Norethisterone

Source: Wikipedia, the free encyclopedia.

Norethisterone
Clinical data
Trade namesMany
Other namesNET; Norethindrone; NSC-9564; LG-202; Ethinylnortestosterone; Norpregneninolone; Anhydrohydroxy-norprogesterone; Ethinylestrenolone; 17α-Ethynyl-19-nortestosterone; 17α-Ethynylestra-4-en-17β-ol-3-one; 17α-Hydroxy-19-norpregn-4-en-20-yn-3-one
AHFS/Drugs.comMonograph
MedlinePlusa604034
License data
Progestin
ATC code
Legal status
Legal status
3β-HSDTooltip 3β-hydroxysteroid dehydrogenase, and aromatase
Elimination half-life5.2–12.8 hours (mean 8.0 hours)[1]
Identifiers
  • (8R,9S,10R,13S,14S,17R)-17-ethynyl-17-hydroxy-13-methyl-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-3-one
JSmol)
Melting point203 to 204 °C (397 to 399 °F)
  • C[C@]12CC[C@H]3[C@H]([C@@H]1CC[C@]2(C#C)O)CCC4=CC(=O)CC[C@H]34
  • InChI=1S/C20H26O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,12,15-18,22H,4-11H2,2H3/t15-,16+,17+,18-,19-,20-/m0/s1 checkY
  • Key:VIKNJXKGJWUCNN-XGXHKTLJSA-N checkY
  (verify)

Norethisterone, also known as norethindrone and sold under many brand names, is a

gynecological disorders.[3][5] The medication is available in both low-dose and high-dose formulations and both alone and in combination with an estrogen.[5][6] It is used by mouth or, as norethisterone enanthate, by injection into muscle.[3][5][7]

hormonal activity.[3][10]

Norethisterone was discovered in 1951 and was one of the first progestins to be developed.[11][12][13] 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.[13][14] It is sometimes referred to as a "first-generation" progestin.[15][16] Along with desogestrel, it is one of the only progestins that is widely available as a progestogen-only "mini pill" for birth control.[17][18] Norethisterone is marketed widely throughout the world.[19] It is available as a generic medication.[20] In 2021, it was the 140th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[21][22] It is on the World Health Organization's List of Essential Medicines.[23]

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.

Another medical use of norethisterone is to alleviate

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.[24]

Formulations and brand names of norethisterone and esters
Composition Dose Brand names Use
NET only Low (e.g., 0.35 mg) Multiple[a]
Progestogen-only oral contraceptive
NET or NETA only High (e.g., 5 mg, 10 mg) Multiple[b]
Gynecological disorders
and other uses
NETE only Injection (e.g., 200 mg) Multiple[c] Progestogen-only injectable contraceptive
NET or NETA with ethinylestradiol Low (e.g., 0.4 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg) Multiple[d]
Combined oral contraceptive
NET with mestranol Low (e.g., 1 mg, 2 mg) Multiple[e] Combined oral contraceptive
NETA with estradiol Low (e.g., 0.1 mg, 0.5 mg) Multiple[f]
Combined menopausal hormone therapy
NETE with estradiol valerate Injection (e.g., 50 mg) Multiple[g]
Combined injectable contraceptive
Abbreviations: NET = Norethisterone. NETA = Norethisterone acetate. NETE = Norethisterone enanthate.
Sources: [25][26] [27][28]
Notes:
  1. ^ Camila, Errin, Heather, Jencycla, Jolivette, Locilan, Micro-Novum, Micronovum, Micronor, Nor-QD, Nora, Noriday, Ortho Micronor
  2. ^ Aygestin, Lupaneta Pack (combination pack with leuprorelin), Norcolut, Norlutate, Primolut N, Primolut Nor, SH-420, Utovlan
  3. ^ Depocon, Doryxas, NET-EN, Noristerat, Norigest, Nur-Isterate
  4. ^ 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
  5. ^ Norethin, Noriday, Norinyl, Norquen, Ortho-Novum, Sophia
  6. ^ 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
  7. ^ Chinese Injectable No. 3, Efectimes, Ginediol, Mesigyna, Mesilar, Meslart, Mesocept, Mesygest, Nofertyl, Nofertyl Lafrancol, Noregyna, Norestrin, Norifam, Norigynon, Nostidyn, Sexseg, Solouna

Contraindications

High-dose (10 mg/day) norethisterone has been associated with

bone marrow transplantation, as it has been associated with substantially lower one-year survival post-transplantation.[29]: 217 [30]

Side effects

At contraceptive and hormone replacement dosages (0.35 to 1 mg/day), norethisterone has essentially progestogenic

HDL cholesterol has been observed.[29]
: 253 

At high doses (5 to 60 mg/day), for instance those used in the treatment of gynecological disorders, norethisterone can cause

antigonadotropic
effects and can have estrogenic and weak androgenic side effects.

High doses of NETA (10 mg/day) have been associated with abnormal

glutamate pyruvate transaminase.[33] Although they were described as having no clinical relevance,[33] the elevated liver enzymes associated with NETA may have precluded its further development for male hormonal contraception.[31][32]

Androgenic

Due to its weak androgenic activity, norethisterone can produce androgenic

combined oral contraceptives that contain norethisterone and EE, however.[10] Such formulations contain low dosages of norethisterone (0.35 to 1 mg/day)[10] in combination with estrogen and are actually associated with improvement in acne symptoms.[34][35] 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.[34][35] 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.[36]

The sebaceous glands are highly androgen-sensitive and their size and activity are potential markers of androgenic effect.[37] 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.[37] 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.[38]

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

genitals.[9] 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.[9] 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.[9] In the remaining 13.3% of the affected cases, marked clitoral enlargement and partial fusion of the labioscrotal folds occurred.[9] The dosages used in these cases were 20 to 40 mg/day.[9]

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.[39]

High-dosage norethisterone has been used to suppress

mood lability in 8.9%, hot flashes in 8.3%, and voice deepening in two women (1.0%).[43]

Estrogenic

Norethisterone is weakly

venous thromboembolism (VTE) analogously to high dosages (above 50 μg/day) of EE, and that even doses of NETA 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.[45][46] 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.[47] This might have been due to additional ethinylestradiol generated by higher doses of norethisterone.[47]

Overdose

There have been no reports of serious side effects with overdose of norethisterone, even in small children.[48] As such, overdose usually does not require treatment.[48] High dosages of as much as 60 mg/day norethisterone have been studied for extended treatment durations without serious adverse effects described.[39]

Interactions

St. John's wort have also been found to accelerate norethisterone clearance.[4]

Pharmacology

Pharmacodynamics

Norethisterone is a potent

antimineralocorticoid activity.[3]

Relative affinities (%) of norethisterone, metabolites, and prodrugs
Compound Typea PRTooltip Progesterone receptor ARTooltip Androgen receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor SHBGTooltip Sex hormone-binding globulin
CBG
Tooltip Corticosteroid binding globulin
Norethisterone – 67–75 15 0 0–1 0–3 16 0
5α-Dihydronorethisterone Metabolite 25 27 0 0 ? ? ?
3α,5α-Tetrahydronorethisterone Metabolite 1 0 0–1 0 ? ? ?
3α,5β-Tetrahydronorethisterone Metabolite ? 0 0 ? ? ? ?
3β,5α-Tetrahydronorethisterone Metabolite 1 0 0–8 0 ? ? ?
Ethinylestradiol Metabolite 15–25 1–3 112 1–3 0 0.18 0
Norethisterone acetate Prodrug 20 5 1 0 0 ? ?
Norethisterone enanthate Prodrug ? ? ? ? ? ? ?
Noretynodrel Prodrug 6 0 2 0 0 0 0
Etynodiol Prodrug 1 0 11–18 0 ? ? ?
Etynodiol diacetate Prodrug 1 0 0 0 0 ? ?
Lynestrenol Prodrug 1 1 3 0 0 ? ?
Notes: Values are percentages (%). Reference
CBGTooltip Corticosteroid-binding globulin. Footnotes: a = Active or inactive metabolite, prodrug
, or neither of norethisterone. Sources: See template.

Progestogenic activity

Norethisterone is a potent

antigonadotropic, ovulation-inhibiting, and thermogenic in women compared to progesterone, which is in accordance with its progestogenic activity.[51][49][52]

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.[3] 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.[3] 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 rodent bioassays.[53][54] 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.[54] As such, it appears that the ethynyl group of norethisterone at the C17α position is responsible for its loss of androgenicity upon 5α-reduction.[54]

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.[38] 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.[38]

Norethisterone is bound to a considerable extent (36%) to SHBG in circulation.[3] Although it has lower affinity for SHBG than endogenous androgens and estrogens,[55] Norethisterone may displace testosterone from SHBG and thereby increase free testosterone levels, and this action may contribute to its weak androgenic effects.[56]

Estrogenic activity

Ethinylestradiol (EE), the metabolite of norethisterone responsible for its estrogenic activity.[3]

Norethisterone binds to the ERs, the

venous thromboembolism due to metabolism into EE.[58]

Neurosteroid activity

Like

3α-androstanediol, respectively, is a topic that does not appear to have been studied and hence requires clarification.[59]

Steroidogenesis inhibition

Norethisterone is a substrate for and is known to be an

nanomolar range, so this action may not be clinically relevant at typical dosages.[3]

Norethisterone and its major active metabolite 5α-DHNET have been found to act as

21-hydroxylase, or 11β-hydroxylase.[60] 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.[60]

Other activities

Norethisterone is a very weak inhibitor of CYP2C9 and CYP3A4 (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.[3]

Norethisterone and some of its 5α-reduced metabolites have been found to produce

sex steroid receptors and hence appear to be non-genomic in mechanism.[61]

Norethisterone stimulates the

progesterone receptor membrane component-1 (PGRMC1).[62] Certain other progestins act similarly in this assay, whereas progesterone acts neutrally.[62] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies.[63]

Antigonadotropic effects

Due to its progestogenic activity, norethisterone suppresses the

antigonadotropic effects.[3][49] The estrogenic activity of norethisterone at high doses would also be expected to contribute to its antigonadotropic effects.[64] Due to its antigonadotropic effects, norethisterone suppresses gonadal sex hormone production, inhibits ovulation in women, and suppresses spermatogenesis in men.[3][49][65]

The ovulation-inhibiting dosage of both oral norethisterone and oral NETA is about 0.5 mg/day in women.[3][66][67] However, some conflicting data exist, suggesting that higher doses might be necessary for full inhibition of ovulation.[68] An intramuscular injection of 200 mg NETE has been found to prevent ovulation and suppress levels of estradiol, progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in women.[69][70][71][72]

Early studies of oral norethisterone in men employing doses of 20 to 50 mg/day observed suppression of

sperm count and to have no effect on libido or erectile function over this short time period.[77][78] In healthy young men, NETA 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%).[79]

estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) in healthy young men.[80] Testosterone levels were maximally suppressed by about 94%, to ~30 ng/dL, when measured at day 7 post-injection.[80]

A single 200 mg intramuscular injection of NETE alone or in combination with 2 mg estradiol valerate has been found to produce a rapid, strong, and sustained decrease in gonadotropin and testosterone levels for up to one month in men.[65][81][82] Intramuscular injections of 200 mg NETE once every 3 weeks have also been found to suppress spermatogenesis in men.[73][83] Similarly, a single intramuscular injection of 50 mg NETE in combination with 5 mg estradiol valerate has been found to strongly suppress testosterone levels in men.[80] 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.[80]

Pharmacokinetics

The pharmacokinetics of norethisterone have been reviewed.[3][84]

Absorption

The

intestinal metabolism.[3][85] 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.[3]

Hormone levels with norethisterone
  • Norethisterone and ethinylestradiol levels over 24 hours after a single oral dose of 10 mg NETA in postmenopausal women.[38]
    Norethisterone and ethinylestradiol levels over 24 hours after a single oral dose of 10 mg NETA in postmenopausal women.[38]
  • Norethisterone and ethinylestradiol levels over 8 weeks after a single intramuscular injection of 200 mg NETE in premenopausal women.[86]
    Norethisterone and ethinylestradiol levels over 8 weeks after a single intramuscular injection of 200 mg NETE in premenopausal women.[86]

Distribution

The plasma protein binding of norethisterone is 97%.[3] It is bound 61% bound to albumin and 36% bound to SHBG.[3]

Metabolism

Metabolism of norethisterone and its prodrugs in humans
Norethisterone structures
The image above contains clickable links
The
hydroxyl (–OH) groups. Sources:[87][88][89][90][91][92][7][49][3][93][94]

Norethisterone has an

steric hindrance by the ethynyl group at C17α.[3] The ethynyl group of norethisterone is preserved in approximately 90% of all of its metabolites.[3]

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.[3]

Elimination

Norethisterone is eliminated 33 to 81% in urine and 35 to 43% in feces.[100]

Chemistry

See also:
List of androgens/anabolic steroids

Norethisterone, also known as 17α-ethynyl-19-nortestosterone or as 17α-ethynylestra-4-en-17β-ol-3-one, is a

anabolic activity.[102]

Derivatives

See also: Progestogen ester and List of progestogen esters

Norethisterone (NET) is the

parent compound of a large group of progestins that includes most of the progestins known as the 19-nortestosterone derivatives.[103] This group is divided by chemical structure into the estranes (derivatives of norethisterone) and the gonanes (18-methylgonanes or 13β-ethylestranes; derivatives of levonorgestrel) and includes the following marketed medications:[104]

Several of these act as prodrugs of norethisterone, including NETA, NETE, etynodiol diacetate, lynestrenol, and quingestanol acetate.[105][106][107] Noretynodrel may also be a prodrug of norethisterone.[3][1] NETA is taken by mouth similarly to norethisterone, while NETE is given by injection into muscle.[10]

Non-17α-ethynylated

19-Nortestosterone (19-NT) progestins which are technically not derivatives of norethisterone (as they do not have a C17α ethynyl group) but are still closely related (with other substitutions at the C17α and/or C16β positions) include the following marketed medications:[101][27]

Many anabolic steroids of the 19-nortestosterone family, like norethandrolone and ethylestrenol, are also potent progestogens, but were never marketed as such.

Synthesis

Chemical syntheses of norethisterone have been published.[101][84]

Synthesis 1

Norethisterone synthesis #1.[11][108]

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.

oral contraceptive to be offered for sale (i.e., Enovid). Treatment of the ethynyl enol ether with strong acid leads to norethisterone (6).[11]

In practice, these and all other combined oral contraceptives are mixtures of 1 to 2% EE or

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 synthesis #2.[109][110][111][112][113]

Norethisterone is made from

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.

History

Norethisterone was synthesized for the first time by chemists

oral contraceptive.[13] In 1964, additional contraceptive preparations containing norethisterone in combination with mestranol or EE, such as Norlestrin and Norinyl, were marketed in the United States.[13]

Society and culture

Generic names

Norethisterone is the

INNTooltip International Nonproprietary Name and BANTooltip British Approved Name of the drug while norethindrone is its USANTooltip United States Adopted Name.[101][27]

Brand names

Norethisterone is available in Bangladesh as Menogia (ACI), Normens (Renata) etc. Norethisterone (NET), including as NETA and NETE, has been marketed under many brand names throughout the world.[27][19]

Availability

United States

See also: List of progestogens available in the 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.[26] However, NETA remains available alone in 5 mg tablets under the brand name Aygestin in the United States.[26] It is one of the only non-contraceptive progestogen-only drug formulations that remains available in the United States.[26] The others include progesterone, medroxyprogesterone acetate, megestrol acetate, and hydroxyprogesterone caproate, as well as the atypical agent danazol.[26]

Both norethisterone and NETA are also available in the United States as contraceptives.[26] 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).[26] NETE is not available in the United States in any form.[26][114][115]

Research

Norethisterone, as NETA and NETE, has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men.[116][117]

Long-acting norethisterone

microspheres for intramuscular injection have been studied for potential use in birth control.[118]

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Further reading