism5α-Reductase5α-reductase inhibitorsfinasteride