The window of uterine receptivity (for embryo implantation) is a relatively short period of time (a few days in humans) during the luteal phase of the menstrual cycle during which an embryo is “allowed” to successfully (adhere to and) implant within the uterus. Gaining a better understanding of this window of receptivity and the factors that control it is an active area of research within the field of human reproduction.
A primary goal of research on the window of uterine receptivity is to identify a “marker” substance (such as a protein) that is easily measured and reliably predicts a receptive uterus. Candidate markers have included histologic assessment of the mid- or late luteal phase endometrium (by endometrial biopsy), production of specific proteins by the progesterone primed endometrium, cellular expression of integrins (or their subunits such as the beta 3 subunit of the alpha v beta 3 integrin) or other cell adhesion molecules, and formation of pinopods (cellular cytoplasmic projections that may be involved in either engulfing uterine secretions or providing receptors for embryonic cell adhesion molecules) along the surface of the midluteal phase endometrium.
At this time (2002), molecular and cellular markers of uterine receptivity to embryo implantation are of “experimental interest” and not generally used to alter clinical management of the patient. It will be very exciting to follow this line of research over the next few years since clinically accepted and useful tests will most certainly be welcome.
The reduced receptivity of the endometrium (uterine lining) to embryo implantation during cycles of controlled ovarian hyperstimulation (COH) has also been a focus of (human reproduction) research. During COH cycles the anticipated day of (successful) embyro implantation is about 7 days after administration of hCG.
The progesterone concentration at the time of administration of hCG and (more dramatically) thereafter (such as at the time of embryo implantation) is elevated during COH cycles when compared to natural cycles. Research suggests that this elevated progesterone concentration (during COH cycles) may result in advanced endometrial histology (appearance on biopsy) or a premature presence (and disappearance) of endometrial pinopods.
During cycles of IVF, progesterone is usually supplemented to enhance pregnancy rates (improvement is well characterized), although the mechanism by which supplementation works (in this context) has not been clarified. Several theories are commonly proposed, including (a) the oocyte (egg) retrieval process can significantly disrupt (damage) the granulosa cells lining the ovarian follicles to limit the ability of these same cells to produce progesterone following “ovulation;” (b) the lupron that is typically administered concurrently with FSH (menotropins) during the COH (IVF) stimulation protocols limits postovulatory (luteal) pituitary secretion of endogenous LH (which is normally required for luteal support of progesterone production); and (c) the estradiol (most biologically active estrogen) concentration during COH (IVF) cycles is enormously elevated compared to natural cycles and exogenous progesterone may be required to bring the ratio of estrogen to progesterone concentrations toward a normal value.
Methods of exogenous progesterone supplementation during IVF vary.
Intramuscular injection of progesterone in oil (peanut or sesame) has been shown to be effective at sustaining pregnancies even in women lacking their own progesterone production (usual daily dose is 50-100 mg progesterone in oil). These injections are probably the most commonly used method of administration during IVF cycles. However, recently (1999) the supply of progesterone in oil in the USA became limited (the major supplier has apparently had general difficulty with the production of their medications). Progesterone in oil is still available at some local pharmacies throughout the USA.
Oral micronized progesterone is readily available in the USA. Micronized progesterone is absorbed (predominantly) intact (previous oral forms of progesterone were almost entirely degraded in the gastrointestinal system prior to absorption) but may then be predominantly degraded during its initial passage through the liver. There is significant concern in the medical literature that oral progesterone is not fully capable of preparing the uterine lining for implantation and the development of a normal pregnancy and therefore should not be used as a sole source of progesterone during IVF cycles. On the other hand, oral progesterone is commonly used to supplement spontaneous cycles with luteal phase deficiencies of progesterone.
Luteal replacement of LH activity (to enhance ovarian production of progesterone) using hCG injections (“boosters”) was effective with respect to preparing the endometrial lining. However, hCG is also the primary trigger for Ovarian Hyperstimulation Syndrome (a major potential complication associated with IVF) so its use as a method of inducing endogenous progesterone production has been almost universally discontinued.
Vaginal application of progesterone appears to effectively enhance pregnancy rates during IVF and is a popular method of progesterone supplementation. The gel in which progesterone is suspended varies, with gels that “melt” when heated to body temperature often being considered (by patients to be) “messy.” A newer product, Crinone 8% was specifically designed for vaginal application using a slow release gel (for once a day application) and some IVF programs use Crinone 8%. Vaginal application of progesterone may have an advantage with respect to “getting the administered progesterone intact to the uterus” since there may be a direct link between vaginal absorption and uterine delivery (the “first uterus pass effect”).