Cyclical Estrogen Therapy Prior to Embryo Transfer, in Post-Menopausal Women and those with Prolonged Hypothalamic Amenorrhea, Can Reduce the Chance of Failed IVF and Miscarriage.

Hypothalamic Amenorrhea

An absence of menstruation (amenorrhea) in reproductive age women is usually due to an absence of ovulation (anovulation). If this becomes prolonged, then these women are at risk for the ill effects associated from chronically low estrogen levels (hypoestrogenemia).   Specifically, the women at risk for this would be those experiencing premature ovarian failure (early menopause) or hypothalamic amenorrhea. Whatever the cause, hypoestrogenemia will eventually lead to a shrinking or involution of the uterine muscle (myometrium) as well as the atrophy of the uterine lining (endometrium), rendering it thin, fragile, and prone to irregular bleeding.  Although the uterine muscle and lining can indeed bounce back upon the return of normal estrogen levels, it does not happen immediately.   Any embryo, created either through a natural random ovulation or via the IVF process, which enters the suboptimal uterine environment created after prolonged hypoestrogenemia will not possess the same “baby potential” that it normally would.

A woman is born with several million eggs. After birth, these eggs rapidly decline in number such that by the time puberty is reached, only about 1 million eggs are present in the ovaries. The progressive decline in ovarian eggs that occurs with advancing age ultimately results in depletion of eggs and the onset of the menopause, which most women experience after their forties.  Unfortunately, some women undergo premature ovarian failure or insufficiency (POF/POI) due to genetically-induced accelerated egg depletion, pelvic disease, ovarian trauma, surgery, or (more rarely) exposure to radiation or chemotherapy.  Regardless of the age or cause of menopause, once the event occurs, ovarian estrogen production falls precipitously and in time will virtually cease.

In hypothalamic amenorrhea, the brain acts in a pre-pubertal manner, failing to hormonally signal the ovaries to initiate the ovulatory process.  In fact, many such women will give a history of having never menstruated (primary amenorrhea).  The reason for their hypoestrogenism is dysfunction of hypothalamic GnRH secretion (gonadotropin releasing hormone or GnRH).  GnRH is the signal required to activate the pituitary gland to produce and release gonadotropins (LH and FSH) that promote ovulation and ovarian estrogen production.  While both are hypoestrogenemic, women with hypothalamic dysfunction differ from menopausal women in that they have very low blood gonadotropin levels while those with ovarian failure have high gonadotropin levels. Women with hypothalamic chronic estrogen deprivation will also develop a small, involuted uterus with an endometrium that is poorly responsive to estrogen. The big difference however, is that unlike menopausal women (who have ovarian failure) and thus require someone else’s eggs (usually from a young anonymous egg donor), women with hypothalamic hypoestrogenism can undergo ovarian stimulation and use their own eggs with IVF.

It is important to bear in mind that when it comes to achieving a pregnancy though egg donation or embryo donation, prolonged estrogen deprivation can have several serious consequences. One of these is that the hypotrophic, estrogen deprived uterus develops a blunted ability to respond to estrogen when it is eventually reintroduced. This can result in a reduced ability of the endometrium to thicken adequately in response to standard durations of estrogen administration, rendering standard embryo transfer protocols inadequate to facilitate implantation and support a growing pregnancy. Fortunately, the above scenarios are avoidable through the administration of cyclical estrogen therapy for at least 3 months before performing embryo transfer or attempting to conceive.  This prolonged exposure will actually increase in a positive feedback the regeneration of uterine estrogen receptors, ultimately restoring optimal myometrial and endometrial growth and development.