High FSH and low inhibin/antral follicle count (AFC) in the first few days of a woman’s cycle suggests diminished ovarian reserve and serve as a warning that the woman will not likely produce an optimal number of mature follicles and eggs in response to ovarian stimulation. They also serve to encourage the use of a more aggressive, yet individualized approach to ovarian stimulation.
Most women develop diminished ovarian reserve about 6-8 years prior to the onset of menopause (that time the period is termed the “climacteric”) but in some cases this happens at a much younger age (i.e. “a premature climacteric”). Thus, the basal FSH, inhibin level, and AFC are quite good indicators of ovarian reserve and the number of follicles that are likely to develop, given an optimal protocol for ovarian stimulation. However, these parameters alone are not good predictors of subsequent egg and/or embryo quality. Rather it is the woman’s age and the protocol designed to effect ovarian stimulation that play the major role and here, these measurements of FSH/inhibin and AFC can assist in designing the ideal stimulation protocol.
Let me explain! Human eggs undergo degradation in quality over time, such that by age 39, an egg (ovulated or harvested at egg retrieval) will on average have about a 20% chance of being genetically/chromosomally normal. This is about one half the chance at age 35 and under. By the time she reaches her mid forties, that number will decrease by half again (i.e. reaching less than 10%). This "wear and tear" effect on egg quality is an inevitable consequence of the advancing "biological clock". So, when it comes to egg quality, it is the woman's age and the protocol of ovarian stimulation that are the most important determinants. You simply cannot stimulate a woman in her 40's or for that matter a woman with diminished ovarian reserve using the same "recipe" (i.e. the stimulation protocol) as you would prescribe for a younger woman who has normal ovarian reserve. If you do not individualize the protocol of stimulation, you are highly likely to propagate the development of poor quality eggs that have a disproportionately increased likelihood of having chromosomal abnormalities.
Again..... the most important factors affecting a woman’s egg quality are 1) her age, and 2) ovarian reserve. While these two variables may be linked (women are more likely to develop diminished ovarian reserve as they get older), women sometimes do experience a “premature climacteric” and egg quality deteriorates with advancing age regardless of ovarian reserve. Thus, these two contributing factors should be seen as related, but independent variables.
So how then does age and/or diminishing ovarian reserve affect egg quality? First, as stated above, it is inevitable that with advancing age, egg quality will decline. Second, for follicles to grow and for eggs to develop normally (an essential prerequisite for proper genetic maturation), the tissue surrounding the follicle (ovarian stroma or theca) must produce testosterone. Stromal testosterone production requires luteinizing hormone (LH), which is produced by the woman's pituitary gland and is also acquired through some varieties of injectable fertility medications (Menopur, Repronex and Luveris) given in the course of ovarian stimulation. The testosterone then gets carried in "bucket brigade” fashion to the granulosa cells lining the inside of the adjacent follicle(s). Here, under the influence of FSH, it gets converted to estrogen (mainly estradiol/E2). In the process, the follicle grows and the egg it harbors within undergoes vital developmental changes in preparation for final genetic maturation ("ripening") that occurs with the spontaneous surge of LH that triggers ovulation (or following the administration of the hCG during ovarian stimulation).
Thus, a small amount of testosterone is needed for optimal egg quality (though too much testosterone can be harmful to the egg as I will discuss below). Eggs that have the genetic potential to transform into genetically “competent,” mature eggs will do so within 36 hours of the spontaneous pre-ovulatory LH surge, or following hCG-induced ovulation.
The important consideration here is that there should not be preovulatory over-exposure of the developing egg to testosterone, something that is most likely to happen when older women and/or those with premature diminution in ovarian reserve are prescribed a suboptimal protocol for ovarian stimulation. If there is overexposure to testosterone, egg development and subsequent egg/embryo quality can be severely compromised along with the chance of a healthy pregnancy. Since older women (>39 years) and women with diminished ovarian reserve tend to produce an excess of LH and have a tendency to over-produce testosterone, this is where the problem lies.
What does this all mean in the context of preparing a woman for a cycle of ovarian stimulation? First, it means that a young woman who has diminished ovarian reserve should still be capable of producing produce good quality eggs, albeit in a smaller number, provided that she gets prescribed an individualized and customized protocol that is designed to prevent over-production of ovarian testosterone. Conversely, an older woman with diminished ovarian reserve will, because of the inevitable effect of age on egg quality, produce a higher percentage of poor quality, genetically “incompetent” eggs.
Finally, when it comes to natural cycle IVF, it should be recognized that some women will produce up to 2 or 3 follicles. Some will be smaller than others, but even the smaller ones can yield eggs. However, as with regular IVF (with ovarian stimulation), the quality of her eggs will be inevitably be influenced by her age. Thus the success rate following natural cycle IVF in such cases will be very much lower than for younger women, especially if they have diminished ovarian reserve. The success rate with natural cycle IVF, even in young women, is only about 10% per cycle. In older women, it is under 5%. Furthermore, older women are more likely to have increased LH production. In addition, the LH they produce becomes more potent with advancing age and thus is much more likely to evoke a greater ovarian testosterone response with a negative effects on egg/embryo quality (and correspondingly on the likelihood of IVF success).
In summary, natural cycle IVF is a much less effective and successful form of IVF across the age spectrum. If it is used, it should be confined to younger, ovulating women who have a normal ovarian reserve.
Posts
8 comments: