There seems to be a preferential distribution of PROGESTERONE to the uterus following vaginal administration

• Studies strongly suggest a direct local “portal” for vagina-to-uterus transport of PROGESTERONE . This phenomenon was found to involve the vascular system and confirmed the existence of the so-called “first uterine pass effect”.  Cicinelli E et al, 1998
• The lymphatic system of the upper part of the vagina, being in direct communication with the lymph vessels of the uterus may also represent a potential route for direct passage to the uterus of substances applied to the vagina.    Transvaginal PROGESTERONE ,1999

Vaginal PROGESTERONE administration results in a high concentration at the local uterine / endometrial level – despite generally lower plasma levels than transdermal or intergluteal routes

• “First Uterine Pass Effect”.    The vaginal route is a better choice if the uterus / endometrium is the target area – PROGESTERONE has a direct impact on the uterus before entering circulation (the so-called first uterine pass effect).    Von Eye et al, 2004;  Alam V et al, 2001; Weckstein LN et al, 1993; Maddocks S et al, 1986; de Ziegler D, 1995;
• Studies showing that vaginal PROGESTERONE resulted in low serum levels, but efficacious endometrial concentrations.    Since PROGESTERONE is absorbed locally, it does not permit high plasma levels of PROGESTERONE , it therefore has less undesirable systemic effects.

Vaginal gel dose used in the luteal phase at 45mg every 48 hours resulted in low serum PROGESTERONE but endometrial efficacy was unhampered.    also, serum PROGESTERONE does not predict effects of vaginal PROGESTERONE on endometrium;   Fanchin R et al, 1997

Miles and coworkers also demonstrated that vaginal administration led to lower serum and higher endometrium PROGESTERONE concentrations compared to measurements after I.M. delivery. Miles RA, 1994

Gibbons and coworkers compared vaginal and intramuscular (I.M.)  PROGESTERONE delivery in women undergoing egg-donor programs, with higher mean serum PROGESTERONE in I.M. group.   All subjects in both groups had an endometrial histology that was “in phase” (meaning the 4 phases, menstrual, proliferative, secretory, and pre-menstrual, of the menstrual cycle were on schedule) Vaginal PROGESTERONE delivery has been shown as effective as intramuscular injections for raising endometrial levels and maintaining pregnancy.  Gibbons WE et al, 1998

Vaginal PROGESTERONE absorption may be influenced by the degree of vaginal mucosa estrogen content after estrogen treatment.  Villanueva et al, 1981

Vaginal PROGESTERONE absorption may be influenced by the type of the formulation used:

Different bases of suppositories.   Tests on glycerinated gelatin, cocoa butter and polyethylene glycol found that they all raised levels above baseline for the same duration, but polyethylene glycol raised the mean peak level of circulating PROGESTERONE the highest.. Price et al, 1983

•  PROGESTERONE particle size.    Micronized PROGESTERONE in non-liquefying cream showed promise for a goal of a single daily application. Kimzey et al, 1991

Vaginal PROGESTERONE delivery has been successful for HRT for various conditions  Warren et al 1999, including menopause de Zeigler et al, 1999

High PROGESTERONE concentration at uterine level has advantages when supplementing PROGESTERONE for luteal phase support

• For pregnancy or HRT.   Which has the goal of inducing adequate endometrial secretory transformation. Before ovulation, PROGESTERONE levels in a woman’s body remain relatively low, but rise after ovulation during the latter part of a woman’s menstrual cycle which is called the luteal phase. The luteal phase begins with the production of PROGESTERONE and ends with either pregnancy or menstruation, when the uterus sheds its lining. During pregnancy, PROGESTERONE helps to maintain the lining of the uterus, providing necessary nutrients to support and nurture a fertilized egg.
• For pregnancy, the dose amount and timing is crucial.   This is because PROGESTERONE may  (i) Act in favor of implantation as a permissive factor in a certain range of concentration or (ii) Block implantation when its concentrations are lower or higher than cut-off values. Villanueva B et al, 1981;  Erny R et al, 1989

E.g. Some of the first contraceptives used a high dose of PROGESTERONE. The timing of the dose should lend support to the natural luteal phase. Penzias et al used Crinone 8%, a vaginal gel containing 90 mg micronized PROGESTERONE in a polycarbophil base, to support luteal phase to support pregnancy after IVF, with rates comparable to intramuscular administration or vaginal suppositories. Penzias AS, Alpcr MM, 2003;   Anserini P et al, 2001;  Lightman et al, 1999

• Vaginal PROGESTERONE Is equally effective In achieving pregnancy outcomes as injectable PROGESTERONE In donor egg cycles.  105 recipients at Boston IVF treated with vaginal PROGESTERONE achieved a 58.1% pregnancy rate and a 51.4% delivery rate, versus a 53.3% pregnancy rate (p=0.503) and a 48.3% delivery rate (p=0.689) for patients receiving intragluteal PROGESTERONE         Med News Today, 16 Apr 2008
• Commonly used in many countries for luteal support in reproduction-assisted therapies.    E.g. for IVF (In vitro fertilization) Bourgain C, et al, 1990;  Artini PG et al, 1995