Medrogestone

Medical uses

In the past, medrogestone was used in the treatment of endometrial cancer and in some regimens for breast cancer, and, in men, for benign prostatic hyperplasia. It still finds use in the treatment of amenorrhea and as the progestin component in certain forms of menopausal hormone replacement therapy.

Breast disorders

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).

Contraindications

Intrahepatic cholestasis of pregnancy (acute or in history), vaginal bleeding of unknown origin, and severe diseases of the liver such as tumors are absolute contraindications for medrogestone, as are thrombotic events such as thrombophlebitis or stroke. Relative contraindications include a history of jaundice or itching in pregnancy or gestational pemphigoid.

Pregnancy and lactation

Medrogestone is contraindicated during pregnancy because progestogens are associated with risks for the fetus in animals and humans. Studies in pregnant rabbits have shown skeletal deformations under 3 mg/kg medrogestone but not under 1 mg/kg. Typical therapeutic doses of the drug are between 0.1 and 0.25 mg/kg.

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.

Side effects

Medrogestone seldom produces side effects, all of which are typical of progestogens. They include nausea, depression, decreased appetite, headache, and dizziness.

Overdose

The acute toxicity of the drug is low. Overdose causes only harmless side effects such as nausea and vaginal bleeding. 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.

Interactions

Enzyme inducers such as barbiturates, phenylbutazone, phenytoin, ampicillin or tetracyclines are expected to reduce plasma concentrations of medrogestone, but no systematic research has been done.

Pharmacology

Medrogestone is described as a pure progestogen similar in profile to progesterone. In contrast to progesterone however, medrogestone is more potent and is orally active. There is reportedly no information available on the receptor binding of medrogestone at the various steroid hormone receptors. 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 antiandrogen and very weak antimineralocorticoid activity. 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. 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. 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.

Medrogestone has been found to be an inhibitor of 3β-hydroxysteroid dehydrogenase/Δ^5-4 isomerase in vitro, preventing conversion of pregnenolone to progesterone and 17α-hydroxypregnenolone to 17α-hydroxyprogesterone in rat testis preparations, and inhibits the biosynthesis of testosterone in vivo in rats. In addition, similarly to progesterone, medrogestone can inhibit 5α-reductase in vitro in microsomal preparations of skin and prostate. Although their clinical relevance is uncertain, these actions of medrogestone could contribute to its weak antiandrogen activity.

Pharmacokinetics

Upon oral administration, medrogestone is rapidly absorbed, and the bioavailability is nearly 100%. After ingestion of a 10 mg dose of medrogestone, peak circulating concentrations (C_max) of 10–15 ng/mL are achieved. The distribution and elimination half-lives of medrogestone are 4 hours and 35–36 hours, respectively. The drug is largely bound (90%) to albumin, and to only small extents to corticosteroid-binding globulin (3%) and sex hormone-binding globulin (2%). Metabolism is most importantly by hydroxylation.

Chemistry

Medrogestone is also known by the chemical names 6,17α-dimethyl-6-dehydroprogesterone and 6,17α-dimethyl-4,6-pregnadiene-3,20-dione. It is a pregnane steroid and derivative of progesterone and is structurally related to the 17α-hydroxyprogesterone derivatives megestrol acetate and medroxyprogesterone acetate. Medrogestone itself is not a 17α-hydroxyprogesterone derivative and is instead a derivative of 17α-methylprogesterone because it features a methyl group at the C17α position instead of a hydroxy or acetoxy group. In addition to its C17α methyl group, medrogestone possesses a methyl group at the C6 position and a double bond between C6 and C7. The only structural difference between medrogestone and megestrol acetate is the replacement of the C17α acetoxy group with a methyl group.

Synthesis

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 developed in the 1960s and appears to have been marketed since at least 1966.

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.

Availability

Medrogestone has been marketed in the United States and Canada and widely throughout Europe, as well as in Argentina, Hong Kong, and other countries. However, it is no longer available in the United States or many other countries, and is reported to remain marketed only in a few countries including France, Germany, Tunisia, and Egypt.