New progestins

R. Sitruk-Ware

Rockefeller University and Population Council, New York, USA

The progestins have different pharmacologic properties depending upon the parent molecule, usually testosterone or progesterone, from which they are derived. Very small structural changes in the parent molecule may induce considerable differences in the activity of the derivative. The development of new generations of progestins with improved selectivity profiles has been a great challenge. Steroidal and nonsteroidal progesterone receptor agonists have been synthesized as well, although the later are still in a very early stage of development. Several new progestins, which have been synthesized in the last decade, may be considered fourth-generation progestins. These include dienogest, drospirenone, Nestorone®, nomegestrol acetate, and trimegestone. The fourth- generation progestins have been designed to have no androgenic or estrogenic actions and to be closer in activity to the physiological hormone progesterone. Drospirenone differs from classic progestins as it is derived from spirolactone. It is essentially an antimineralocorticoid steroid with no androgenic effect but a partial antiandrogenic effect. The antiovulatory potency of the different progestins varies. All progestins achieve the expected effect, but the less active compounds require higher doses to exert antigonadotropic effect. Trimegestone and Nestorone are the most potent progestins synthesized to date, followed by two of the gonanes: keto-desogestrel and levonorgestrel. The new molecules drospirenone and dienogest have less potent antigonadotropic activity and higher doses are required to suppress ovulation. Levonorgestrel, etonogestrel and Nestorone have been incorporated into long-acting delivery systems for use as long-term progestin-only contraceptives.

Nestorone, has high progestational activity yet is not active orally; it must be administered parenterally due to its rapid hepatic metabolism. The anti-ovulatory potency of Nestorone (s.c) is twice greater than levonorgestrel. Due to its high potency, very low doses of Nestorone may be delivered via long-term sustained-release delivery systems. Nestorone, 75 or 100 µg per day, released by vaginal ring for 6 to 12 months, has suppressed ovulation with inhibition of follicular maturation in a high percentage of women. A vaginal ring releasing both 150 µg of Nestorone and 15 µg of ethinyl estradiol per day has effectively suppressed ovulation for 13 consecutive cycles. Nestorone has also been used effectively in a single implant for contraception in breastfeeding women and shows promise for use in transdermal systems as a contraceptive or for hormone therapy.

Natural progesterone and some of its derivatives, such as the 19-norprogesterone molecules, and the new molecules drospirenone and dienogest are not androgenic and, therefore, have no negative effect on the lipid profile. The antimineralocorticoid effect of drospirenone leading to a better control of blood pressure is likely to offer potential cardiovascular benefits and further studies with this progestin are warranted. The effects of progestins on breast tissue remain controversial. However, depending on the progestin and the duration of application, cell differentiation and apoptosis may predominate over proliferation. It is still unclear if the currently available progestins are able to bind specifically to the progesterone receptors PR-A or PR-B and whether this is of clinical relevance to breast cell proliferation is unknown. Further research in this direction is warranted.