New knowledge in the physiology of hormonal contraceptives

Abstract

The present review addresses some of the new knowledge regarding the physiology and mechanisms of action of hormonal contraceptives. Specific topics that are discussed include oral contraceptives, intravaginal rings, long-term contraception, gonadotropin-releasing hormone agonists and antagonists, and antiprogestins. It has been shown that in combined oral contraceptives, lower doses of the new progestins (desogestrel, norgestimate, and gestodene) can be used to inhibit ovulation compared with norethindrone and levonorgestrel. In addition, lower doses of ethinyl estradiol are now used with progestins. Estrogen has been added to intravaginal rings containing levonorgestrel or norethindrone acetate to reduce frequency of bleeding. A new ring containing 3-keto-desogestrel is under evaluation. The use of subdermal implants containing levonorgestrel is currently a popular and highly effective method of long-term contraception. Studies show that gonadotropin-releasing hormone agonists and antagonists can provide ovarian suppression, and antiprogestins such as RU486 effectively block the midcycle gonadotropin surge. These and other novel methods of hormonal contraception are still years away from general use.

PIP: The actions of progestins largely determine the contraceptive efficacy of hormonal contraceptives (e.g., oral contraceptives [OCs]), while the estrogenic component primarily controls bleeding. Progestin contraceptive agents are derived from progesterone and testosterone. Little is known about the metabolism of norethindrone (NET), levonorgestrel (LNG), and their derivatives in OC users. The bioavailability of gestodene, LNG, 3-keto-desogestrel, and NET is about 100%, about 100%, 75%, and 65%, respectively. The mean binding of sex hormone binding globulin is 75% for gestodene, 50% for LNG, and 30-35% for 3-keto-desogestrel and NET. LNG and its derivatives appear to have a progestational potency 5-10 times that of NET. The new progestins inhibit ovulation at lower doses than do LNG and NET. Low doses of progestins thicken cervical mucus, inhibit spinnbarkeit, prevent sperm penetration, reduce the karyopyknotic index, and suppress endometrial glands. The bioavailability of ethinyl estradiol (EE2) is 40-50%. Oral EE2 is more than 200 times more potent than estradiol. Progestins and estrogens work synergistically to inhibit ovulation. They interfere with release of gonadotropin releasing hormone (GnRH) from the hypothalamus and suppress gonadotropin-producing cells of the pituitary. Progestin only and combined steroid-releasing vaginal rings are an effective method that the user can initiate and terminate herself. Problems include breakthrough bleeding, expulsion, and interference with coitus. Injectable contraceptives (depot medroxyprogesterone acetate) and subdermal contraceptive implants (levonorgestrel) are effective, long acting methods. GnRH agonists and antagonists can suppress ovulation, but often cause hypoestrogenism. They cannot be delivered orally. RU-486, an antiprogestin, interrupts early pregnancy.