Journal of Contraception Reproductive Health Care - The European ...

The 8th Congress of The European Society of Contraception Abstracts of Invited Speakers
IS-29
Abstract not available at the time of printing
IS-30
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 1 , 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 mg 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 mg of Nestorone and 15 mg 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.
26 The European Journal of Contraception and Reproductive Health Care