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

It is not uncommon for women with prolonged absence of menstruation (amenorrhea) (whether due to prolonged menopause or hypothalamic (central) dysfunction) to have chronic estrogen deprivation. In many such cases this causes the uterus to shrink (involute) and/or renders the uterine lining (endometrium)  relatively refractory (unresponsive) to subsequent estrogen therapy, increases the risk of miscarriage, and potentially compromises fetal development. All these sequelae are potentially avoidable if women who have  prolonged amenorrhea ( >6 months) associated with hypoestrogenism, first have their blood gonadotropins (FSH and LH) and blood estradiol (E2) levels measured to differentiate between menopause (ovarian failure) and  hypothalamic hypoestrogenism (where the  low estrogen is due to under-stimulation of the ovaries. Thereupon they should be evaluated for physical evidence of uterine involution (shrinkage) and/or the ability of the uterine lining to thicken in response to a therapeutic trial with supplementary estrogen. This should be followed by several months of cyclical estrogen therapy in an attempt to restore uterine size and endometrial responsiveness to estrogen, prior to their undergoing embryo transfer.

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. Thereupon, with every consecutive  ovulatory cycle a significant number of these eggs begin a “recruitment journey in which they undergo (still relatively poorly understood) developmental changes , finally presenting in the ovaries, 4 months later, as small (4-6mm) fluid-filled spaces called “antral follicles” . It is from these antral follicles that one (and sometimes >1) follicles  differentiate from the rest by growing more rapidly in response to FSH. These become identifiable by ultrasound, as “dominant” follicles that will ultimately ovulate and release an egg for fertilization.

The progressive decline in ovarian eggs that occurs with advancing age ultimately results in progressive  depletion of eggs and ultimately,  the onset of the menopause.  Most women do not enter the physiological menopause until well after the age of 40y, but some women undergo premature ovarian failure (POF) due to genetically induced accelerated egg depletion, pelvic disease, ovarian trauma, surgery or (more rarely) exposure to radiation or cancer chemotherapy.

Regardless of the age or cause of menopause, once the event occurs, ovarian estrogen production falls precipitously and in time, often will virtually cease.

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 uterus begins to involute (shrink) and the uterine lining (endometrium) starts losing its ability to respond to estrogen. This can result in a reduced ability of the endometrium to thicken adequately in response to required preparatory estrogen therapy and in the process be rendered unable to support embryo implantation,  resulting in repeated failure to achieve pregnancy, miscarriage and worst of all, should implantation occur in  an increased  risk  of poor fetal growth and development .

Fortunately, the above scenarios are avoidable through the administration of cyclical estrogen therapy for several months before performing embryo transfer in such women , to encourage regeneration of uterine estrogen receptors and  restore optimal uterine and endometrial growth and development.

While menopause is the commonest reason for such endometrial and uterine involution, it is NOT the only cause. A similar situation (of chronic estrogen deprivation), is sometimes encountered in non-menopausal women who fail to menstruate for protracted periods of time (usually longer than 6 months in a row). In fact, many such women, will give a history of never ever having seen a period in their lifetimes (primary amenorrhea).  The reason for their hypoestrogenism is dysfunction of the  hypothalamus (an area in the brain that releases gonadotropin releasing hormone-GnRH) which in turn causes the pituitary gland to produce and release gonadotropins (LH and FSH) that promote ovarian estrogen production).  What differentiates such women from menopausal women (whose ovaries fail to respond to gonadotropin stimulation) is that women with such hypothalamic dysfunction have very low blood gonadotropin as well as estrogen levels while those with ovarian failure have high gonadotropin and low estrogen blood concentrations. Nevertheless, women with hypothalamic chronic estrogen deprivation will over time also develop a small, involuted uterus with an endometrium that is poorly responsive to estrogen. These women also require several months of estrogen “priming”, prior to undergoing embryo transfer. The big difference however, is that unlike menopausal women (who have ovarian failure) and thus require someone else’s eggs (usually an egg donor) women with hypothalamic hypoestrogenism can undergo ovarian stimulation and use their own eggs with IVF.

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