Endometrin Mechanism of Action

Pharmacotherapeutic group: Sex hormones and modulators of the genital system; Progestogens; Pregnen-(4) derivatives. ATC code: G03DA04.
Pharmacology: Pharmacodynamics: Mechanism of action: Progesterone is a naturally occurring steroid that is secreted by the ovary, placenta, and adrenal gland. In the presence of adequate estrogen, progesterone transforms a proliferative endometrium into a secretory endometrium. Progesterone is necessary to increase endometrial receptivity for implantation of an embryo. Once an embryo is implanted, progesterone acts to maintain the pregnancy.
Clinical efficacy and safety: Ongoing pregnancy and live birth rates following 10-week luteal support with ENDOMETRIN 100 mg TID (N=390) in patients who had an embryo transfer in the Phase III clinical trial were 44% (95% CI 38.9; 48.9) and with 39.5% (95% CI 34.6; 44.5), respectively.
Pharmacokinetics: Absorption: Progesterone serum concentrations increased following the administration of the ENDOMETRIN vaginal tablets in 12 healthy premenopausal females. On day 1 of treatment, the mean C_max 19.8 ± 2.9 ng/mL with a T_max of 17.3 ± 3.0 hours after administration of ENDOMETRIN three times daily 8 hours apart.
On multiple dosing, steady state concentrations were attained within approximately 1 day after initiation of treatment with ENDOMETRIN. Trough values of 10.9 ± 2.7 ng/mL were observed with an AUC_0-24 of 436 ± 43 ng*hr/mL on Day 5.
Distribution: Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin and corticosteroid binding globulin.
Biotransformation: Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites that are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization.
Elimination: Progesterone undergoes renal and biliary elimination.
Following injection of labelled progesterone, 50-60% of the excretion of metabolites occurs via the kidney; approximately 10% occurs via the bile and faeces. Overall recovery of the labelled material accounts for 70% of an administered dose. Only a small portion of unchanged progesterone is excreted in the bile.
Toxicology: Preclinical Safety Data: Progesterone is a well known natural reproductive steroidal hormone in humans and animals, with no known toxicological effects. Therefore no toxicity studies have been performed with this progesterone vaginal dosage form, with the exception of local tolerance and skin sensitization studies.
ENDOMETRIN was found to be non-irritative for up to 90 days of twice daily vaginal administration in rabbits and was also shown to be non-sensitising in Guinea pigs.