Norethisterone was discovered in 1951 and was one of the first progestins to be developed.[19][20][21] 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.[21][22] It is sometimes referred to as a "first-generation" progestin.[23][24] Likedesogestrel andNorgestrel, Norethisterone is available as aprogestogen-only "mini pill" for birth control.[25][26][27] Norethisterone is marketed widely throughout the world.[28] It is available as ageneric medication.[29] In 2023, it was the 136th most commonly prescribed medication in the United States, with more than 4million prescriptions.[30][31] It is on theWorld Health Organization's List of Essential Medicines.[32]
Another medical use of norethisterone is to alleviateendometriosis related pain. In fact, 50% of patients who received medical or surgical treatment for endometriosis-related pelvic pain have benefited fromprogestin 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 ofovulation. Endometriosis pain and discomfort is worse during ovulation.[33]
High-dose (10 mg/day) norethisterone has been associated withhepatic veno-occlusive disease, and because of this adverse effect, norethisterone should not be given to patients undergoingallogeneicbone marrow transplantation, as it has been associated with substantially lower one-year survival post-transplantation.[38][39]
At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), norethisterone has essentially progestogenicside 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 andtolerability. In clinical studies, the most common side effect with norethisterone enanthate has beenmenstrual disturbances, includingprolonged bleeding or spotting andamenorrhea.[38]: 253 Other side effects have included periodicabdominal bloating andbreast tenderness, both of which are thought to be due towater retention and can be relieved withdiuretics.[38]: 253 There has been no association withweight gain, andblood pressure,blood clotting, andglucose tolerance have all remained normal.[38]: 253 However, a decrease inHDL cholesterol has been observed.[38]: 253
At high doses (5 to 60 mg/day), for instance those used in the treatment of gynecological disorders, norethisterone can causehypogonadism due to itsantigonadotropic effects and can have estrogenic and weak androgenic side effects.
Due to its weak androgenic activity, norethisterone can produce androgenicside effects such asacne,hirsutism, andvoice changes of slight severity in some women at high dosages (e.g., 10 to 40 mg/day).[17] This is notably not the case withcombined oral contraceptives that contain norethisterone and EE, however.[18] Such formulations contain low dosages of norethisterone (0.35 to 1 mg/day)[18] in combination withestrogen and are actually associated with improvement in acne symptoms.[43][44] In accordance, they are in fact approved by theFDATooltip Food and Drug Administration for the treatment of acne in women in the United States.[43][44] The improvement in acne symptoms is believed to be due to a 2- to 3-fold increase insex hormone-binding globulin (SHBG) levels and a consequent decrease in freetestosterone levels caused by EE, which results in an overall decrease in androgenic signaling in the body.[45]
Thesebaceous glands are highly androgen-sensitive and their size and activity are potential markers of androgenic effect.[46] 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.[46] 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.[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 preventmiscarriage inpregnant women found that 5.5% of the women experienced mild androgenic side effects such as mildvoice changes (hoarseness), acne, andhirsutism and that 18.3% of female infants born to the mothers showed, in most cases only slight,virilization of thegenitals.[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 thelabioscrotal folds occurred.[17] The dosages used in these cases were 20 to 40 mg/day.[17]
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.[48]
High-dosage norethisterone has been used to suppressmenstruation in women with severeintellectual disability who were incapable of handling their own menses.[49][50] 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 producingamenorrhea in 86% of the women, withbreakthrough bleeding occurring in the remaining 14%.[49] Side effects includingweight gain,hirsutism,acne,headache,nausea, andvomiting all did not appear to increase in incidence and no "disturbing side effects" were noted in any of the women.[49][50] Another study of 5 mg/day norethisterone in 132 women also made no mention of androgenic side effects.[51] These findings suggest little to no risk of androgenic side effects with norethisterone at a dosage of 5 mg/day.[49][50] 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 ofendometriosis 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%).[52]
Norethisterone is weaklyestrogenic (via conversion into itsmetabolite EE), and for this reason, it has been found at high dosages to be associated with high rates of estrogenic side effects such asbreast enlargement in women andgynecomastia in men, but also with improvement ofmenopausalsymptoms infully menopausal women.[53] It has been suggested that very high dosages (e.g., 40 mg/day, which are sometimes used in clinical practice for various indications) of norethisterone acetate (and by extension norethisterone) may result in an increased risk ofvenous thromboembolism (VTE) analogously to high dosages (above 50 μg/day) of EE, and that even doses of norethisterone acetate 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.[54][55] A study also found that ethinylestradiol and norethisterone had a greater influence on coagulation factors when the dose of norethisterone was 3 or 4 mg than when it was 1 mg.[56] This might have been due to additional ethinylestradiol generated by higher doses of norethisterone.[56]
There have been no reports of seriousside effects with overdose of norethisterone, even in small children.[8] As such, overdose usually does not require treatment.[8] High dosages of as much as 60 mg/day norethisterone have been studied for extended treatment durations without serious adverse effects described.[48]
Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,estradiol for theERTooltip estrogen receptor,dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Footnotes:a =Active or inactivemetabolite,prodrug, or neither of norethisterone.Sources: See template.
Norethisterone is a potentprogestogen and binds to the PR with approximately 150% of theaffinity ofprogesterone.[11] In contrast, its parent compounds,testosterone,nandrolone (19-nortestosterone), andethisterone (17α-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR.[57] Unlike norethisterone, its major active metabolite5α-dihydronorethisterone (5α-DHNET), which is formed by transformation via5α-reductase, has been found to possess both progestogenic and markedantiprogestogenic activity,[58] although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone.[11] Norethisterone produces similar changes in theendometrium andvagina, such asendometrial transformation, and is similarlyantigonadotropic,ovulation-inhibiting, andthermogenic in women compared to progesterone, which is in accordance with its progestogenic activity.[59][57][60]
Norethisterone has approximately 15% of the affinity of theanabolic–androgenic steroid (AAS)metribolone (R-1881) for the AR, and in accordance, is weakly androgenic.[11] In contrast to norethisterone, 5α-DHNET, the major metabolite of norethisterone, shows higher affinity for the AR, with approximately 27% of the affinity of metribolone.[11] However, although 5α-DHNET has higher affinity for the AR than norethisterone, it has significantly diminished and in fact almost abolished androgenic potency in comparison to norethisterone in rodentbioassays.[61][62] Similar findings were observed forethisterone (17α-ethynyltestosterone) and its 5α-reduced metabolite, whereas 5α-reduction enhanced both the AR affinity and androgenic potency oftestosterone andnandrolone (19-nortestosterone) in rodent bioassays.[62] As such, it appears that the ethynyl group of norethisterone at the C17α position is responsible for its loss of androgenicity upon 5α-reduction.[62]
Norethisterone (0.5 to 3 mg/day) has been found to dose-dependently decrease circulating SHBG levels, which is a common property of androgens and is due to AR-mediated suppression of hepatic SHBG production.[47] The drug also has estrogenic activity, and estrogens are known to increase SHBG hepatic production and circulating levels, so it would appear that the androgenic activity of norethisterone overpowers its estrogenic activity in this regard.[47]
Norethisterone is bound to a considerable extent (36%) to SHBG in circulation.[11] Although it has lower affinity for SHBG than endogenous androgens and estrogens,[63] Norethisterone may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects.[64]
Norethisterone binds to the ERs, theERα and theERβ, with 0.07% and 0.01% of therelative binding affinity ofestradiol.[65] Due to these very low relative affinities, it is essentially inactive itself as aligand of the ERs at clinical concentrations.[11] However, norethisterone has been found to be asubstrate foraromatase and is converted in theliver to a small extent (0.35%) to the highlypotent estrogenethinylestradiol (EE), and for this reason, unlike most other progestins, norethisterone has some estrogenic activity.[11] However, with typical dosages of norethisterone used inoral 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] Conversely, doses of 5 and 10 mg of norethisterone, which are used in the treatment ofgynecological disorders, are converted at rates of 0.7% and 1.0% and produce levels of EE that correspond to those produced by 30 and 60 μg dosages of EE, respectively.[9][11] The levels of EE formed by 0.5 and 1 mg of norethisterone have been estimated based on higher dosages as corresponding to 2 and 10 μg dosages of EE, respectively.[9] At high doses, norethisterone may increase the risk ofvenous thromboembolism due to metabolism into EE.[66]
Likeprogesterone andtestosterone, norethisterone is metabolized into 3,5-tetrahydrometabolites.[67] Whether these metabolites of norethisterone interact with theGABAA receptor similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone likeallopregnanolone and3α-androstanediol, respectively, is a topic that does not appear to have been studied and hence requires clarification.[67]
Norethisterone is a substrate for and is known to be aninhibitor of5α-reductase, with 4.4% and 20.1% inhibition at 0.1 and 1 μM, respectively.[11] However, therapeutic concentrations of norethisterone are in the lownanomolar range, so this action may not be clinically relevant at typical dosages.[11]
Norethisterone and its major active metabolite 5α-DHNET have been found to act asirreversiblearomatase inhibitors (Ki = 1.7 μM and 9.0 μM, respectively).[68] However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages.[11] 5α-DHNET specifically has been assessed and found to be selective in its inhibition of aromatase, and does not affectcholesterol side-chain cleavage enzyme (P450scc),17α-hydroxylase/17,20-lyase,21-hydroxylase, or11β-hydroxylase.[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-positivebreast cancer.[68]
Norethisterone is a very weak inhibitor ofCYP2C9 andCYP3A4 (IC50 = 46 μM and 51 μM, respectively), but these actions require very high concentrations of norethisterone that are far above therapeutic circulating levels (which are in the nanomolar range) and hence are probably not clinically relevant.[11]
Norethisterone and some of its 5α-reduced metabolites have been found to producevasodilating effects in animals that are independent ofsex steroid receptors and hence appear to be non-genomic in mechanism.[69]
Theovulation-inhibiting dosage of both oral norethisterone and oral norethisterone acetate is about 0.5 mg/day in women.[11][74][75] However, some conflicting data exist, suggesting that higher doses might be necessary for full inhibition of ovulation.[76] An intramuscular injection of 200 mg norethisterone enanthate has been found to prevent ovulation and suppress levels ofestradiol,progesterone,luteinizing hormone (LH), andfollicle-stimulating hormone (FSH) in women.[77][78][79][80]
Early studies of oral norethisterone in men employing doses of 20 to 50 mg/day observed suppression of17-ketosteroidexcretion, increasedestrogen excretion (due to conversion intoethinylestradiol), suppression of spermatogenesis,libido, anderectile function, and incidence ofgynecomastia.[81][82][83][53][84] A dosage of oral norethisterone of 25 mg/day for 3 weeks in men has been reported to suppress testosterone levels by about 70%, to 100 to 200 ng/dL, within 4 or 5 days, as well as to suppresssperm count and to have no effect on libido or erectile function over this short time period.[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%).[87]
Hormone levels following a single intramuscular injection ofestradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) in healthy young men.[88] Testosterone levels were maximally suppressed by about 94%, to ~30 ng/dL, when measured at day 7 post-injection.[88]
A single 200 mg intramuscular injection of norethisterone enanthate alone or in combination with 2 mgestradiol valerate has been found to produce a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men.[73][89][90] Intramuscular injections of 200 mg norethisterone enanthate once every 3 weeks have also been found to suppress spermatogenesis in men.[81][91] Similarly, a single intramuscular injection of 50 mg norethisterone enanthate in combination with 5 mg estradiol valerate has been found to strongly suppress testosterone levels in men.[88] Levels of testosterone decreased from ~503 ng/dL at baseline to ~30 ng/dL at the lowest point (–94%) which occurred at day 7 post-injection.[88]
Theoralbioavailability of norethisterone is between 47 and 73%, with a mean oral bioavailability of 64%.[9][10]Micronization has been found to significantly improve the oral bioavailability of norethisterone by increasingintestinalabsorption and reducingintestinalmetabolism.[11][93] A single 2 mg oral dose of norethisterone has been found to result in peak circulating levels of the drug of 12 ng/mL (40 nmol/L), whereas a single 1 mg oral dose of norethisterone in combination with 2 mg estradiol resulted in peak levels of norethisterone of 8.5 ng/mL (29 nmol/L) one-hour post-administration.[11]
Hormone levels with norethisterone
Norethisterone and ethinylestradiol levels over 24 hours after a single oral dose of 10 mg norethisterone acetate in postmenopausal women.[47]
Norethisterone and ethinylestradiol levels over 8 weeks after a single intramuscular injection of 200 mg norethisterone enanthate in premenopausal women.[94]
Norethisterone is used in birth control pills, opposed to progesterone itself, because it is not metabolized as rapidly as progesterone when consumed orally. When progesterone is consumed orally it is rapidly metabolized in the gastrointestinal tract and the liver, and broken down into many different metabolites. Whereas, norethisterone is not as rapidly metabolized allowing norethisterone to be present in higher quantities allowing it to more effectively compete for progesterone receptor binding sites.[11]
Norethisterone (NET) is theparent compound of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives.[112] This group is divided bychemical structure into theestranes (derivatives of norethisterone) and thegonanes (18-methylgonanes or 13β-ethylestranes; derivatives oflevonorgestrel) and includes the following marketed medications:[113]
19-Nortestosterone (19-NT) progestins which are technically not derivatives of norethisterone (as they do not have a C17αethynyl group) but are still closely related (with other substitutions at the C17α and/or C16β positions) include the following marketed medications:[109][110]
Estradiol 3-methyl ether (1, EME) is partially reduced to the 1,5-diene (2) as also occurs for the first step in the synthesis of nandrolone.Oppenauer oxidation then transforms the C17β hydroxyl group into a ketone functionality (3). This is then reacted with metalacetylide into the corresponding C17αethynyl compound (4). Hydrolysis of the enol ether under mild conditions leads directly to (5),[117] which appears to benoretynodrel (although Lednicer states that it is "etynodrel" in his book (which may be a synonymetynodiol); etynodrel is with achlorine atom attached), an orally active progestin. This is the progestogen component of the firstoral contraceptive to be offered for sale (i.e., Enovid). Treatment of the ethynyl enol ether with strong acid leads to norethisterone (6).[19]
In practice, these and all other combined oral contraceptives are mixtures of 1 to 2% EE ormestranol and an oralprogestin. 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 of2. This when subjected to oxidation andethynylation, would of course lead to mestranol (3). In any event, the need for the presence of estrogen in the mixture is now well established experimentally.
Norethisterone is made fromestr-4-ene-3,17-dione (bolandione), which in turn is synthesized by partial reduction of the aromatic region of the 3-O-methyl ether ofestrone with lithium in liquid ammonia, and simultaneously of the keto group at C17α to a hydroxyl group, which is then oxidized back to a keto group bychromium trioxide inacetic acid. The conjugated C4-C5 olefin and the carbonyl group at C3 is then transformed to dienol ethyl ether usingethyl orthoformate. The obtained product is ethynylated byacetylene in the presence ofpotassium tert-butoxide. Afterhydrochloride 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 chemistsLuis Miramontes,Carl Djerassi, andGeorge Rosenkranz atSyntex inMexico City in 1951.[19] It wasderived fromethisterone, and was found to possess about 20-fold greater potency as a progestogen in comparison.[citation needed] Norethisterone was the first highly active oralprogestogen to be synthesized, and was preceded (as a progestogen) byprogesterone (1934), ethisterone (1938),19-norprogesterone (1944), and17α-methylprogesterone (1949) as well as bynandrolone (1950), whereasnoretynodrel (1952) andnorethandrolone (1953) followed the synthesis of norethisterone.[20][21] The drug was introduced as Norlutin in the United States in 1957.[22] Norethisterone was subsequently combined withmestranol and marketed as Ortho-Novum in the United States in 1963. It was the second progestin, afternoretynodrel in 1960, to be used in anoral contraceptive.[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.[21]
Norethisterone is theINNTooltip International Nonproprietary Name andBANTooltip British Approved Name of the drug while norethindrone is itsUSANTooltip United States Adopted Name.[109][110]
Norethisterone is available in Bangladesh as Menogia (ACI), Normens (Renata) etc. Norethisterone (NET), including as norethisterone acetate and norethisterone enanthate, has been marketed under many brand names throughout the world.[110][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.[123] However, norethisterone acetate remains available alone in 5 mg tablets under the brand name Aygestin in the United States.[123] It is one of the only non-contraceptive progestogen-only drug formulations that remains available in the United States.[123] The others includeprogesterone,medroxyprogesterone acetate,megestrol acetate, andhydroxyprogesterone caproate, as well as the atypical agentdanazol.[123]
Both norethisterone and norethisterone acetate are also available in the United States as contraceptives.[123] Norethisterone is available both alone (brand names Camila, Errin, Heather, Micronor, Nor-QD, others) and in combination with EE (Norinyl, Ortho-Novum, others) or mestranol (Norinyl, Ortho-Novum, others), while norethisterone acetate is available only in combination with EE (Norlestrin, others).[123] Norethisterone enanthate is not available in the United States in any form.[123][124][125]
^abcdefghStanczyk FZ (September 2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception".Reviews in Endocrine & Metabolic Disorders.3 (3):211–24.doi:10.1023/A:1020072325818.PMID12215716.S2CID27018468.
^abFotherby K (August 1996). "Bioavailability of orally administered sex steroids used in oral contraception and hormone replacement therapy".Contraception.54 (2):59–69.doi:10.1016/0010-7824(96)00136-9.PMID8842581.
^abcdKorhonen T, Turpeinen M, Tolonen A, Laine K, Pelkonen O (May 2008). "Identification of the human cytochrome P450 enzymes involved in the in vitro biotransformation of lynestrenol and norethindrone".The Journal of Steroid Biochemistry and Molecular Biology.110 (1–2):56–66.doi:10.1016/j.jsbmb.2007.09.025.PMID18356043.S2CID10809537.
^abcdTaitel HF, Kafrissen ME (1995). "Norethindrone – a review of therapeutic applications".International Journal of Fertility and Menopausal Studies.40 (4):207–23.PMID8520623.
^Hussain SF (February 2004). "Progestogen-only pills and high blood pressure: is there an association? A literature review".Contraception.69 (2):89–97.doi:10.1016/j.contraception.2003.09.002.PMID14759612.
^World Health Organization (2023).The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list. Geneva: World Health Organization.hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
^Hägglund H, Remberger M, Klaesson S, Lönnqvist B, Ljungman P, Ringdén O (December 1998). "Norethisterone treatment, a major risk-factor for veno-occlusive disease in the liver after allogeneic bone marrow transplantation".Blood.92 (12):4568–72.doi:10.1182/blood.V92.12.4568.PMID9845522.
^abPochi PE, Strauss JS (December 1965). "Lack of androgen effect on human sebaceous glands with low-dosage norethindrone".American Journal of Obstetrics and Gynecology.93 (7):1002–04.doi:10.1016/0002-9378(65)90162-6.PMID5843402.
^abcdKuhnz W, Heuner A, Hümpel M, Seifert W, Michaelis K (December 1997). "In vivo conversion of norethisterone and norethisterone acetate to ethinyl etradiol in postmenopausal women".Contraception.56 (6):379–85.doi:10.1016/s0010-7824(97)00174-1.PMID9494772.
^abcRoxburgh DR, West MJ (August 1973). "The use of norethisterone to suppress menstruation in the intellectually severely retarded woman".The Medical Journal of Australia.2 (7):310–13.doi:10.1097/00006254-197408000-00021.PMID4746398.
^Kaser DJ, Missmer SA, Berry KF, Laufer MR (April 2012). "Use of norethindrone acetate alone for postoperative suppression of endometriosis symptoms".Journal of Pediatric and Adolescent Gynecology.25 (2):105–08.doi:10.1016/j.jpag.2011.09.013.PMID22154396.
^abPaulsen CA, Leach RB, Lanman J, Goldston N, Maddock WO, Heller CG (October 1962). "Inherent estrogenicity of norethindrone and norethynodrel: comparison with other synthetic progestins and progesterone".The Journal of Clinical Endocrinology and Metabolism.22 (10):1033–39.doi:10.1210/jcem-22-10-1033.PMID13942007.
^abFarris M, Bastianelli C, Rosato E, Brosens I, Benagiano G (October 2017). "Pharmacodynamics of combined estrogen-progestin oral contraceptives: 2. effects on hemostasis".Expert Review of Clinical Pharmacology.10 (10):1129–44.doi:10.1080/17512433.2017.1356718.PMID28712325.S2CID205931204.
^abcdeKuhl H (2011)."Pharmacology of Progestogens"(PDF).J Reproduktionsmed Endokrinol.8 (1):157–77.Archived(PDF) from the original on 11 October 2016. Retrieved10 October 2016.
^Chu YH, Li QA, Zhao ZF, Zhou YP, Cao DC (June 1985). "[Antiprogestational action of 5 alpha-dihydronorethisterone]".Zhongguo Yao Li Xue Bao = Acta Pharmacologica Sinica (in Chinese).6 (2):125–29.PMID2934946.
^Greenblatt RB (July 1956). "The progestational activity of 17-alpha-ethinyl-19-nortestosterone".The Journal of Clinical Endocrinology and Metabolism.16 (7):869–75.doi:10.1210/jcem-16-7-869.PMID13332050.
^Fragkaki AG, Angelis YS, Koupparis M, Tsantili-Kakoulidou A, Kokotos G, Georgakopoulos C (February 2009). "Structural characteristics of anabolic androgenic steroids contributing to binding to the androgen receptor and to their anabolic and androgenic activities. Applied modifications in the steroidal structure".Steroids.74 (2):172–97.doi:10.1016/j.steroids.2008.10.016.PMID19028512.S2CID41356223.Many synthetic steroids with high myotrophic activity exhibit myotrophic–androgenic dissociation, since, due to changes introduced in the structure of ring A, they will probably not be substrates for the 5α-reductases [85]. 5α-Reduction does not always amplify the androgenic potency in spite of high RBA of androgens to the AR. This is the case for norethisterone (Fig. 1, 34), a synthetic 19-nor-17α-ethynyl testosterone derivative, which also undergoes enzyme-mediated 5α-reduction and exerts potent androgenic effects in target organs. 5α-Reduced norethisterone displays a higher AR binding but shows a significantly lower androgenic potency than unchanged norethisterone [102, 103].
^abcLemus AE, Enríquez J, García GA, Grillasca I, Pérez-Palacios G (January 1997). "5alpha-reduction of norethisterone enhances its binding affinity for androgen receptors but diminishes its androgenic potency".The Journal of Steroid Biochemistry and Molecular Biology.60 (1–2):121–29.doi:10.1016/s0960-0760(96)00172-0.PMID9182866.S2CID33771349.
^Wiegratz I, Kuhl H (September 2006). "Metabolic and clinical effects of progestogens".The European Journal of Contraception & Reproductive Health Care.11 (3):153–61.doi:10.1080/13625180600772741.PMID17056444.S2CID27088428.
^abcYamamoto T, Tamura T, Kitawaki J, Osawa Y, Okada H (June 1994). "Suicide inactivation of aromatase in human placenta and uterine leiomyoma by 5 alpha-dihydronorethindrone, a metabolite of norethindrone, and its effect on steroid-producing enzymes".European Journal of Endocrinology.130 (6):634–40.doi:10.1530/eje.0.1300634.PMID8205267.
^Perusquía M, Villalón CM, Navarrete E, García GA, Pérez-Palacios G, Lemus AE (August 2003). "Vasodilating effect of norethisterone and its 5 alpha metabolites: a novel nongenomic action".European Journal of Pharmacology.475 (1–3):161–69.doi:10.1016/s0014-2999(03)02106-x.PMID12954372.
^abKamischke A, Nieschlag E (January 2004). "Progress towards hormonal male contraception".Trends in Pharmacological Sciences.25 (1):49–57.doi:10.1016/j.tips.2003.11.009.PMID14723979.
^Endrikat J, Gerlinger C, Richard S, Rosenbaum P, Düsterberg B (December 2011). "Ovulation inhibition doses of progestins: a systematic review of the available literature and of marketed preparations worldwide".Contraception.84 (6):549–57.doi:10.1016/j.contraception.2011.04.009.PMID22078182.
^Weiner E, Johansson ED (April 1975). "Plasma levels of norethindrone after i.m. injection of 200 mg norethindrone enanthate".Contraception.11 (4):419–25.doi:10.1016/0010-7824(75)90004-9.PMID1122756.
^Fotherby K, Howard G, Shrimanker K, Elder M, Bye PG (December 1977). "Effect of norethisterone oenanthate on serum gonadotrophin levels".Contraception.16 (6):591–604.doi:10.1016/0010-7824(77)90060-9.PMID606499.
^Goebelsmann U, Stanczyk FZ, Brenner PF, Goebelsmann AE, Gentzschein EK, Mishell DR (March 1979). "Serum norethindrone (NET) concentrations following intramuscular NET enanthate injection. Effect upon serum LH, FSH, estradiol and progesterone".Contraception.19 (3):283–313.doi:10.1016/0010-7824(79)90022-2.PMID572279.
^Heller CG, Laidlaw WM, Harvey HT, Nelson WO (July 1958). "Effects of progestational compounds on the reproductive processes of the human male".Annals of the New York Academy of Sciences.71 (5):649–65.doi:10.1111/j.1749-6632.1958.tb54641.x.PMID13583821.S2CID32637425.
^Kamischke A, Diebäcker J, Nieschlag E (September 2000). "Potential of norethisterone enanthate for male contraception: pharmacokinetics and suppression of pituitary and gonadal function".Clinical Endocrinology.53 (3):351–58.doi:10.1046/j.1365-2265.2000.01097.x.PMID10971453.S2CID70515136.
^Petry R, Mauss J, Senge T, Rausch-Stroomann JG (1970). "Über den Einflu#x00DF; von Cyproteronacetat, Norethisteron#x00F6;nanthat und Gestonoroncapronat auf die Hypophysen-Gonadenachse beim Mann".Endokrinologie der Entwicklung und Reifung [Influence of Cyproterone-acetate, Norethisterone-enanthate and Gestonorone-capronate on the Hypophyseal-Gonadal-Axis in the Male]. Symposion der Deutschen Gesellschaft für Endokrinologie in Ulm vom 26–28 Februar 1970. Springer. pp. 428–30.doi:10.1007/978-3-642-80591-2_118.ISBN978-3-642-80591-2.
^Saperstein S, Edgren RA, Jung D, Mroszczak EJ, Lee GJ, Dorr A, et al. (December 1989). "Pharmacokinetics of norethindrone: effect of particle size".Contraception.40 (6):731–40.doi:10.1016/0010-7824(89)90075-9.PMID2620531.
^Friedrich C, Berse M, Klein S, Rohde B, Höchel J (June 2018). "In Vivo Formation of Ethinylestradiol After Intramuscular Administration of Norethisterone Enantate".Journal of Clinical Pharmacology.58 (6):781–89.doi:10.1002/jcph.1079.PMID29522253.S2CID3813229.
^Briggs MH (1980). "Comparative Pharmacodynamics and Pharmacokinetics of Contraceptive Steroids in Animals and Man: A Selective Review".Clinical Pharmacology & Therapeutics. Palgrave Macmillan UK. pp. 493–518.doi:10.1007/978-1-349-05952-2_57.ISBN978-1-349-05954-6.
^Fotherby K (1974). "Metabolism of synthetic steroids by animals and man".Acta Endocrinologica. Supplementum.185:119–47.doi:10.1530/acta.0.075s119.PMID4206183.
^Kuhl H, Wiegratz I (August 2007). "Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications?".Climacteric.10 (4):344–53.doi:10.1080/13697130701380434.PMID17653961.S2CID20759583.
^Stanczyk FZ, Roy S (July 1990). "Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids".Contraception.42 (1):67–96.doi:10.1016/0010-7824(90)90093-B.PMID2143719.
^abSchoonen WG, Deckers GH, de Gooijer ME, de Ries R, Kloosterboer HJ (November 2000). "Hormonal properties of norethisterone, 7alpha-methyl-norethisterone and their derivatives".The Journal of Steroid Biochemistry and Molecular Biology.74 (4):213–22.doi:10.1016/s0960-0760(00)00125-4.PMID11162927.S2CID19797254.[...] several mono- and disulphated as well as mono- and diglucuronidated metabolites of NET have been detected in urine from NET treated women [16,17]. In unconjugated form these NET (or MeNET) metabolites are represented by 5α- and 5β-reduced NET (5α-NET or 5β-NET) and by 3α- and 3β-hydrogenated 5α-NET and 5β-NET, leading to 3α,5α-NET, 3β,5α-NET, 3α,5β-NET and 3β,5β-NET or their corresponding MeNET metabolites (Figs. 1 and 2). These steroid conversions of NET or MeNET may take place in the liver, but also in the pituitary, endometrium, prostate, vagina and breast. The enzymes involved in these metabolic processes are 5α- and 5β-reductase as well as 3α- and 3β-hydroxysteroid dehydrogenase (HSD).
^Garza-Flores J, Vilchis F, García GA, Menjívar M, Pérez-Palacios G (June 1986). "A-ring reduction enhances the antigonadotropic potency of norethisterone".Acta Endocrinologica.112 (2):278–83.doi:10.1530/acta.0.1120278.PMID3090814.
^Chwalisz K, Surrey E, Stanczyk FZ (June 2012). "The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis".Reproductive Sciences.19 (6):563–71.doi:10.1177/1933719112438061.PMID22457429.S2CID2882899.
^Hammerstein J (December 1990). "Prodrugs: advantage or disadvantage?".American Journal of Obstetrics and Gynecology.163 (6 Pt 2):2198–203.doi:10.1016/0002-9378(90)90561-K.PMID2256526.
^Edelman AB, Cherala G, Stanczyk FZ (October 2010). "Metabolism and pharmacokinetics of contraceptive steroids in obese women: a review".Contraception.82 (4):314–23.doi:10.1016/j.contraception.2010.04.016.PMID20851224.
^Raynaud JP, Ojasoo T (November 1986). "The design and use of sex-steroid antagonists".Journal of Steroid Biochemistry.25 (5B):811–33.doi:10.1016/0022-4731(86)90313-4.PMID3543501.Similar androgenic potential is inherent to norethisterone and its prodrugs (norethisterone acetate, ethynodiol diacetate, lynestrenol, norethynodrel, quingestanol [acetate]).
^Ringold HJ, Rosenkranz G, Sondheimer F (1956). "Steroids. LXXX.11-Methyl-19-nortestosterone and 1-Methyl-17α-ethinyl-19-nortestosterone".Journal of the American Chemical Society.78 (11):2477–79.Bibcode:1956JAChS..78.2477R.doi:10.1021/ja01592a037.
^Ueberwasser H, Heusler K, Kalvoda J, Meystre C, Wieland P, Anner G, et al. (1963). "19-Norsteroide II. Ein einfaches Herstellungsverfahren für 19-Norandrostan-Derivate. über Steroide, 193. Mitteilung".Helvetica Chimica Acta.46:344–52.doi:10.1002/hlca.19630460135.
^Onken D, Heublein D (January 1970). "[Ethinylated steroids]".Die Pharmazie.25 (1):3–9.PMID4914401.
^Nieschlag E, Behre HM, Nieschlag E, Behre HM, Nieschlag S (2012). Nieschlag E, Behre HM, Nieschlag S (eds.). "The essential role of testosterone in hormonal male contraception".Testosterone:470–93.doi:10.1017/CBO9781139003353.023.ISBN978-1-139-00335-3.
Brogden RN, Speight TM, Avery GS (1973). "Progestagen-only oral contraceptives: a preliminary report of the action and clinical use of norgestrel and norethisterone".Drugs.6 (3):169–81.doi:10.2165/00003495-197306030-00004.PMID4130566.S2CID42295736.
"Norethisterone and norethisterone acetate".IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.21:441–60. December 1979.PMID120838.
Stanczyk FZ, Roy S (July 1990). "Metabolism of levonorgestrel, norethindrone, and structurally related contraceptive steroids".Contraception.42 (1):67–96.doi:10.1016/0010-7824(90)90093-b.PMID2143719.
Wiseman LR, McTavish D (March 1994). "Transdermal estradiol/norethisterone. A review of its pharmacological properties and clinical use in postmenopausal women".Drugs & Aging.4 (3):238–56.doi:10.2165/00002512-199404030-00006.PMID8199397.S2CID68007924.
Taitel HF, Kafrissen ME (1995). "Norethindrone – a review of therapeutic applications".International Journal of Fertility and Menopausal Studies.40 (4):207–23.PMID8520623.
Maier WE, Herman JR (August 2001). "Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals".Regulatory Toxicology and Pharmacology.34 (1):53–61.doi:10.1006/rtph.2001.1483.PMID11502156.
Riis BJ, Lehmann HJ, Christiansen C (October 2002). "Norethisterone acetate in combination with estrogen: effects on the skeleton and other organs. A review".American Journal of Obstetrics and Gynecology.187 (4):1101–16.doi:10.1067/mob.2002.122852.PMID12389012.
Kuhl H, Wiegratz I (August 2007). "Can 19-nortestosterone derivatives be aromatized in the liver of adult humans? Are there clinical implications?".Climacteric.10 (4):344–53.doi:10.1080/13697130701380434.PMID17653961.S2CID20759583.
Paulen ME, Curtis KM (October 2009). "When can a woman have repeat progestogen-only injectables--depot medroxyprogesterone acetate or norethisterone enantate?".Contraception.80 (4):391–408.doi:10.1016/j.contraception.2009.03.023.PMID19751863.
Chwalisz K, Surrey E, Stanczyk FZ (June 2012). "The hormonal profile of norethindrone acetate: rationale for add-back therapy with gonadotropin-releasing hormone agonists in women with endometriosis".Reproductive Sciences.19 (6):563–71.doi:10.1177/1933719112438061.PMID22457429.S2CID2882899.
