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| Clinical data | |
|---|---|
| Trade names | Colprone, others |
| Other names | Metrogestone; Medrogesterone; AY-62022, NSC-123018, R-13615; 6,17α-Dimethyl-6-dehydroprogesterone; 6,17α-Dimethyl-4,6-pregnadiene-3,20-dione |
| Pregnancy category |
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| Routes of administration | By mouth |
| Drug class | Progestogen;Progestin |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | Nearly 100%[1][2] |
| Protein binding | 95%:Albumin (90%),CBGTooltip corticosteroid-binding globulin (3%),SHBGTooltip sex hormone-binding globulin (2%)[2] |
| Metabolism | Hepatic (hydroxylation)[1] |
| Eliminationhalf-life | 35–36 hours[3][4][5] |
| Identifiers | |
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| CAS Number | |
| PubChemCID | |
| DrugBank | |
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| UNII | |
| KEGG | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.012.323 |
| Chemical and physical data | |
| Formula | C23H32O2 |
| Molar mass | 340.507 g·mol−1 |
| 3D model (JSmol) | |
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Medrogestone, sold under the brand nameColprone among others, is aprogestin medication which has been used inmenopausal hormone therapy and in the treatment ofgynecological disorders.[6][2] It is available both alone and in combination with anestrogen.[7] It is takenby mouth.[2][8]
Medrogestone is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[2] It has weakantiandrogenic,glucocorticoid, andantimineralocorticoid activity and no other importanthormonal activity.[2][1][9][10] Due to its progestogenic activity, medrogestone hasantigonadotropic effects.[1][2]
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]
In the past, medrogestone was used in the treatment ofendometrial cancer and in some regimens forbreast cancer, and, in men, forbenign prostatic hyperplasia. It still finds use in the treatment ofamenorrhea[14] and as the progestin component in certain forms ofmenopausal hormone therapy.[15]
Cyclic treatment with low-dose (10 mg/day) medrogestone has been found to be effective in the treatment offibrocystic breast changes and associatedmastodynia (breast pain).[16]
Medrogestone is used as a form ofprogestogen-only birth control, although it is not specifically licensed as such.[17]
Intrahepatic cholestasis of pregnancy (acute or in history),vaginal bleeding of unknown origin, and severe diseases of theliver such astumors are absolutecontraindications for medrogestone, as arethrombotic events such asthrombophlebitis orstroke.[18]
Medrogestone is contraindicated duringpregnancy because progestogens are associated with risks for thefetus in animals and humans.[19]
It is not known whether medrogestone passes intobreast milk, but it is to be expected given itslipophilicity and studies with structurally related progestins.[19]
Medrogestone seldom producesside effects, all of which are typical of progestogens. They includenausea,depression.[18]
Theacute toxicity of the drug is low.Overdose causes only harmless side effects such as nausea andvaginal bleeding.[19] TheLD50 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 ofprostatic weight inrhesus 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 withepilepsy orimpaired kidney function, can result in central nervouscramping.[18]
Enzyme inducers such asbarbiturates,phenylbutazone,phenytoin,ampicillin ortetracyclines are expected to reduce plasma concentrations of medrogestone, but no systematic research has been done.[19]
Medrogestone is described as a pureprogestogen similar in profile toprogesterone.[9][20] In contrast to progesterone however, medrogestone is more potent and is orally active.[9] There is reportedly no information available on thereceptor binding of medrogestone at the varioussteroid hormone receptors.[2] However, based onanimal research (e.g., theClauberg test and otherassays), medrogestone appears to be a potent progestogen, devoid ofandrogenic,estrogenic, andglucocorticoid activity, but with weakantiandrogenic and very weakantimineralocorticoid activity.[9] Accordingly, no evidence of androgenic or glucocorticoid activity, including effects on the estrogen-induced increase intriglycerides andHDL cholesterol andadrenal suppression, were observed in clinical studies.[2][21] However, in a very high-dosage (100 mg/day for 6 months) study of medrogestone forbenign prostatic hyperplasia, ahyperglycemic effect and changes in plasmacortisol levels were observed and considered likely to be secondary to glucocorticoid activity, and decreased sodium levels were also observed and attributed toantimineralocorticoid activity.[10] In any case, under normal circumstances (i.e., at typical clinical dosages), medrogestone is described as a progestogen andantigonadotropin and weak antiandrogen in humans without other clinically relevant activity.[1][2]
Medrogestone has been found to be aninhibitor of3β-hydroxysteroid dehydrogenase/Δ5-4 isomerasein vitro, preventing conversion ofpregnenolone toprogesterone and17α-hydroxypregnenolone to17α-hydroxyprogesterone in rattestis preparations, and inhibits thebiosynthesis oftestosteronein vivo in rats.[22][23][24] In addition, similarly to progesterone, medrogestone can inhibit5α-reductasein vitro inmicrosomal preparations ofskin andprostate.[25] Although their clinical relevance is uncertain, these actions of medrogestone could contribute to its weak antiandrogen activity.[26]
Uponoral administration, medrogestone is rapidlyabsorbed, and thebioavailability is nearly 100%.[1][2] After ingestion of a 10 mg dose of medrogestone, peak circulating concentrations (Cmax) of 10–15 ng/mL are achieved.[2] Thedistribution andelimination half-lives of medrogestone are 4 hours and 35–36 hours, respectively.[2][3][4] The drug is largely bound (90%) toalbumin, and to only small extents tocorticosteroid-binding globulin (3%) andsex hormone-binding globulin (2%).[2] Themetabolism of medrogestone is most importantly byhydroxylation.[1][2]
Medrogestone, also known as 6,17α-dimethyl-6-dehydroprogesterone or as 6,17α-dimethyl-4,6-pregnadiene-3,20-dione, is asyntheticpregnanesteroid and aderivative ofprogesterone. It is structurally related to the17α-hydroxyprogesterone derivativesmegestrol acetate andmedroxyprogesterone acetate.[1][2] Medrogestone itself is not a 17α-hydroxyprogesterone derivative and is instead a derivative of17α-methylprogesterone.[1][2] This is because it features amethyl group at the C17α position instead of ahydroxy oracetoxy group.[1][2] In addition to its C17α methyl group, medrogestone possesses a methyl group at the C6 position and adouble bond between the C6 and C7 positions.[1] The only structural difference between medrogestone and megestrol acetate is the replacement of the C17α acetoxy group with a methyl group.[11][13][7]
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 coveredhere.
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 withaluminum isopropoxide and a ketone (Oppenauer conditions) as well aschloranil in a single reaction; the 4,6-diene, (medrogesterone), is obtained directly from this step.
Medrogestone was first described as early as 1963 and appears to have been marketed since at least 1966.[11][12][9]
Medrogestone is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name, andBANTooltip British Approved Name.[11][13][6][7] It is also known by its developmental code namesAY-62022,NSC-123018, andR-13615.[11][13][6][7]
Medrogestone is or has been marketed under the brand names Ayerluton,Colpro,Colpron,Colprone, Etogyn, Prothil, and, in combination withconjugated estrogens,Presomen.[11][13][7]
Medrogestone has been marketed in theUnited States[9] andCanada and widely throughoutEurope, as well as inArgentina,Hong Kong, and other countries.[13] However, it is no longer available in theUnited States[28] or many other countries, and is reported to remain marketed only in a few countries includingFrance,Germany,Tunisia, andEgypt.[7]
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.
The natural preparations of P4 include progesterone, dydrogesterone, and medrogestone.
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.
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.
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 ...
Pharmacologic doses of medrogestone can inhibit 5a reduction of testosterone by microsomal preparations from the skin and the prostate.
medrogestone has marked antiandrogenic activity as well, although not as much as flutamide or cyproterone acetate.