MICRONIZED PROGESTERONE THERAPY - THE IMPORTANCE OF ROUTE OF ADMINISTRATION AND PHARMACOKINETICS ON CLINICAL OUTCOME

We assessed the oral pharmacokinetics of micronized progesterone (Utrogestan(R), Besins-Iscovesco, Paris). Feeding effects and dose proportionality were determined and compared with intramuscular and intravaginal administration. Biopotency was ascertained by induction of withdrawal bleeding and compared with established endometrial morphology. Oral administration led to Cmax equalling 19,9 ng / ml (200 mg dose) by 2,2 h. Food ingestion nearly doubled absorption (AUC 0-24) and Cmax without affecting Tmax (p < 0,05). Dose proportionality was confirmed. For comparison, vaginal administration led to a later Cmax (2-6 h) plateauing over 24 h with a mean concentration of 9.7 ng / ml (200 mg / day). Following intramuscular injection of progesterone. Cmax was higher and Tmax was later compared with oral administration (p < 0,05). Endometrial effects have not been closely correlated with any short term pharmacokinetic parameter however. as little as 200 mg day caused reduced mitotic activity (oral x 10-14d) or full secretory transformation (vaginal x 10-14d). Withdrawal bleeding in secondary amenorrhea was oral dose-dependent, but progestin-related side effects were not different from placebo. These findings demonstrate that micronized progesterone can induce withdrawal bleeding. and either only decreased mitotic activity or full secretory transformation, depending on dose and route administered.