Noretynodrel was introduced for medical use in 1957.[8] It was specifically approved at this time in combination with mestranol for the treatment of gynecological and menstrual disorders.[8] Subsequently, in 1960, this formulation was approved for use as a birth control pill.[8][14] It was the first birth control pill to be introduced, and was followed by birth control pills containing norethisterone and other progestins shortly thereafter.[8][14][15] Due to its nature as a relatively weak progestogen, noretynodrel is no longer used in medicine.[10] As such, it is no longer marketed.[6][16]
No adverse effects have been observed in breastfeeding infants whose mothers were treated with noretynodrel.[6] Because of this, the American Academy of Pediatrics has considered noretynodrel to be usually compatible with breastfeeding.[6]
Noretynodrel is closely related to norethisterone and tibolone, which are the δ4-isomer and the 7α-methyl derivative of noretynodrel, respectively.[2][21] It is metabolized in a very similar manner to tibolone, whereas the metabolism of norethisterone differs.[2] Both noretynodrel and tibolone are transformed into 3α- and 3β-hydroxylated metabolites and a δ4-isomer metabolite (in the case of noretynodrel, this being norethisterone), whereas norethisterone is not 3α- or 3β-hydroxylated (and of course does not form a δ4-isomer metabolite).[2][21] The major metabolites of noretynodrel are 3α-hydroxynoretynodrel and to a lesser extent 3β-hydroxynoretynodrel, formed respectively by 3α- and 3β-hydroxysteroid dehydrogenases (AKR1C1–4), while the δ4-isomer norethisterone is a minor metabolite formed in small amounts.[2]
Tibolone is considered to be a prodrug of both its 3α- and 3β-hydroxylated and δ4-isomerized metabolites.[2] Noretynodrel is also thought to be a prodrug, as it is rapidly metabolized and cleared from circulation and shows very weak relative affinity for the progesterone receptor (PR), although it appears to form norethisterone in only minor quantities.[2][5][13]
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, E2 for the ERTooltip estrogen receptor, DEXATooltip dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, DHTTooltip dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Sources: See template.
Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the PRTooltip progesterone receptor, metribolone for the ARTooltip androgen receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, aldosterone for the MRTooltip mineralocorticoid receptor, dihydrotestosterone for SHBGTooltip sex hormone-binding globulin, and cortisol for CBGTooltip Corticosteroid-binding globulin. Footnotes:a = Active or inactive metabolite, prodrug, or neither of norethisterone. Sources: See template.
Progestogenic activity
Noretynodrel is a relatively weak progestogen, with only about one-tenth of the progestogenic activity of norethisterone.[10] The ovulation-inhibiting dosage of noretynodrel is 4.0 mg/day, relative to 0.4 mg/day in the case of norethisterone.[1] Conversely, the endometrial transformation dosage of noretynodrel is 150 mg per cycle, relative to 120 mg per cycle for norethisterone.[1] In terms of the PR, noretynodrel possesses only about 6 to 19% of the affinity of norethisterone for the PRA, whereas the affinity of the two drugs for the PRB is similar (noretynodrel possesses 94% of the affinity of norethisterone for the PRB).[21] Tibolone and the δ4-isomer metabolite of tibolone have similar affinity for the PRs as noretynodrel and norethisterone, respectively, whereas the 3α- and 3β-hydroxylated metabolites of tibolone are virtually devoid of affinity for the PRs.[21] Since the structurally related androgen/anabolic steroidtrestolone (7α-methyl-19-nortestosterone) is known to be a potent progestogen,[22] suggesting that a 7α-methyl substitution does not interfere with progestogenic activity, 3α- and 3β-hydroxynoretynodrel likely are devoid of affinity for the PR similarly to the 3α- and 3β-hydroxylated metabolites of tibolone.[21]
Androgenic activity
Noretynodrel has been said to possess no or only very weak androgenic activity.[8][11][12] This is in contrast to norethisterone, which shows mild but significant androgenicity.[8][3] Relative to norethisterone, noretynodrel has 45 to 81% lower affinity for the androgen receptor (AR).[21] In accordance, no androgenic effects (such as hirsutism, clitoral enlargement, or voice changes) have been observed with noretynodrel even when used in large dosages (e.g., 60 mg/day) for prolonged periods of time (9–12 months) in the treatment of women with endometriosis.[23] Additionally, noretynodrel has not been found to virilize female fetuses, in contrast to many other testosterone-derived progestins including ethisterone, norethisterone, and norethisterone acetate.[24] However, at least one case of pseudohermaphroditism (virilized genitalia) has been observed that may have been due to noretynodrel.[20] The δ4-isomer metabolite of tibolone shows dramatically and disproportionately increased affinity for the AR relative to norethisterone and noretynodrel (5.7- to 18.5-fold greater than that of norethisterone), indicating that the 7α-methyl group of tibolone markedly increases its androgenic activity and is responsible for the greater androgenic effects of tibolone relative to noretynodrel.[21]
Estrogenic activity
Noretynodrel, unlike most progestins but similarly to etynodiol diacetate, has some estrogenic activity.[11] Relative to other 19-nortestosterone progestins, noretynodrel is said to possess much stronger estrogenic activity.[5] In the Allen–Doisy test of estrogenicity in animals, noretynodrel has been reported to possess 100-fold greater estrogenic activity than norethisterone.[3] Whereas norethisterone has virtually no affinity for the estrogen receptors (ERs), noretynodrel shows some, albeit very weak affinity for both the ERα and the ERβ (in terms of relative binding affinity, 0.7% and 0.22% of that of estradiol, respectively).[21][25] The estrogenic activity of 3α- and 3β-hydroxynoretynodrel has never been assessed.[2] However, while tibolone shows similar affinity for the ERs as noretynodrel, the 3α- and 3β-hydroxylated metabolites of tibolone have several-fold increased affinity for the ERs.[2][21] As such, the 3α- and 3β-hydroxylated metabolites of noretynodrel may also show increased estrogenic activity, and this may account for the known estrogenic effects of noretynodrel.[2][21]
The δ4-isomer of tibolone, similarly to norethisterone, is virtually devoid of affinity for the ERs.[21] Neither tibolone nor its metabolites are aromatized, whereas trestolone is readily aromatized similarly to testosterone and 19-nortestosterone, and for these reasons, it is unlikely that noretynodrel or its metabolites, aside from norethisterone, are aromatized either.[26] As such, aromatization likely does not play a role in the estrogenic activity of tibolone or noretynodrel.[26] However, controversy on this matter exists, and other researchers have suggested that tibolone and noretynodrel may be aromatized in small amounts to highly potent estrogens (ethinylestradiol and its 7α-methyl derivative, respectively).[27][28]
Noretynodrel, also known as 17α-ethynyl-δ5(10)-19-nortestosterone or as 17α-ethynylestr-5(10)-en-17β-ol-3-one, is a syntheticestranesteroid and a derivative of testosterone.[18][31] It is specifically a derivative of testosterone that has been ethynylated at the C17α position, demethylated at the C19 position, and dehydrogenated (i.e., has a double bond) between the C5 and C10 positions).[18][31] As such, noretynodrel is also a combined derivative of nandrolone (19-nortestosterone) and ethisterone (17α-ethynyltestosterone).[18][31] In addition, it is an isomer of norethisterone (17α-ethynyl-19-nortestosterone) in which the C4 double bond has been replaced with a double bond between the C5 and C10 positions.[18][31] For this reason, noretynodrel is also known as 5(10)-norethisterone.[18][31] Few other 19-nortestosterone progestins share the C5(10) double bond of noretynodrel, but examples of a couple that do include tibolone, the C7α methyl derivative of noretynodrel (i.e., 7α-methylnoretynodrel), and norgesterone, the C17α vinylanalogue of noretynodrel.[18][31]
Noretynodrel was first synthesized by Frank B. Colton of G. D. Searle & Company in 1952, and this was preceded by the synthesis of norethisterone by Luis E. Miramontes and Carl Djerassi of Syntex in 1951.[8] In 1957, both noretynodrel and norethisterone, in combination with mestranol, were approved in the United States for the treatment of menstrual disorders.[15] In 1960, noretynodrel, in combination with mestranol (as Enovid), was introduced in the United States as the first oral contraceptive, and the combination of norethisterone and mestranol followed in 1963 as the second oral contraceptive to be introduced.[15] In 1988, Enovid, along with other oral contraceptives containing high doses of estrogen, was discontinued.[32][33]
Noretynodrel was first studied in the treatment of endometriosis in 1961 and was the first progestin to be investigated for the treatment of the condition.[17]
Society and culture
Generic names
Noretynodrel is the INNTooltip International Nonproprietary Name of the drug while norethynodrel is its USANTooltip United States Adopted Name and BANTooltip British Approved Name.[6][16][18][31] It is also known by its developmental code name SC-4642.[6][16][18][31]
Brand names
Noretynodrel has been marketed by alone under the brand names Enidrel, Orgametril, and Previson and in combination with mestranol under the brand names Conovid, Conovid E, Enavid, Enavid E, Enovid, Enovid E,
Norolen, and Singestol.[9]
Availability
Noretynodrel is no longer available in any formulation in the U.S.,[34] nor does it appear to still be marketed in any other country.[16][18]
^ abcdeStanczyk FZ (September 2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Reviews in Endocrine & Metabolic Disorders. 3 (3): 211–224. doi:10.1023/A:1020072325818. PMID12215716. S2CID27018468. Although there is no convincing evidence for the in vivo transformation of norethynodrel to norethindrone, data from receptor-binding tests and bioassays suggest that norethynodrel is also a prodrug.
^ abKorn GW (1961). "The use of norethynodrel (enovid) in clinical practice". Can Med Assoc J. 84 (11): 584–7. PMC1939348. PMID13753182. Pseudohermaphroditism should not be a problem in these patients as it appears that norethynodrel does not possess androgenic properties, but it is believed that Wilkins has now found one such case in a patient who has been on norethynodrel therapy.
^Beri R, Kumar N, Savage T, Benalcazar L, Sundaram K (November 1998). "Estrogenic and progestational activity of 7alpha-methyl-19-nortestosterone, a synthetic androgen". The Journal of Steroid Biochemistry and Molecular Biology. 67 (3): 275–283. doi:10.1016/S0960-0760(98)00114-9. PMID9879986. S2CID21302338.
^Kistner RW (1964). "Steroid compounds with progestational activity". Postgrad Med. 35 (3): 225–32. doi:10.1080/00325481.1964.11695038. PMID14129897. This difference is important clinically since no androgenic effects (hirsutism, enlarged clitoris, voice change) have been reported even with large dosages of norethynodrel (60 mg. daily) continued from 9 to 12 months in patients with endometriosis.
^Simpson JL, Kaufman RH (1998). "Fetal effects of estrogens, progestogens and diethylstilbestrol". In Fraser IS (ed.). Estrogens and Progestogens in Clinical Practice (3rd ed.). London: Churchill Livingstone. pp. 533–53. ISBN978-0-443-04706-0.
^ abde Gooyer ME, Oppers-Tiemissen HM, Leysen D, Verheul HA, Kloosterboer HJ (March 2003). "Tibolone is not converted by human aromatase to 7alpha-methyl-17alpha-ethynylestradiol (7alpha-MEE): analyses with sensitive bioassays for estrogens and androgens and with LC-MSMS". Steroids. 68 (3): 235–243. doi:10.1016/S0039-128X(02)00184-8. PMID12628686. S2CID29486350.
^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. PMID17653961. S2CID20759583.
