Medrogestone was described as early as 1963 and was introduced for medical use by at least 1966.[11][12][9] It has mostly been discontinued and remains available only in a few countries.[13][7]
Cyclic treatment with low-dose (10 mg/day) medrogestone has been found to be effective in the treatment of fibrocystic breast changes and associated mastodynia (breast pain).[16]
Medrogestone is contraindicated during pregnancy because progestogens are associated with risks for the fetus in animals and humans.[19]
It is not known whether medrogestone passes into breast milk, but it is to be expected given its lipophilicity and studies with structurally related progestins.[19]
The acute toxicity of the drug is low. Overdose causes only harmless side effects such as nausea and vaginal bleeding.[19] The LD50 has been found to range between 500 mg/kg in dogs and over 3000 mg/kg in rats. Chronic toxicity has been examined in animals, but nothing but the typical adverse effects of progestogens, and reduction of prostatic weight in rhesus monkeys, have been found. Accidental intake of the drug, including in children, is normally not dangerous. Intake of extremely large doses, or intake by patients with epilepsy or impaired kidney function, can result in central nervous cramping.[18]
Medrogestone is described as a pure progestogen similar in profile to progesterone.[9][20] In contrast to progesterone however, medrogestone is more potent and is orally active.[9] There is reportedly no information available on the receptor binding of medrogestone at the various steroid hormone receptors.[2] However, based on animal research (e.g., the Clauberg test and other assays), medrogestone appears to be a potent progestogen, devoid of androgenic, estrogenic, and glucocorticoid activity, but with weak antiandrogenic and very weak antimineralocorticoid activity.[9] Accordingly, no evidence of androgenic or glucocorticoid activity, including effects on the estrogen-induced increase in triglycerides and HDL cholesterol and adrenal suppression, were observed in clinical studies.[2][21] However, in a very high-dosage (100 mg/day for 6 months) study of medrogestone for benign prostatic hyperplasia, a hyperglycemic effect and changes in plasma cortisol levels were observed and considered likely to be secondary to glucocorticoid activity, and decreased sodium levels were also observed and attributed to antimineralocorticoid activity.[10] In any case, under normal circumstances (i.e., at typical clinical dosages), medrogestone is described as a progestogen and antigonadotropin and weak antiandrogen in humans without other clinically relevant activity.[1][2]
The oral activity of 17α-methylprogesterone has already been alluded to. This compound, which may well owe this property to the inhibition of metabolism in a manner analogous to synthetic androgens and estrogens, is not sufficiently potent in its own right to constitute a useful drug. Incorporation of known potentiating modifications yields the commercially available oral progestin medrogestone (4).
The preparation of the 6-methyl-16-dehydropregnenolone acetate (1) precursor is covered here.
Reduction of the conjugated 16,17 double bond of 6-methyl-16-dehydropregnenolone acetate by means of lithium in liquid ammonia leads initially to the 17 enolate ion; this is alkylated in situ with methyl iodide. The now-familiar steric control asserts itself to afford the 17α-methyl compound,.
The acetate group is lost as a side reaction. In an interesting modification on the usual scheme, (3) is treated with aluminum isopropoxide and a ketone (Oppenauer conditions) as well as chloranil in a single reaction; the 4,6-diene, (medrogesterone), is obtained directly from this step.
History
Medrogestone was first described as early as 1963 and appears to have been marketed since at least 1966.[11][12][9]
Society and culture
Generic names
Medrogestone is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, and BANTooltip British Approved Name.[11][13][6][7] It is also known by its developmental code names AY-62022, NSC-123018, and R-13615.[11][13][6][7]
Brand names
Medrogestone is or has been marketed under the brand names Ayerluton, Colpro, Colpron, Colprone, Etogyn, Prothil, and, in combination with conjugated estrogens, Presomen.[11][13][7]
^ abStanczyk FZ (2002). "Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception". Reviews in Endocrine & Metabolic Disorders. 3 (3): 211–24. doi:10.1023/A:1020072325818. PMID12215716. S2CID27018468. Medrogestone The pharmacokinetics of medrogestone (5 mg dose) was studied in 12 Chinese young males who received a single oral dose of this drug [20]. The mean ± standard deviation Cmax was 8.21 ± 2.78 ng/ml and Tmax was 2.57 ± 1.02; the half-life of elimination was 34.9 ± 17.0 hours.
^Sweetman SC, ed. (2009). "Sex hormones and their modulators". Martindale: the complete drug reference (36th ed.). London: Pharmaceutical Press. p. 2113. ISBN978-0-85369-840-1.
^Winkler UH, Schindler AE, Brinkmann US, Ebert C, Oberhoff C (2001). "Cyclic progestin therapy for the management of mastopathy and mastodynia". Gynecol. Endocrinol. 15 (Suppl 6): 37–43. doi:10.1080/gye.15.s6.37.43. PMID12227885. S2CID27589741.
^Gourdy P, Bachelot A, Catteau-Jonard S, Chabbert-Buffet N, Christin-Maître S, Conard J, Fredenrich A, Gompel A, Lamiche-Lorenzini F, Moreau C, Plu-Bureau G, Vambergue A, Vergès B, Kerlan V (November 2012). "Hormonal contraception in women at risk of vascular and metabolic disorders: guidelines of the French Society of Endocrinology". Ann. Endocrinol. (Paris). 73 (5): 469–87. doi:10.1016/j.ando.2012.09.001. PMID23078975.
^ abcd"Fachinformation zu Colpro" [Colpro summary of product characteristics] (in German). Open Drug Database. November 1997. Archived from the original on 9 December 2009. Retrieved 15 August 2010.
^Carter WF, Faucher GL, Greenblatt RB (July 1964). "Evaluation of a new progestational agent, 6, 17α-dimethyl-6-dehydroprogesterone". American Journal of Obstetrics and Gynecology. 89 (5): 635–641. doi:10.1016/0002-9378(64)90158-9. PMID14176912.
^Givner ML, Dvornik D (September 1972). "Inhibition of testosterone biosynthesis by medrogestone". Experientia. 28 (9): 1105–1106. doi:10.1007/BF01918702. PMID4269193. S2CID21037270. In vitro, medrogestone blocks the synthesis of hormones in the gonads through inhibition of 3β-hydroxysteroid Δ4,5 isomerase. In vivo, medrogestone reduced testosterone levels in the rat testis.
^French F (6 December 2012). Hormonal Regulation of Spermatogenesis. Springer Science & Business Media. pp. 159–. ISBN978-1-4613-4440-7. Consequently, we infused Medrogestone into the perfused testis since Medrogestone is a potent inhibitor of the Δ5-3-ketosteroid isomerase enzyme (52) and should therefore inhibit testosterone biosynthesis.
^Canadian Federation of Biological Societies. Proceedings of the Annual Meeting. With a rat testicular enzyme preparation, Medrogestone (lxlO'^M) inhibited the conversion of pregnenolone to progesterone (92%) and 17- hydroxyprogesterone (59%); and 17-hydroxy- pregnenolone to 17- hydroxyprogesterone (83%). With a ...
^Benign Prostatic Hypertrophy. Springer Science & Business Media. 6 December 2012. pp. 266–. ISBN978-1-4612-5476-8. medrogestone has marked antiandrogenic activity as well, although not as much as flutamide or cyproterone acetate.
^Deghenghi R, Revesz C, Gaudry R (May 1963). "New Synthesis and Structure Activity Relationship in the 17-Alkylated Progesterone Series". Journal of Medicinal Chemistry. 6 (3): 301–4. doi:10.1021/jm00339a019. PMID14185989.