Is There an Ideal Stimulation for Women with Low Ovarian Reserve?

Follicle_MaturationSince there is considerable confusion about the terminology that describes a woman’s functional ovarian reserve (FOR), it is essential to start discussing this topic by defining the terminology. FOR is defined as the so-called small growing follicle pool between primary follicles (immediately after recruitment) and small preantral follicles. It is this pool of follicles that in the end determines how many follicles are likely to respond to ovarian stimulation and how many oocytes will be retrieved in an IVF cycle. At least at younger ages, it is best described by anti-Müllerian hormone (AMH) values. If AMH values are very low, AMH, however, loses its ability to predict ovarian response to stimulation, and FSH becomes a better predictive tool.

FOR declines with advancing age and, therefore, is not stable. This means that ovaries will increasingly poorly respond to ovarian stimulation as women get older and develop diminished ovarian reserve, or low functional ovarian reserve. This phenomenon is also called increasing ovarian resistance to stimulation. Besides age, FOR can also be diminished by diseases affecting ovarian function at younger ages. In such cases FOR declines and ovarian resistance to stimulation increases already at unusually young ages, a condition we have given the clinical term premature ovarian aging (POA), and others have called occult primary ovarian insufficiency (oPOI). Here, younger women demonstrate the same clinical presentation (phenotype) as usually only seen in older women, including falling AMH and rising FSH levels, which is why we have given this condition the term POA.

While physiological ovarian aging (i.e., aging because of advancing age) and POA have much in common, there are also significant differences. Those include that the chance of pregnancy per oocyte/embryo at young ages is much higher. Therefore, younger women need fewer embryos to achieve pregnancy, and overall pregnancy rates, even with identical FOR, will be higher in younger women. Another difference lies in the fact that increasing gonadotropin dosages in younger women will be more effective in raising oocyte numbers than in older women.

Whether the cause of low FOR is POA or physiological aging, low FOR, interestingly, is almost always associated with relatively low androgen and elevated SHBG (sex hormone binding globulin) levels. Good testosterone levels are, however, now recognized as essential for normal follicle development at above noted small growing follicle stages because at those stages testosterone, acting via the androgen receptor on granulosa cells, synergistically enhances FSH effects on follicles. We, therefore, raise androgen levels in women with low FOR by pre-supplementing usually with DHEA, but sometimes, when DHEA is not effective, with testosterone directly.

Only recently described in the literature by CHR investigators (Wu et al., J Endocrinol 2015;100:736-41) was the observation that in women with low FOR, ovarian stimulation leads to premature luteinization of follicles. This means that in women with low FOR (as we now know, whether low FOR is due to age or POA) follicles “mature” biologically much quicker than in women with normal FOR. Women with low FOR, therefore, have to have egg retrievals when their follicles are much smaller, in order to get best quality oocytes and best pregnancy and live birth outcomes.

Women with DOR, therefore, require highly individualized protocols in IVF to maximize their obviously limited outcome chances. There is no one ideal stimulation protocol, which is why we, at CHR, place so much emphasis on individualized IVF protocols for most patients.

This is a part of the January 2016 issue of the CHR VOICE. Read this issue in PDF.

Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned reproductive endocrinologist, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.