Lynestrenol

Medical uses

Lynestrenol is used as a component of oral contraceptives in combination with an estrogen and is used in the treatment of gynecological disorders such as menstrual disorders.

Side effects

Main article: Norethisterone#Side effects, Progestin#Side effects

Pharmacology

Lynestrenol itself does not bind to the progesterone receptor and is inactive as a progestogen. It is a prodrug, and upon oral administration, is rapidly and almost completely converted into norethisterone, a potent progestogen, in the liver during first-pass metabolism. No other metabolites besides norethisterone are formed from lynestrenol. As such, its pharmacological activity is essentially identical to that of norethisterone. The conversion of lynestrenol into norethisterone is catalyzed by CYP2C9 (28.0%), CYP2C19 (49.8%), and CYP3A4 (20.4%), while other cytochrome P450 enzymes are each responsible for no more than 1.0% of the total conversion. It appears that lynestrenol first undergoes hydroxylation of the C3 position, forming etynodiol as an intermediate, followed by oxygenation of the hydroxyl group to form norethisterone.

The peak blood levels are reached within 2 to 4 hours after oral administration, 97% of the administered dose being bound to plasma proteins. Lynestrenol and its metabolites are predominantly excreted in urine, less in feces, active metabolite norethisterone elimination half-life being 16 or 17 hours.

The pharmacokinetics of lynestrenol have been reviewed.

Chemistry

Lynestrenol, also known as 17α-ethynyl-3-desoxy-19-nortestosterone or as 17α-ethynylestr-4-en-17β-ol, is a synthetic estrane steroid and a derivative of 19-nortestosterone. It differs from norethisterone (17α-ethynyl-19-nortestosterone) and etynodiol (17α-ethynyl-3-deketo-3β-hydroxy-19-nortestosterone) only by the lack of a ketone group and hydroxyl group at the C3 position, respectively.

Synthesis

Chemical syntheses of lynestrenol have been published.

In another approach to analogues, nortestosterone (1) is first converted to the dithioketal (2) by treatment with dithioglycol in the presence of boron trifluoride. (The mild conditions of this reaction compared to those usually employed in preparing the oxygen ketals probably accounts for the double bond remaining at 4,5). Treatment of this derivative with sodium in liquid ammonia affords the 3-desoxy analog (3). Oxidation by means of Jones reagent followed by ethynylation of the 17-ketone leads to the orally active progestin (6).

History

Lynestrenol was developed by the Dutch pharmaceutical company Organon in the late 1950s and was introduced for medical use in 1961. It received a Dutch patent for lynestrenol in 1957, and lynestrenol subsequently became a component of Lyndiol, the first Dutch contraceptive pill, in 1962. Around this time, pre- and post-marketing clinical trials of lynestrenol were conducted, and in 1965, a study consisting of 200 Dutch women was published. Lynestrenol was approved, in the United Kingdom, in combination with mestranol in 1963 and in combination with ethinylestradiol in 1969.

Society and culture

Generic names

Lynestrenol is the generic name of the drug and its , , , and , while lynestrénol is its and linestrenolo is its . Lynoestrenol was formerly the of the drug, but it was eventually changed to lynestrenol.

Brand names

Lynestrenol has been marketed alone as Exluton, Exlutona, and Orgametril, in combination with mestranol as Anacyclin, Lyndiol, Lyndiol 1, Lyndiol 2.5, Nonovul, and Noracycline, and in combination with ethinylestradiol as Anacyclin, Fysioquens, Minilyn, and Ministat, among other formulations and brand names.

Availability

Lynestrenol has been used mainly in Europe and is also marketed elsewhere throughout the world. The drug was never marketed in the United States.

References

References

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