**4.1. Comparison between routes of progesterone administration**

Progesterone can be administered orally, vaginally, or through I.M. injection and all these routes of administration have demonstrated characteristic endometrial histological changes [26]. Oral dosing requires a higher concentration in order to compensate for "first-pass" liver metabolism. The bioavailability of the orally administered progesterone can be as low as 10% [27].Micronized dosage forms of progesterone are utilized to increase efficiency of delivery. Micronization decreases particle size and shortens its dissolution time according to the equation of Noyes–Whitney[28].However, oral administration may result in noticeable sedative and anxiolytic effects due to progesterone metabolites that enhance inhibitory neurotransmission by binding to the GABAA receptor complex [29].

Intramuscular injections of micronized progesterone in oil result in a higher peak and longer lasting plasma concentrations when compared to aqueous solutions. But, a daily administration is required due to a rapid metabolism. Progesterone in oil (USP) is formulated with sesame oil (50 mg/ml) and 10% v/v benzyl alcohol that functions as preservative. Intramuscular injections are difficult to self-administer and are often painful. A common practice is to warm up the oil solution in order to decrease its viscosity in an attempt to reduce pain with injection [28].

Bulletti et al[30] first described a preferential trafficking of vaginally delivered progesterone to the uterus leading to a higher progesterone concentration in the endometrial tissue compared to the blood serum. Therefore, targeted delivery of progesterone directly to the uterus is thus achievable through utilizing this 'uterine first pass effect' [31] .The anatomy of the vagina with its rich vascular plexus provides an ideal environment for absorbing drugs. The rugae of the vaginal wall increase the total available surface area. The vascular system around the vagina and the venous drainage of the vagina does not initially pass through the liver, and thus bypasses the first pass hepatic effect [32] .By avoiding the hepatic first pass effect, vaginal progesterone does not create high concentrations of metabolites that cause undesired side effects. Vaginal administration of progesterone results in more consistent serum levels, which can remain elevated for up to 48
