Medrogestone

Not to be confused with medroxyprogesterone acetate.

Medrogestone

Systematic (IUPAC) name
6,17-dimethylpregna-4,6-diene-3,20-dione
Clinical data
Pregnancy category	X
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	100%
Metabolism	Hydroxylation and glucuronidation
Biological half-life	4 to 5 hours
Excretion	Renal and fecal, as metabolites
Identifiers
CAS Number	977-79-7
ATC code	G03DB03 (WHO) G03FB07 (with estrogen)
PubChem	CID: 9949848
ChemSpider	8125459
UNII	077DN93G5B Y
KEGG	D04885
Chemical data
Formula	C23H32O2
Molecular mass	340.5 g/mol
SMILES O=C4\C=C3\C(=C/[C@@H]1[C@H](CC[C@@]2([C@@](C(=O)C)(CC[C@@H]12)C)C)[C@@]3(C)CC4)C

Medrogestone (INN) (trade names Colpro(ne) by Wyeth and Prothil by Solvay), also known as 6,17α-dimethyl-6-dehydroprogesterone, is a progestin, a synthetic drug with similar effects as progesterone, a hormone involved in the menstrual cycle and pregnancy. As of 2010, it is no longer available in Germany or Austria.

Indications

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.

Contraindications

Intrahepatic cholestasis of pregnancy (acute or in history), vaginal bleeding of unknown origin, and severe diseases of the liver such as tumours are absolute contraindications for medrogestone. 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 foetus in animals and humans. Studies in pregnant rabbits have shown skeletal deformations under 3 mg medrogestone per kilogram body weight but not under 1 mg/kg. Typical therapeutic doses 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 chemically related progestins.

Adverse effects

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

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 not dangerous.

Chemical properties

Medrogestone is a steroid. More specifically, it is a derivative of pregna-4,6-diene structurally related to the progestin chlormadinone acetate and the antiandrogen cyproterone acetate. As is frequently found in other synthetic steroid hormones, medrogestone possesses a lipophilic group at position 6. However, in contrast to chlormadinone acetate and cyproterone acetate or to fluocinolone that contain a chlorine or fluorine respectively at position 6, medrogestone contains a methyl substituent at this position. The methyl in position 17 is unusual for a steroid, as many such drugs carry an oxygen atom in that position.

Pharmacology

Pharmacokinetics

The drug is absorbed quickly and completely from the gut and reaches peak plasma concentrations after about one to four hours. Unlike many other steroids it binds neither to transcortin (corticosteroid-binding globulin, CBG, which binds progesterone) nor to sex hormone-binding globulin (SHBG), but to albumin. Medrogestone itself cannot be excreted. The substance is hydroxylised and glucuronidised in the liver, and the resulting metabolites are eliminated via urine and faeces.

Pharmacodynamics

The profile of medrogestone is similar to the natural hormone progesterone. It has pronounced progestogenic effects and opposes the proliferative effects of estrogen in the utereus, but lacks anabolic, androgenic, estrogenic and corticoid activity. In extremely high doses it is an androgen antagonist (in 2500-fold therapeutic doses) as well as an antigonadotropin.

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.

Synthesis

The oral activity of 17α-methyl progesterone has already been alluded to. This agent, which may well owe this property to the inhibition of metabolism in a manner analogous to the gonadal steroids, 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 on the Melengestrol (acetate) page.

Medrogestone synthesis:

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.

See also

• Demegestone
• Dydrogesterone
• Haloprogesterone
• Proligestone
• Promegestone
• Trengestone
• Trimegestone