Uses of progesterone in clinical practice

Progesterone is the natural progestagen produced by the corpus luteum durin g the luteal phase. It is absorbed when administered orally, but is greater than 90% metabolized during the first hepatic pass. This greatly limits th e efficacy of once-daily administration and also results in unphysiological ly high levels of progesterone metabolites, particularly those reduced at t he 5-a position. These metabolites can cause dizziness and drowsiness to th e point of preventing the operation of a motor vehicle. Synthetic progestin s, such as medroxyprogesterone acetate and norethindrone acetate (NETA), ha ve been specifically designed to resist enzymatic degradation and remain ac tive after oral administration. However, these compounds exert undesirable effects on the Liver and often cause severe psychological side effects. The permeability of the skin does not allow for administration of progesterone in the quantities normally produced by the corpus luteum, i.e., up to 25 m g/day during the mid-luteal phase. To avoid this problem, synthetic progest ins such as NETA have been administered transdermally. These compounds, tho ugh, just like synthetic estrogens administered non-orally, retain undesira ble hepatic effects even when administered transdermally. Transvaginal administration of progesterone is a practical non-oral route a vailable for administering progesterone. Early experience was gained with v aginal suppositories, which lack manufacturing controls. Recently, a new pr ogesterone gel formulation has been designed for vaginal use. The clinical acceptability of this product has been enhanced by the bioadhesive characte ristics of its polycarbophil-based gel, which conveys controlled and sustai ned-released properties. Investigations have shown that because of local di rect vagina-to-uterus transport, which results in a preferential uterine up take of progesterone, this formulation given in conjunction with physiologi cal amounts of estradiol produces endometrial changes similar to those seen in the luteal phase, despite plasma progesterone levels that remain subphy siologic. Studies in infertility show that vaginal progesterone in this for m allows secretory transformation of the endometrium and the development of pregnancy despite providing low systemic progesterone concentrations. Fewe r side effects occur when used for hormone replacement than typically encou ntered with progestins and oral progesterone. Uses in patients with inferti lity and hypoestrogenism and secondary amenorrhea are reviewed.