gen-induced increases in a cellular, elastic cervical mucus, and induces a cellular, viscous, scanty mucus that is hostile to sperm. Although the impact of endogenous progesterone on circulating lipids is probably small, synthetic progestins, especially those with androgenic properties, antagonize the enhancement of high-density lipoprotein (HDL) cholesterol levels caused by estrogen. Progesterone is important in the feedback regulation of the gonadotropins, especially luteinizing hormone (LH). Although 1-2 mg of progesterone is secreted daily in the follicular phase, its impact is most clear during the luteal phase, when secretion rates rise to 25 mg/day, and circulating levels may reach 10 mg/ml. At this time, progesterone decreases LH pulse frequency and amplitude. Progesterone may have other central actions: at high doses in lower animals it acts as an anesthetic, and speculation regarding its role in the mood changes of pregnancy and in the premenstrual syndrome are long-standing, but unconfirmed.

Given the importance of progesterone to female reproductive competence, the availability of progesterone antagonists was hailed as providing new venues for exploration of progesterone action and for treatment of progesterone-dependent conditions. Much of this speculation was based on the assumption that progesterone antagonists would simply reverse or inhibit progesterone actions. This assumption has not always been proven to be correct. Thus, a number of assessment issues must be addressed in the design and interpretation of studies to evaluate progesterone antagonists.

Assessment Issues in Evaluating Antiprogestins

First, a dose and route of administration must be chosen to maximize the desired effect. RU 486 has glucocorticoid, androgen, and progesterone antagonist properties and little, if any, agonist activity. It does not react with the mineralocorticoid or estrogen receptor (Baulieu, 1989). Only an oral preparation is available for human administration. RU 486 has a prolonged half-life of about 20 hours when given in this way, probably because of extensive binding to plasma proteins (Kawai et al., 1987). Although antiglucocorticoid effects are seen at single doses of >3 mg/kg, antiprogestational activity is seen at smaller doses, in part allowing for the exploitation of antiprogestin properties without clinical compromise of glucocorticoid status.

Second, the physiologic status of the subject must be considered. The effects of an antiprogestin may differ dramatically in the absence or presence of progesterone or estrogen. Thus, stage of the menstrual cycle, anovulation, and pregnancy might all show differing effects. Also, end points must be chosen to measure efficacy, to evaluate potential



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