Norethisterone

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Norethisterone
Norethisterone.svg
Norethisterone molecule ball.png
Clinical data
Trade names Alone: Aygestin, Camila, Heather, Micronor, Primolut N, others; With EE Tooltip ethinylestradiol: Lo Loestrin, Loestrin, Microgestin, Modicon, Norinyl, Ortho-Novum, others; With E2: Activella, Activelle, Estalis, Kliogest, Necon, Novofem, Trisequens, others
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.com International Drug Names
MedlinePlus a604034
License data
Routes of
administration 		By mouth, intramuscular injection (as NETE Tooltip norethisterone enanthate)
Drug class Progestogen (medication); Progestin
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 47–73% (mean 64%) [1] [2]
Protein binding 97%: [3]
Albumin: 61%; [3]
SHBG Tooltip Sex hormone-binding globulin: 36% [3]
Metabolism Mainly CYP3A4 (liver); [4] also 5α-/5β-reductase, 3α- Tooltip 3α-hydroxysteroid dehydrogenase/3β-HSD Tooltip 3β-hydroxysteroid dehydrogenase, and aromatase
Elimination half-life 5.2–12.8 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
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.619 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H26O2
Molar mass 298.426 g·mol−1
3D model (JSmol)
Melting point 203 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 Yes check.svgY
  • Key:VIKNJXKGJWUCNN-XGXHKTLJSA-N Yes check.svgY
   (verify)

Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of 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]

Contents

Side effects of norethisterone include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth. [8] [9] Norethisterone is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. [3] [5] It has weak androgenic and estrogenic activity, mostly at high dosages, and no other important 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 2020, it was the 137th 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 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. [24]

Formulations and brand names of norethisterone and esters
CompositionDoseBrand namesUse
NET onlyLow (e.g., 0.35 mg)Multiple [lower-alpha 1] Progestogen-only oral contraceptive
NET or NETA onlyHigh (e.g., 5 mg, 10 mg)Multiple [lower-alpha 2] Gynecological disorders and other uses
NETE onlyInjection (e.g., 200 mg)Multiple [lower-alpha 3] 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 [lower-alpha 4] Combined oral contraceptive
NET with mestranol Low (e.g., 1 mg, 2 mg)Multiple [lower-alpha 5] Combined oral contraceptive
NETA with estradiol Low (e.g., 0.1 mg, 0.5 mg)Multiple [lower-alpha 6] Combined menopausal hormone therapy
NETE with estradiol valerate Injection (e.g., 50 mg)Multiple [lower-alpha 7] 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 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. [29] : 217  [30]

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. [29] : 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. [29] : 253  There has been no association with weight gain, and blood pressure, blood clotting, and glucose tolerance have all remained normal. [29] : 253  However, a decrease in 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 hypogonadism due to its antigonadotropic effects and can have estrogenic and weak androgenic side effects.

High doses of NETA (10 mg/day) have been associated with abnormal liver function tests, including significant elevations in liver enzymes. [31] [32] [33] These liver enzymes included lactate dehydrogenase and 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 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). [9] This is notably not the case with 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 FDA Tooltip 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 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. [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 menstruation in women with severe intellectual disability who were incapable of handling their own menses. [40] [41] 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%. [40] 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. [40] [41] Another study of 5 mg/day norethisterone in 132 women also made no mention of androgenic side effects. [42] These findings suggest little to no risk of androgenic side effects with norethisterone at a dosage of 5 mg/day. [40] [41] 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%). [43]

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. [44] 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 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

5α-Reductase plays an important role in the metabolism of norethisterone, and 5α-reductase inhibitors such as finasteride and dutasteride can inhibit its metabolism.[ citation needed ] Norethisterone is partially metabolized via hydroxylation by CYP3A4, and inhibitors and inducers of CYP3A4 can significantly alter circulating levels of norethisterone. [4] 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. [4]

Pharmacology

Pharmacodynamics

Norethisterone is a potent progestogen and a weak androgen and estrogen. [3] 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). [3] 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. [3] 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. [3]

Relative affinities (%) of norethisterone, metabolites, and prodrugs
CompoundTypea PR Tooltip Progesterone receptor AR Tooltip Androgen receptor ER Tooltip Estrogen receptor GR Tooltip Glucocorticoid receptor MR Tooltip Mineralocorticoid receptor SHBG Tooltip Sex hormone-binding globulin CBG Tooltip Corticosteroid binding globulin
Norethisterone–67–751500–10–3160
5α-Dihydronorethisterone Metabolite252700 ? ? ?
3α,5α-TetrahydronorethisteroneMetabolite100–10 ? ? ?
3α,5β-TetrahydronorethisteroneMetabolite ?00 ? ? ? ?
3β,5α-TetrahydronorethisteroneMetabolite100–80 ? ? ?
Ethinylestradiol Metabolite15–251–31121–300.180
Norethisterone acetate Prodrug205100 ? ?
Norethisterone enanthate Prodrug ? ? ? ? ? ? ?
Noretynodrel Prodrug6020000
Etynodiol Prodrug1011–180 ? ? ?
Etynodiol diacetate Prodrug10000 ? ?
Lynestrenol Prodrug11300 ? ?
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PR Tooltip progesterone receptor, metribolone for the AR Tooltip androgen receptor, estradiol for the ER Tooltip estrogen receptor, dexamethasone for the GR Tooltip glucocorticoid receptor, aldosterone for the MR Tooltip mineralocorticoid receptor, dihydrotestosterone for SHBG Tooltip sex hormone-binding globulin, and cortisol for CBG Tooltip Corticosteroid-binding globulin. Footnotes:a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.

Progestogenic activity

Norethisterone is a potent progestogen and binds to the PR with approximately 150% of the affinity of progesterone. [3] In contrast, its parent compounds, testosterone, nandrolone (19-nortestosterone), and ethisterone (17α-ethynyltestosterone), have 2%, 22%, and 44% of the relative binding affinity of progesterone for the PR. [49] Unlike norethisterone, its major active metabolite 5α-dihydronorethisterone (5α-DHNET), which is formed by transformation via 5α-reductase, has been found to possess both progestogenic and marked antiprogestogenic activity, [50] although its affinity for the PR is greatly reduced relative to norethisterone at only 25% of that of progesterone. [3] 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. [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. Ethinylestradiol.svg
Ethinylestradiol (EE), the metabolite of norethisterone responsible for its estrogenic activity.

Norethisterone binds to the ERs, the ERα and the ERβ, with 0.07% and 0.01% of the relative binding affinity of estradiol. [57] Due to these very low relative affinities, it is essentially inactive itself as a ligand of the ERs at clinical concentrations. [3] 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 ethinylestradiol (EE), and for this reason, unlike most other progestins, norethisterone has some estrogenic activity. [3] 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. [3] 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 μg dosages of EE, respectively. [1] [3] 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. [1] At high doses, norethisterone may increase the risk of venous thromboembolism due to metabolism into EE. [58]

Neurosteroid activity

Like progesterone and testosterone, norethisterone is metabolized into 3,5-tetrahydro metabolites. [59] Whether these metabolites of norethisterone interact with the GABAA receptor similarly to the 3,5-tetrahydro metabolites of progesterone and testosterone like allopregnanolone and 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 inhibitor of 5α-reductase, with 4.4% and 20.1% inhibition at 0.1 and 1 μM, respectively. [3] However, therapeutic concentrations of norethisterone are in the low 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 irreversible aromatase inhibitors (Ki = 1.7 μM and 9.0 μM, respectively). [60] However, like the case of 5α-reductase, the concentrations required are probably too high to be clinically relevant at typical dosages. [3] 5α-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), 17α-hydroxylase/17,20-lyase, 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 vasodilating effects in animals that are independent of sex steroid receptors and hence appear to be non-genomic in mechanism. [61]

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). [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 hypothalamic–pituitary–gonadal axis (HPG axis) and hence has 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 17-ketosteroid excretion, increased estrogen excretion (due to conversion into ethinylestradiol), suppression of spermatogenesis, libido, and erectile function, and incidence of gynecomastia. [73] [74] [75] [44] [76] 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 suppress 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]

Hormone levels following a single intramuscular injection of estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) in healthy young men. Testosterone levels were maximally suppressed by about 94%, to ~30 ng/dL, when measured at day 7 post-injection. Hormone levels in men with a single intramuscular injection of 5 mg estradiol valerate and 50 mg norethisterone enanthate in oil.png
Hormone levels following a single intramuscular injection of estradiol valerate/norethisterone enanthate (5 mg/50 mg) (Mesigyna) in healthy young men. Testosterone levels were maximally suppressed by about 94%, to ~30 ng/dL, when measured at day 7 post-injection.

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 oral bioavailability of norethisterone is between 47 and 73%, with a mean oral bioavailability of 64%. [1] [2] Micronization has been found to significantly improve the oral bioavailability of norethisterone by increasing intestinal absorption and reducing 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]

Distribution

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

Metabolism

Norethisterone has an elimination half-life of 5.2 to 12.8 hours, with a mean elimination half-life of 8.0 hours. [1] The metabolism of norethisterone is very similar to that of testosterone (and nandrolone) and is mainly via reduction of the Δ4 double bond to 5α- and 5β-dihydronorethisterone, which is followed by the reduction of the C3 keto group to the four isomers of 3,5-tetrahydronorethisterone. [3] These transformations are catalyzed by 5α- and 5β-reductase and 3α- and 3β-hydroxysteroid dehydrogenase both in the liver and in extrahepatic tissues such as the pituitary gland, uterus, prostate gland, vagina, and breast. [95] With the exception of 3α,5α- and 3β,5α-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). [96] [97] [98] A small amount of norethisterone is also converted by aromatase into EE. [1] [3] [45] Norethisterone is metabolized in the liver via hydroxylation as well, mainly by CYP3A4. [4] Some conjugation (including glucuronidation and sulfation) [95] [99] of norethisterone and its metabolites occurs in spite of 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

Norethisterone, also known as 17α-ethynyl-19-nortestosterone or as 17α-ethynylestra-4-en-17β-ol-3-one, is a synthetic estrane steroid and a derivative of testosterone. [101] [27] It is specifically a derivative of testosterone in which an ethynyl group has been added at the C17α position and the methyl group at the C19 position has been removed; hence, it is a combined derivative of ethisterone (17α-ethynyltestosterone) and nandrolone (19-nortestosterone). [101] [27] These modifications result in increased progestogenic activity and oral bioavailability as well as decreased androgenic/anabolic activity. [102]

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. [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. Norethisterone synthesis.svg
Norethisterone 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 C17β hydroxyl group into a ketone functionality (3). This is then reacted with metal acetylide into the corresponding C17α ethynyl compound (4). Hydrolysis of the enol ether under mild conditions leads directly to (5), [108] 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). [11]

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 synthesis #2. Norethindrone synthesis.svg
Norethisterone 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 C17α 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.

History

Norethisterone was synthesized for the first time by chemists Luis Miramontes, Carl Djerassi, and George Rosenkranz at Syntex in Mexico City in 1951. [11] It was derived from ethisterone, and was found to possess about 20-fold greater potency as a progestogen in comparison.[ citation needed ] 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 17α-methylprogesterone (1949) as well as by nandrolone (1950), whereas noretynodrel (1952) and norethandrolone (1953) followed the synthesis of norethisterone. [12] [13] The drug was introduced as Norlutin in the United States in 1957. [14] Norethisterone was subsequently combined with mestranol and marketed as Ortho-Novum in the United States in 1963. It was the second progestin, after noretynodrel in 1960, to be used in an 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 INN Tooltip International Nonproprietary Name and BAN Tooltip British Approved Name of the drug while norethindrone is its USAN Tooltip 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

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]

Related Research Articles

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Desogestrel</span> Medication

Desogestrel is a progestin medication which is used in birth control pills for women. It is also used in the treatment of menopausal symptoms in women. The medication is available and used alone or in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone acetate</span> Chemical compound

Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among 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 low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.

<span class="mw-page-title-main">Norgestimate</span> Chemical compound

Norgestimate, sold under the brand names Ortho Tri-Cyclen and Previfem among others, is a progestin medication which is used in birth control pills for women and in menopausal hormone therapy. The medication is available in combination with an estrogen and is not available alone. It is taken by mouth.

Maternal use of androgens or high doses of certain weakly androgenic synthetic progestogens (progestins) structurally related to testosterone can masculinize (virilize) the vulva of a female fetus during susceptible times in pregnancy.

<span class="mw-page-title-main">Gestodene</span> Progestin medication

Gestodene, sold under the brand names Femodene and Minulet among others, is a progestin medication which is used in birth control pills for women. It is also used in menopausal hormone therapy. The medication is available almost exclusively in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Norgestrienone</span> Chemical compound

Norgestrienone, sold under the brand names Ogyline, Planor, and Miniplanor, is a progestin medication which has been used in birth control pills, sometimes in combination with ethinylestradiol. It was developed by Roussel Uclaf and has been registered for use only in France. Under the brand name Planor, it has been marketed in France as 2 mg norgestrienone and 50 μg ethinylestradiol tablets. It is taken by mouth.

<span class="mw-page-title-main">Lynestrenol</span> Androgen and anabolic steroid

Lynestrenol, sold under the brand names Exluton and Ministat among others, is a progestin medication which is used in birth control pills and in the treatment of gynecological disorders. The medication is available both alone and in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Ethisterone</span> Chemical compound

Ethisterone, also known as ethinyltestosterone, pregneninolone, and anhydrohydroxyprogesterone and formerly sold under the brand names Proluton C and Pranone among others, is a progestin medication which was used in the treatment of gynecological disorders but is now no longer available. It was used alone and was not formulated in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">Dienogest</span> Chemical compound

Dienogest, sold under the brand name Visanne among others, is a progestin medication which is used in birth control pills and in the treatment of endometriosis. It is also used in menopausal hormone therapy and to treat heavy periods. Dienogest is available both alone and in combination with estrogens. It is taken by mouth.

<span class="mw-page-title-main">Chlormadinone acetate</span> Chemical compound

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

<span class="mw-page-title-main">Norethisterone enanthate</span> Chemical compound

Norethisterone enanthate (NETE), also known as norethindrone enanthate, is a form of hormonal birth control which is used to prevent pregnancy in women. It is used both as a form of progestogen-only injectable birth control and in combined injectable birth control formulations. It may be used following childbirth, miscarriage, or abortion. The failure rate per year in preventing pregnancy for the progestogen-only formulation is 2 per 100 women. Each dose of this form lasts two months with only up to two doses typically recommended.

<span class="mw-page-title-main">Normethandrone</span> Chemical compound

Normethandrone, also known as methylestrenolone or methylnortestosterone and sold under the brand name Metalutin among others, is a progestin and androgen/anabolic steroid (AAS) medication which is used in combination with an estrogen in the treatment of amenorrhea and menopausal symptoms in women. It is taken by mouth.

<span class="mw-page-title-main">Allylestrenol</span> Chemical compound

Allylestrenol, sold under the brand names Gestanin and Turinal among others, is a progestin medication which is used to treat recurrent and threatened miscarriage and to prevent premature labor in pregnant women. However, except in the case of proven progesterone deficiency, its use for such purposes is no longer recommended. It is also used in Japan to treat benign prostatic hyperplasia (BPH) in men. The medication is used alone and is not formulated in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Noretynodrel</span> Chemical compound

Noretynodrel, or norethynodrel, sold under the brand name Enovid among others, is a progestin medication which was previously used in birth control pills and in the treatment of gynecological disorders but is now no longer marketed. It was available both alone and in combination with an estrogen. The medication is taken by mouth.

<span class="mw-page-title-main">Quingestanol acetate</span> Chemical compound

Quingestanol acetate, sold under the brand names Demovis and Pilomin among others, is a progestin medication which was used in birth control pills but is no longer marketed. It is taken by mouth.

<span class="mw-page-title-main">Segesterone acetate</span> Progestin medication

Segesterone acetate (SGA), sold under the brand names Nestorone, Elcometrine, and Annovera, is a progestin medication which is used in birth control and in the treatment of endometriosis in the United States, Brazil, and other South American countries. It is available both alone and in combination with an estrogen. It is not effective by mouth and must be given by other routes, most typically as a vaginal ring or implant that is placed into fat.

<span class="mw-page-title-main">Progestogen ester</span> Drug class

A progestogen ester is an ester of a progestogen or progestin. The prototypical progestogen is progesterone, an endogenous sex hormone. Esterification is frequently employed to improve the pharmacokinetics of steroids, including oral bioavailability, lipophilicity, and elimination half-life. In addition, with intramuscular injection, steroid esters are often absorbed more slowly into the body, allowing for less frequent administration. Many steroid esters function as prodrugs.

<span class="mw-page-title-main">5α-Dihydronorethisterone</span> Chemical compound

5α-Dihydronorethisterone is a major active metabolite of norethisterone (norethindrone). Norethisterone is a progestin with additional weak androgenic and estrogenic activity. 5α-DHNET is formed from norethisterone by 5α-reductase in the liver and other tissues.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

References

  1. 1 2 3 4 5 6 7 8 Stanczyk 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. PMID   12215716. S2CID   27018468.
  2. 1 2 Fotherby 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. PMID   8842581.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 Kuhl H (August 2005). "Pharmacology of estrogens and progestogens: influence of different routes of administration" (PDF). Climacteric. 8 (Suppl 1): 3–63. doi:10.1080/13697130500148875. PMID   16112947. S2CID   24616324. Archived (PDF) from the original on 22 August 2016. Retrieved 6 September 2018.
  4. 1 2 3 4 Korhonen 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. PMID   18356043. S2CID   10809537.
  5. 1 2 3 4 Taitel HF, Kafrissen ME (1995). "Norethindrone--a review of therapeutic applications". International Journal of Fertility and Menopausal Studies. 40 (4): 207–23. PMID   8520623.
  6. ↑ Alden KR, Lowdermilk DL, Cashion MC, Perry SE (27 December 2013). Maternity and Women's Health Care - E-Book. Elsevier Health Sciences. pp. 135–. ISBN   978-0-323-29368-6. Archived from the original on 9 March 2023. Retrieved 8 January 2018.
  7. 1 2 Kuhl H (September 1990). "Pharmacokinetics of oestrogens and progestogens". Maturitas. 12 (3): 171–197. doi:10.1016/0378-5122(90)90003-o. PMID   2170822.
  8. ↑ https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/018405s023lbl.pdf Archived 10 February 2017 at the Wayback Machine [ bare URL PDF ]
  9. 1 2 3 4 5 6 7 Jacobson BD (October 1962). "Hazards of norethindrone therapy during pregnancy". American Journal of Obstetrics and Gynecology. 84 (7): 962–8. doi:10.1016/0002-9378(62)90075-3. PMID   14450719.
  10. 1 2 3 4 IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; World Health Organization; International Agency for Research on Cancer (2007). Combined Estrogen-progestogen Contraceptives and Combined Estrogen-progestogen Menopausal Therapy. World Health Organization. pp. 417–. ISBN   978-92-832-1291-1. Archived from the original on 10 January 2023. Retrieved 12 October 2016. Norethisterone and its acetate and enanthate esters are progestogens that have weak estrogenic and androgenic properties.
  11. 1 2 3 4 Djerassi C, Miramontes L, Rosenkranz G, Sondheimer F, Longo LD (January 2006). "Steroids LIV. Synthesis of 19-nor-17alpha-ethynyltestosterone and 19-nor-17alpha-methyltestosterone. 1954". American Journal of Obstetrics and Gynecology. 194 (1): 289, discussion 290. doi:10.1021/ja01645a010. PMID   16389045.
  12. 1 2 Shoupe D (7 November 2007). The Handbook of Contraception: A Guide for Practical Management. Springer Science & Business Media. pp. 15–. ISBN   978-1-59745-150-5.
  13. 1 2 3 4 5 Marks L (2010). Sexual Chemistry: A History of the Contraceptive Pill. Yale University Press. pp. 74, 76. ISBN   978-0-300-16791-7.
  14. 1 2 William Andrew Publishing (22 October 2013). Pharmaceutical Manufacturing Encyclopedia, 3rd Edition. Elsevier. pp. 2935–. ISBN   978-0-8155-1856-3.
  15. ↑ Hatcher RA, Nelson AL (2007). Contraceptive Technology. Ardent Media. pp. 195–. ISBN   978-1-59708-001-9. Archived from the original on 10 January 2023. Retrieved 8 January 2018.
  16. ↑ Gunasheela S (14 March 2011). Practical Management of Gynecological Problems. JP Medical Ltd. pp. 31–. ISBN   978-93-5025-240-6. Archived from the original on 9 March 2023. Retrieved 8 January 2018.
  17. ↑ Grimes DA, Lopez LM, O'Brien PA, Raymond EG (November 2013). "Progestin-only pills for contraception". The Cochrane Database of Systematic Reviews (11): CD007541. doi:10.1002/14651858.CD007541.pub3. PMID   24226383.
  18. ↑ 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. PMID   14759612.
  19. 1 2 "Norethisterone". Archived from the original on 15 September 2018. Retrieved 8 January 2018.
  20. ↑ "Generic Aygestin Availability". Archived from the original on 24 August 2018. Retrieved 8 January 2018.
  21. ↑ "The Top 300 of 2020". ClinCalc. Archived from the original on 18 March 2020. Retrieved 7 October 2022.
  22. ↑ "Norethindrone - Drug Usage Statistics". ClinCalc. Archived from the original on 3 March 2021. Retrieved 7 October 2022.
  23. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl: 10665/345533 . WHO/MHP/HPS/EML/2021.02.
  24. ↑ Kim JJ, Kurita T, Bulun SE (February 2013). "Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer". Endocrine Reviews. 34 (1): 130–62. doi:10.1210/er.2012-1043. PMC   3565104 . PMID   23303565.
  25. ↑ "Norethisterone". Drugs.com.
  26. 1 2 3 4 5 6 7 8 "Drugs@FDA: FDA Approved Drug Products". United States Food and Drug Administration. Archived from the original on 16 November 2016. Retrieved 27 November 2016.
  27. 1 2 3 4 5 6 Index Nominum 2000: International Drug Directory. Taylor & Francis. January 2000. pp. 749–. ISBN   978-3-88763-075-1.
  28. ↑ IARC Working Group on the Evaluation of Carcinogenic Risks to Humans; International Agency for Research on Cancer (1 January 1999). Hormonal Contraception and Post-menopausal Hormonal Therapy (PDF). IARC. p. 65. ISBN   978-92-832-1272-0.
  29. 1 2 3 4 5 Aronson JK (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 217, 253, 275. ISBN   978-0-08-093292-7.
  30. ↑ 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. PMID   9845522.
  31. 1 2 Cornia PB, Anawalt BD (November 2004). "Male hormonal contraception". Expert Opinion on Emerging Drugs. 9 (2): 335–344. doi:10.1517/14728214.9.2.335. PMID   15571489. S2CID   26886374.
  32. 1 2 Cornia PB, Anawalt BD (2005). "Male hormonal contraceptives: a potentially patentable and profitable product". Expert Opinion on Therapeutic Patents. 15 (12): 1727–1737. doi:10.1517/13543776.15.12.1727. ISSN   1354-3776. S2CID   83941717.
  33. 1 2 3 Kamischke A, Heuermann T, Krüger K, von Eckardstein S, Schellschmidt I, Rübig A, Nieschlag E (February 2002). "An effective hormonal male contraceptive using testosterone undecanoate with oral or injectable norethisterone preparations". The Journal of Clinical Endocrinology and Metabolism. 87 (2): 530–539. doi: 10.1210/jcem.87.2.8218 . PMID   11836281.
  34. 1 2 Junkins-Hopkins JM (March 2010). "Hormone therapy for acne". Journal of the American Academy of Dermatology. 62 (3): 486–8. doi:10.1016/j.jaad.2009.12.002. PMID   20159314.
  35. 1 2 Arowojolu AO, Gallo MF, Lopez LM, Grimes DA (July 2012). Arowojolu AO (ed.). "Combined oral contraceptive pills for treatment of acne". The Cochrane Database of Systematic Reviews (7): CD004425. doi:10.1002/14651858.CD004425.pub6. PMID   22786490.
  36. ↑ van Vloten WA, Sigurdsson V (2004). "Selecting an oral contraceptive agent for the treatment of acne in women". American Journal of Clinical Dermatology. 5 (6): 435–41. doi:10.2165/00128071-200405060-00008. PMID   15663340. S2CID   9947402.
  37. 1 2 Pochi 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): 1002–4. doi:10.1016/0002-9378(65)90162-6. PMID   5843402.
  38. 1 2 3 4 Kuhnz 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. PMID   9494772.
  39. 1 2 Curwen S (1962). "Virilization with Norethisterone". BMJ. 1 (5289): 1415. doi:10.1136/bmj.1.5289.1415-a. ISSN   0959-8138. PMC   1958463 .
  40. 1 2 3 4 Roxburgh 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): 310–3. doi:10.5694/j.1326-5377.1973.tb128175.x. PMID   4746398. S2CID   204094551. Archived from the original on 20 December 2016. Retrieved 6 December 2016.
  41. 1 2 3 Roxburgh 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): 310–3. doi:10.1097/00006254-197408000-00021. PMID   4746398.
  42. ↑ Board JA (April 1965). "Clinical Evaluation of the Oral Contraceptive Use of Norethindrone 5 Mg. Plus Mestranol 0.075 Mg". Canadian Medical Association Journal. 92 (15): 814–7. PMC   1927985 . PMID   14272499.
  43. ↑ 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): 105–108. doi:10.1016/j.jpag.2011.09.013. PMID   22154396.
  44. 1 2 Paulsen 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): 1033–9. doi:10.1210/jcem-22-10-1033. PMID   13942007.
  45. 1 2 Chu MC, Zhang X, Gentzschein E, Stanczyk FZ, Lobo RA (June 2007). "Formation of ethinyl estradiol in women during treatment with norethindrone acetate". The Journal of Clinical Endocrinology and Metabolism. 92 (6): 2205–7. doi: 10.1210/jc.2007-0044 . PMID   17341557.
  46. ↑ Connolly A, Britton AG (31 March 2017). Women's Health in Primary Care. Cambridge University Press. pp. 153–. ISBN   978-1-108-16595-2.
  47. 1 2 Farris 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): 1129–1144. doi:10.1080/17512433.2017.1356718. PMID   28712325. S2CID   205931204.
  48. 1 2 https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016954s106lbl.pdf Archived 10 February 2017 at the Wayback Machine [ bare URL PDF ]
  49. 1 2 3 4 5 Kuhl H (2011). "Pharmacology of Progestogens" (PDF). J Reproduktionsmed Endokrinol. 8 (1): 157–177. Archived (PDF) from the original on 11 October 2016. Retrieved 10 October 2016.
  50. ↑ 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): 125–9. PMID   2934946.
  51. ↑ McCuistion LE, Kee JL, Hayes ER (25 March 2014). Pharmacology: A Patient-Centered Nursing Process Approach. Elsevier Health Sciences. pp. 846–. ISBN   978-0-323-29348-8.
  52. ↑ 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. PMID   13332050.
  53. ↑ 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. PMID   19028512. S2CID   41356223. 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].
  54. 1 2 3 Lemus 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): 121–9. doi:10.1016/s0960-0760(96)00172-0. PMID   9182866. S2CID   33771349.
  55. ↑ Filshie M, Guillebaud J (22 October 2013). Contraception: Science and Practice. Elsevier Science. pp. 26–. ISBN   978-1-4831-6366-6. Norethisterone binds to SHBG with less affinity than endogenous androgens and oestrogens [...]
  56. ↑ Azziz R (8 November 2007). Androgen Excess Disorders in Women. Springer Science & Business Media. pp. 124–. ISBN   978-1-59745-179-6.
  57. ↑ Kuiper GG, Carlsson B, Grandien K, Enmark E, Häggblad J, Nilsson S, Gustafsson JA (March 1997). "Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta". Endocrinology. 138 (3): 863–70. doi: 10.1210/endo.138.3.4979 . PMID   9048584.
  58. ↑ 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. PMID   17056444. S2CID   27088428.
  59. 1 2 Giatti S, Melcangi RC, Pesaresi M (August 2016). "The other side of progestins: effects in the brain". Journal of Molecular Endocrinology. 57 (2): R109-26. doi: 10.1530/JME-16-0061 . PMID   27339142.
  60. 1 2 3 Yamamoto 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. PMID   8205267.
  61. ↑ 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): 161–9. doi:10.1016/s0014-2999(03)02106-x. PMID   12954372.
  62. 1 2 Neubauer H, Ma Q, Zhou J, Yu Q, Ruan X, Seeger H, et al. (October 2013). "Possible role of PGRMC1 in breast cancer development". Climacteric. 16 (5): 509–13. doi:10.3109/13697137.2013.800038. PMID   23758160. S2CID   29808177.
  63. ↑ Trabert B, Sherman ME, Kannan N, Stanczyk FZ (April 2020). "Progesterone and Breast Cancer". Endocrine Reviews. 41 (2): 320–344. doi: 10.1210/endrev/bnz001 . PMC   7156851 . PMID   31512725.
  64. ↑ Anderson RA, Baird DT (December 2002). "Male contraception" (PDF). Endocrine Reviews. 23 (6): 735–62. doi: 10.1210/er.2002-0002 . PMID   12466187. Archived (PDF) from the original on 28 August 2021. Retrieved 11 December 2019.
  65. 1 2 Kamischke 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. PMID   14723979.
  66. ↑ Rudel HW (September 1968). "Pharmacology of oral contraceptives". Clinical Obstetrics and Gynecology. 11 (3): 632–44. doi:10.1097/00003081-196811030-00002. PMID   4878826.
  67. ↑ Stanczyk FZ (November 2003). "All progestins are not created equal". Steroids. 68 (10–13): 879–90. doi:10.1016/j.steroids.2003.08.003. PMID   14667980. S2CID   44601264.
  68. ↑ 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. PMID   22078182.
  69. ↑ Shoupe D (1993). "Injectable Contraceptives and Contraceptive Vaginal Rings". Contraception. Clinical Perspectives in Obstetrics and Gynecology. Springer. pp. 144–157. doi:10.1007/978-1-4612-2730-4_13. ISBN   978-1-4612-7645-6. ISSN   0178-0328.
  70. ↑ 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. PMID   1122756.
  71. ↑ 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. PMID   606499.
  72. ↑ 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. PMID   572279.
  73. 1 2 Neumann F, Diallo FA, Hasan SH, Schenck B, Traore I (1976). "The influence of pharmaceutical compounds on male fertility". Andrologia. 8 (3): 203–235. doi: 10.1111/j.1439-0272.1976.tb02137.x . PMID   793446. S2CID   24859886.
  74. ↑ 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. PMID   13583821. S2CID   32637425.
  75. ↑ Heller CG, Moore DJ, Paulsen CA, Nelson WO, Laidlaw WM (December 1959). "Effects of progesterone and synthetic progestins on the reproductive physiology of normal men". Federation Proceedings. 18: 1057–65. PMID   14400846. Archived from the original on 18 December 2018. Retrieved 11 December 2019.
  76. ↑ Paulsen CA (March 1965). "Progestin Metabolism: Special Reference to Estrogenic Pathways". Metabolism. 14 (3): SUPPL:313–9. doi:10.1016/0026-0495(65)90018-1. PMID   14261416.
  77. ↑ Moudgal NR, Suresh R (1995). "Some thoughts on development of chemically based male contraceptives" (PDF). Current Science (Bangalore). 68 (4): 470–474. ISSN   0011-3891. Archived from the original (PDF) on 11 December 2019. Retrieved 11 December 2019.
  78. ↑ Johonsson ED, Nygren KG (1973). "Depression of plasma testosterone levels in men with norethindrone". Contraception. 8 (3): 219–226. doi:10.1016/0010-7824(73)90032-2. ISSN   0010-7824.
  79. ↑ Zitzmann M, Rohayem J, Raidt J, Kliesch S, Kumar N, Sitruk-Ware R, Nieschlag E (May 2017). "Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial". Andrology. 5 (3): 516–526. doi: 10.1111/andr.12328 . PMID   28189123. S2CID   41502711.
  80. 1 2 3 4 Alvarez BD (11 May 2011). Efecto de una Dosis de 50 mg de Enantato de Noretisterona y 5 mg de Valerato de Estradiol en los Niveles de Testosterona Total en Hombres Mexicanos Sanos [Effect of a Dose of 50 mg of Norethisterone Enanthate and 5 mg of Estradiol Valerate on Total Testosterone Levels in Healthy Mexican Men] (MSc). National Polytechnic Institute of Mexico. Archived from the original on 16 September 2022. Retrieved 12 September 2022.
  81. ↑ Amory JK (2003). "Androgens and Male Contraception". Androgens in Health and Disease. Contemporary Endocrinology. Humana Press. pp. 405–417. doi:10.1007/978-1-59259-388-0_21. ISBN   978-1-61737-314-5.
  82. ↑ 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): 351–358. doi:10.1046/j.1365-2265.2000.01097.x. PMID   10971453. S2CID   70515136.
  83. ↑ Petry R, Mauss J, Senge T, Rausch-Stroomann JG (1970). "Influence of Cyproterone-acetate, Norethisterone-enanthate and Gestonorone-capronate on the Hypophyseal-Gonadal-Axis in the Male". Über den Einfluß von Cyproteronacetat, Norethisteronönanthat und Gestonoroncapronat auf die Hypophysen-Gonadenachse beim Mann[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. 428–430. doi:10.1007/978-3-642-80591-2_118. ISBN   9783642805912.{{cite book}}: |journal= ignored (help)
  84. 1 2 Die Gestagene. Springer-Verlag. 27 November 2013. pp. 13–14, 283–284. ISBN   978-3-642-99941-3. Archived from the original on 10 January 2023. Retrieved 19 September 2018.
  85. ↑ Saperstein S, Edgren RA, Jung D, Mroszczak EJ, Lee GJ, Dorr A, Pritchard R, Kushinsky S, Fong JC, Combs DL (December 1989). "Pharmacokinetics of norethindrone: effect of particle size". Contraception. 40 (6): 731–40. doi:10.1016/0010-7824(89)90075-9. PMID   2620531.
  86. ↑ 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): 781–789. doi:10.1002/jcph.1079. PMID   29522253. S2CID   3813229.
  87. ↑ Thijssen JH (September 1972). "Metabolism of Orally Active Synthetic Progestational Compounds". In Tausk M (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 217–273. ISBN   978-0080168128. OCLC   278011135.
  88. ↑ Okada H (2010). "Receptors and Mechanism Action of Synthetic Progestogens". Asia-Oceania Journal of Obstetrics and Gynaecology. 7 (1): 15–27. doi:10.1111/j.1447-0756.1981.tb00511.x. ISSN   0389-2328.
  89. ↑ 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. ISBN   978-1-349-05954-6.
  90. ↑ Thomas JA, Keenan EJ (1986). "Progestins and Oral Contraceptives". Principles of Endocrine Pharmacology. Springer. pp. 167–196. doi:10.1007/978-1-4684-5036-1_8. ISBN   978-1-4684-5036-1.
  91. ↑ Orme ML, Back DJ, Breckenridge AM (1983). "Clinical pharmacokinetics of oral contraceptive steroids". Clinical Pharmacokinetics. 8 (2): 95–136. doi:10.2165/00003088-198308020-00001. PMID   6342899. S2CID   43298472.
  92. ↑ Fotherby K (1974). "Metabolism of synthetic steroids by animals and man". Acta Endocrinologica. Supplementum. 185: 119–147. doi:10.1530/acta.0.075s119. PMID   4206183.
  93. ↑ 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): 344–353. doi:10.1080/13697130701380434. PMID   17653961. S2CID   20759583.
  94. ↑ 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. PMID   2143719.
  95. 1 2 Schoonen 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. PMID   11162927. S2CID   19797254. [...] 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).
  96. ↑ Chávez BA, Vilchis F, Pérez AE, García GA, Grillasca I, Pérez-Palacios G (January 1985). "Stereospecificity of the intracellular binding of norethisterone and its A-ring reduced metabolites". Journal of Steroid Biochemistry. 22 (1): 121–6. doi: 10.1016/0022-4731(85)90151-7 . PMID   3871879.
  97. ↑ 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. PMID   3090814.
  98. ↑ Lemus AE, Enríquez J, Hernández A, Santillán R, Pérez-Palacios G (February 2009). "Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells". The Journal of Endocrinology. 200 (2): 199–206. doi: 10.1677/JOE-08-0166 . PMID   19008332.
  99. ↑ Scarsi KK, Darin KM, Chappell CA, Nitz SM, Lamorde M (November 2016). "Drug-Drug Interactions, Effectiveness, and Safety of Hormonal Contraceptives in Women Living with HIV". Drug Safety. 39 (11): 1053–1072. doi:10.1007/s40264-016-0452-7. PMC   5048570 . PMID   27562873.
  100. ↑ DeGroot LJ (2001). Endocrinology. W.B. Saunders Co. p. 2617. ISBN   978-0-7216-7843-6.
  101. 1 2 3 4 5 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 886–. ISBN   978-1-4757-2085-3. Archived from the original on 10 January 2023. Retrieved 5 October 2016.
  102. ↑ 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. PMID   22457429. S2CID   2882899.
  103. ↑ Shoupe D, Haseltine FP (6 December 2012). Contraception. Springer Science & Business Media. pp. 112–. ISBN   978-1-4612-2730-4.
  104. ↑ Ryan KJ (1999). Kistner's Gynecology and Women's Health. Mosby. p. 292. ISBN   978-0-323-00201-1.
  105. ↑ 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. PMID   2256526.
  106. ↑ 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. PMID   20851224.
  107. ↑ 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. PMID   3543501. Similar androgenic potential is inherent to norethisterone and its prodrugs (norethisterone acetate, ethynodiol diacetate, lynestrenol, norethynodrel, quingestanol [acetate]).
  108. 1 2 Frank B. Colton, U.S. Patent 2,655,518 (1952 to Searle & Co).
  109. ↑ 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): 2477–2479. doi:10.1021/ja01592a037.
  110. ↑ Ueberwasser H, Heusler K, Kalvoda J, Meystre C, Wieland P, Anner G, Wettstein A (1963). "19-Norsteroide II. Ein einfaches Herstellungsverfahren für 19-Norandrostan-Derivate. über Steroide, 193. Mitteilung". Helvetica Chimica Acta. 46: 344–352. doi:10.1002/hlca.19630460135.
  111. ↑ Onken D, Heublein D (January 1970). "[Ethinylated steroids]". Die Pharmazie. 25 (1): 3–9. PMID   4914401.
  112. ↑ U.S. Patent 2,744,122
  113. ↑ U.S. Patent 2,774,777
  114. ↑ Bullough VL (2001). Encyclopedia of Birth Control. ABC-CLIO. pp. 145–. ISBN   978-1-57607-181-6. Archived from the original on 10 January 2023. Retrieved 27 November 2016.
  115. ↑ Moskowitz EH, Jennings B (13 September 1996). Coerced Contraception?: Moral and Policy Challenges of Long Acting Birth Control. Georgetown University Press. pp. 40–. ISBN   978-1-58901-807-5.
  116. ↑ Nieschlag E (November 2010). "Clinical trials in male hormonal contraception" (PDF). Contraception. 82 (5): 457–70. doi:10.1016/j.contraception.2010.03.020. PMID   20933120. Archived (PDF) from the original on 5 December 2020. Retrieved 28 December 2018.
  117. ↑ 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: 470–493. doi:10.1017/CBO9781139003353.023. ISBN   9781139003353.
  118. ↑ Benagiano G, Primiero FM (June 1983). "Long acting contraceptives. Present status". Drugs. 25 (6): 570–609. doi:10.2165/00003495-198325060-00003. PMID   6223801. S2CID   45898359.

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