Norethisterone

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Norethisterone, also known as norethindrone and sold under the brand names Aygestin and Primolut N among many others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in both low-dose and high-dose formulations and is used and formulated both alone and in combination with an estrogen. It is taken by mouth.

Side effects of norethisterone include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others. 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. Along with desogestrel, it is one of the only progestins that is widely 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 addition to norethisterone itself, a variety of prodrugs of norethisterone, such as norethisterone acetate (NETA) and norethisterone enanthate (NETE) among others, have been marketed and have similar effects and uses. NETA is taken by mouth similarly to norethisterone, while NETE is given by injection into muscle. Many derivatives of norethisterone, such as levonorgestrel and desogestrel, have also been developed and marketed.

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Medical uses

Norethisterone is used as a hormonal contraceptive in combination with an estrogen - usually ethinylestradiol (EE) - in combined oral contraceptive pills and alone in progestogen-only pills. Norethisterone has also been shown to be effective in inhibiting leutinizing hormone and follicle-stimulating hormone secretion in men as well. Without these hormones, mature sperm cannot survive in the testes. This means that norethisterone could also be an effective male hormonal contraceptive. Aside from its use as a contraceptive, norethisterone can be used to treat premenstrual syndrome, dysmenorrhea, menorrhagia, irregular menstruation, menopausal symptoms (in combination with estrogen), or to postpone a period. It is also commonly used to help prevent uterine hemorrhage in complicated non-surgical or pre-surgical gynecologic cases and in treating non responsive cyclical mastalgia.

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.

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Contraindications

High-dose (10 mg/day) 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.

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Side effects

At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), 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, NETE, 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 NETE 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 HDL cholesterol has been observed.

At high dosages (5 to 60 mg/day), 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.

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 (e.g., 10 to 40 mg/day). This is notably not the case with combined oral contraceptives that contain norethisterone and EE, however. Such formulations contain low dosages of norethisterone (0.35 to 1 mg/day) in combination with estrogen and are actually associated with improvement in acne symptoms. 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. 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 NETA 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 (1.0%).

Estrogenic

Norethisterone is weakly estrogenic (via conversion into its metabolite EE), and for this reason, it has been found at high dosages to be associated with high rates of estrogenic side effects such as breast enlargement in women and gynecomastia in men, but also with improvement of menopausal symptoms in postmenopausal women. It has been suggested that very high dosages (e.g., 40 mg/day, which are sometimes used in clinical practice for various indications) of NETA (and by extension norethisterone) may result in an increased risk of venous thromboembolism (VTE) analogously to high dosages (above 50 ?g/day) of EE, and that even dosages of NETA of 10 to 20 mg, which correspond to EE dosages of approximately 20 to 30 ?g/day, may in certain women be associated with increased risk.

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Overdose

There have been no reports of serious side effects with overdose of norethisterone, even in small children. As such, overdose usually does not require treatment. High dosages of as much as 60 mg/day norethisterone have been studied for extended treatment durations without serious adverse effects described.

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Interactions

5?-Reductase plays an important role in the metabolism of norethisterone, and 5?-reductase inhibitors such as finasteride and dutasteride can inhibit its metabolism. Norethisterone is partially metabolized via hydroxylation by CYP3A4, and inhibitors and inducers of CYP3A4 can significantly alter circulating levels of norethisterone. For instance, the CYP3A4 inducers rifampicin and bosentan have been found to decrease norethisterone exposure by 42% and 23%, respectively, and the CYP3A4 inducers carbamazepine and St. John's wort have also been found to accelerate norethisterone clearance.

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Pharmacology

Pharmacodynamics

Norethisterone is a potent progestogen and a weak androgen and estrogen. That is, it is a potent agonist of the progesterone receptor (PR) and a weak agonist of the androgen receptor (AR) and the estrogen receptor (ER). Norethisterone itself has insignificant affinity for the ER; its estrogenic activity is from an active metabolite that is formed in very small amounts, ethinylestradiol (EE), which is a very potent estrogen. Norethisterone and its metabolites have negligible affinity for the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) and hence have no glucocorticoid, antiglucocorticoid, mineralocorticoid, or antimineralocorticoid activity.

Progestogenic activity

Norethisterone displays 8 times higher progestational activity than progesterone. It is also a potent progestogen and binds to the PR with approximately 150% of the affinity of progesterone. In contrast, its parent compounds, testosterone, nandrolone (19-nortestosterone), and ethisterone (17?-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR. Unlike norethisterone, its major active metabolite 5?-dihydronorethisterone (5?-DHNET), which is formed by 5?-reductase, has been found to possess both progestogenic and marked antiprogestogenic activity, although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone. Norethisterone produces similar changes in the endometrium and vagina, such as endometrial transformation, and is similarly antigonadotropic, ovulation-inhibiting, and thermogenic in women compared to progesterone, which is in accordance with its progestogenic activity.

Androgenic activity

Norethisterone has approximately 15% of the affinity of the anabolic-androgenic steroid (AAS) metribolone (R-1881) for the AR, and in accordance, is weakly androgenic. In contrast to norethisterone, 5?-DHNET, the major metabolite of norethisterone, shows higher affinity for the AR, with approximately 27% of the affinity of metribolone. However, although 5?-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 rodent bioassays. Similar findings were observed for ethisterone (17?-ethynyltestosterone) and its 5?-reduced metabolite, whereas 5?-reduction enhanced both the AR affinity and androgenic potency of testosterone and nandrolone (19-nortestosterone) in rodent bioassays. As such, it appears that the ethynyl group of norethisterone at the C17? position is responsible for its loss of androgenicity upon 5?-reduction.

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. 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.

Norethisterone is bound to a considerable extent (36%) to SHBG in circulation. Although it has lower affinity for SHBG than endogenous androgens and estrogens, Norethisterone may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects.

Estrogenic activity

Norethisterone binds to the ERs, the ER? and the ER?, with 0.07% and 0.01% of the relative binding affinity of estradiol. Due to these very low relative affinities, it is essentially inactive itself as a ligand of the ERs at clinical concentrations. However, norethisterone has been found to be a substrate for aromatase and is converted in the liver to a small extent (0.35%) to the highly potent estrogen EE, and for this reason, unlike most other progestins, norethisterone has some estrogenic activity. 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. Conversely, doses of 5 and 10 mg of norethisterone, which are used in the treatment of gynecological 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 ?g dosages of EE, respectively. 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 ?g dosages of EE, respectively.

Neurosteroid activity

Like progesterone and testosterone, norethisterone is metabolized into 3,5-tetrahydro metabolites. Whether these metabolites of norethisterone interact with the GABA_A receptor similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone like allopregnanolone and 3?-androstanediol, respectively, is a topic that does not appear to have been studied and hence requires clarification.

Steroidogenesis inhibition

Norethisterone is a substrate for and is known to be an inhibitor of 5?-reductase, with 4.4% and 20.1% inhibition at 0.1 and 1 ?M, respectively. However, therapeutic concentrations of norethisterone are in the low nanomolar range, so this action may not be clinically relevant at typical dosages.

Norethisterone and its major active metabolite 5?-DHNET have been found to act as irreversible aromatase inhibitors (K_i = 1.7 ?M and 9.0 ?M, respectively). However, like the case of 5?-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages. 5?-DHNET specifically has been assessed and found to be selective in its inhibition of aromatase, and does not affect cholesterol side-chain cleavage enzyme (P450scc), 17?-hydroxylase/17,20-lyase, 21-hydroxylase, or 11?-hydroxylase. Since it is not aromatized (and hence cannot be transformed into an estrogenic metabolite), unlike norethisterone, 5?-DHNET has been proposed as a potential therapeutic agent in the treatment of ER-positive breast cancer.

Other activities

Norethisterone is a very weak inhibitor of CYP2C9 and CYP3A4 (IC₅₀ = 46 ?M and 51 ?M, 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.

Norethisterone and some of its 5?-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.

Pharmacokinetics

Absorption

The oral bioavailability of norethisterone is between 47 and 73%, with a mean oral bioavailability of 64%. Micronization has been found to significantly improve the oral bioavailability of norethisterone by increasing intestinal absorption and reducing intestinal metabolism. 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.

Distribution

Norethisterone is 61% bound to albumin and 36% bound to SHBG in the blood.

Metabolism

Norethisterone has a terminal half-life of 5.2 to 12.8 hours, with a mean terminal half-life of 8.0 hours. The metabolism of norethisterone is very similar to that of testosterone (and nandrolone) and is mainly via reduction of the ?⁴ double bond to 5?- and 5?-dihydronorethisterone, which is followed by the reduction of the C3 keto group to the four isomers of 3,5-tetrahydronorethisterone. These transformations are catalyzed by 5?- and 5?-reductase and 3?- and 3?-hydroxysteroid dehydrogenase both in the liver and in extrahepatic tissues such as the pituitary gland, uterus, prostate gland, vagina, and breast. With the exception of 3?,5?- and 3?,5?-tetrahydronorethisterone, which have significant affinity for the ER and are estrogenic to some degree, the 3,5-tetrahydro metabolites of norethisterone are inactive in terms of affinity for sex steroid receptors (specifically, the PR, AR, and ER). A small amount of norethisterone is also converted by aromatase into EE. Norethisterone is metabolized in the liver via hydroxylation as well, mainly by CYP3A4. Some conjugation (including glucuronidation and sulfation) of norethisterone and its metabolites occurs in spite of steric hindrance by the ethynyl group at C17?. The ethynyl group of norethisterone is preserved in approximately 90% of all of its metabolites.

Elimination

Norethisterone is eliminated 33 to 81% in urine and 35 to 43% in feces.

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Chemistry

Norethisterone, also known as 17?-ethynyl-19-nortestosterone or as 17?-ethynylestra-4-en-17?-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. It is specifically a derivative of testosterone in which an ethynyl group has been added at the C17? position and the methyl group at the C19 position has been removed; hence, it is a combined derivative of ethisterone (17?-ethynyltestosterone) and nandrolone (19-nortestosterone). These modifications result in increased progestogenic and oral activity and decreased androgenic activity.

Derivatives

Norethisterone (NET) is the parent compound of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives. This group is divided by chemical structure into the estranes (derivatives of norethisterone) and the gonanes (13?-ethylestranes; derivatives of levonorgestrel) and includes the following marketed medications:

Several of these act as prodrugs of norethisterone, including NETA, NETE, etynodiol diacetate, lynestrenol, and quingestanol acetate. Noretynodrel may also be a prodrug of norethisterone.

Non-17?-ethynylated

19-Nortestosterone (19-NT) progestins which are technically not derivatives of norethisterone (as they do not have a C17? ethynyl group) but are still closely related (with other substitutions at the C17? and/or C16? positions) include the following marketed medications:

The C17? vinyl (ethenyl) derivatives norgesterone (17?-vinyl-?⁵⁽¹⁰⁾-19-NT) and norvinisterone (17?-vinyl-19-NT)
The C17? allyl derivatives allylestrenol (3-deketo-17?-allyl-19-NT) and altrenogest (17?-allyl-?^9,11-19-NT)
The C17? alkyl derivative normethandrone (17?-methyl-19-NT)
The C17? cyanomethyl derivative dienogest (17?-cyanomethyl-?⁹-19-NT)
The C16? ethyl derivative oxendolone (16?-ethyl-19-NT)

Synthesis

Synthesis 1

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 C17? hydroxyl group into a ketone functionality (3). This is then reacted with metal acetylide into the corresponding C17? ethynyl compound (4). Hydrolysis of the enol ether under mild conditions leads directly to (5), which appears to be noretynodrel (although Lednicer states that it is "etynodrel" in his book (which may be a synonym etynodiol); etynodrel is with a chlorine atom attached), an orally active progestin. This is the progestogen component of the first oral contraceptive to be offered for sale (i.e., Enovid). Treatment of the ethynyl enol ether with strong acid leads to norethisterone (6).

In practice, these and all other combined oral contraceptives are mixtures of 1 to 2% EE or mestranol and an oral progestin. 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. This when subjected to oxidation and ethynylation, 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.

Synthesis 2

Norethisterone is made from estr-4-ene-3,17-dione (bolandione), which in turn is synthesized by partial reduction of the aromatic region of the 3-O-methyl ether of estrone with lithium in liquid ammonia, and simultaneously of the keto group at C17? to a hydroxyl group, which is then oxidized back to a keto group by chromium trioxide in acetic acid. The conjugated C4-C5 olefin and the carbonyl group at C3 is then transformed to dienol ethyl ether using ethyl orthoformate. The obtained product is ethynylated by acetylene in the presence of potassium tert-butoxide. 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.

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History

Norethisterone was synthesized for the first time by chemists Luis Miramontes, Carl Djerassi, and George Rosenkranz at Syntex in Mexico City in 1951. It was derived from ethisterone, and was found to possess about 20-fold greater potency as a progestogen in comparison. Norethisterone was the first highly active oral progestogen to be synthesized, and was preceded (as a progestogen) by progesterone (1934), ethisterone (1938), 19-norprogesterone (1944), and 17?-methylprogesterone (1949) as well as by nandrolone (1950), whereas noretynodrel (1952) and norethandrolone (1953) followed the synthesis of norethisterone. The drug was first introduced, alone as Norlutin, in the United States in 1957. Norethisterone was subsequently introduced in combination with mestranol as Ortho-Novum in the United States in 1963, and was the second progestin, after noretynodrel in 1960, to be used in an oral contraceptive. In 1964, additional contraceptive preparations containing norethisterone in combination with mestranol or EE, such as Norlestrin and Norinyl, were marketed in the United States.

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Society and culture

Generic names

Norethisterone is the INN and BAN of the drug while norethindrone is its USAN.

Brand names

Norethisterone, including as NETA and NETE, has been marketed under very large number of brand names throughout the world. These including the following among others:

Alone low-dose (e.g., 0.35 mg): Camila, Errin, Heather, Jencycla, Jolivette, Locilan, Micro-Novum, Micronovum, Micronor, Nor-QD, Nora, Noriday, Ortho Micronor
Alone high-dose (e.g., 5 mg, 10 mg): Aygestin, Lupaneta Pack (combination pack with leuprorelin), Norcolut, Norlutate, Primolut N, Primolut Nor, SH-420, Utovlan
Alone intramuscular (e.g., 200 mg, as NETE only): Noristerat, Nur-Isterate.
With ethinylestradiol: Aranelle, Balziva, Binovum, Brevicon, Brevinor, Briellyn, Cyclafem, Dasetta, Estrostep, Femcon, Generess, Gildagia, Gildess, Jinteli, Junel, Larin, Leena, Lo Loestrin, Lo Minastrin, Loestrin, Lolo, Lomedia, Microgestin, Minastrin, Modicon, Nelova, Norimin, Norinyl, Nortrel, Ortho, Ortho-Novum, Ovcon, Ovysmen, Philith, Primella, Select, Synphase, Synphasic, Tilia, Tri-Legest, Tri-Norinyl, Trinovum, Vyfemla, Wera, Wymzya, Zenchent, Zeosa.
With mestranol: Norethin, Noriday, Norinyl, Norquen, Ortho-Novum, Sophia.
With estradiol: Activella, Activelle, Alyacen, Cliane, Climagest, Climesse, Cliovelle, CombiPatch, Elleste Duet, Estalis, Estropause, Eviana, Evorel, Kliane, Kliofem, Kliogest, Kliovance, Mesigyna, Mesygest, Mimvey, Necon, Novofem, Nuvelle, Sequidot, Systen, Trisequens.

Availability

United States

Norethisterone was previously available alone in 5 mg tablets under the brand names Norlutin in the United States, but this formulation has since been discontinued in this country. However, NETA remains available alone in 5 mg tablets under the brand name Aygestin in the United States. It is one of the only non-contraceptive progestogen-only drug formulations that remains available in the United States. The others include progesterone, medroxyprogesterone acetate, megestrol acetate, and hydroxyprogesterone caproate, as well as the atypical agent danazol.

Both norethisterone and NETA are also available in the United States as contraceptives. 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 NETA is available only in combination with EE (Norlestrin, others). NETE is not available in the United States in any form.

Research

Norethisterone, as NETA and NETE, has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.

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Norethisterone

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Medical uses

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Contraindications