Ovarian reserve is the term used to describe the extent of a woman’s ovarian egg supply. Diminished ovarian reserve (DOR) refers to a reduction in the total number of eggs left in the ovaries such that resistance builds to ovarian stimulation with fertility drugs. With progressively diminishing ovarian reserve, an ever increasing amount of fertility drugs is required to stimulate optimal follicle and egg development. This reduction in the woman’s egg supply is inevitably accompanied by a progressive egg depletion and when the eggs run out, the woman enters menopause.
The precise point at which the onset of diminishing ovarian reserve can be diagnosed based upon blood tests is inexact. However, it usually coincides with an elevation in basal follicle stimulating hormone (FSH) level (measured on day 2-4 of the menstrual cycle) above >9.0 MIU/ml and an antimullerian hormone (AMH) level of less than 2.0 ng/ml or <15 pmol/L). As the FSH rises above 10 MIU/ml and the AMH drops below 1.0 ng/ml or <8 pmol/l) DOR becomes ever more clinically apparent, and by the time the basal FSH blood level rises above >15 MIU/ml and the blood AMH concentration falls below 0.5 ng/ml or 5 pmol/l, the degree of DOR is likely to be so severe as to render the likelihood of a “fresh” IVF cycle (using own eggs) resulting in a viable pregnancy very low indeed. In such cases, either IVF with egg donation or “staggered IVF” with “embryo banking” of vitrified PGS selected blastocysts should be given preferential consideration (see below).
Causes of Diminished Ovarian Reserve (DOR): Biochemical evidence of DOR usually first appears about 5-8 years prior to the onset of menopause, which in the vast majority of American women occurs between the age of 40 and 55. When it occurs prior to age 40 it is referred to as “premature menopause.” DOR occurs because of an age related “wear and tear” which progressively erodes the woman’s ovarian egg supply; It can be hastened in onset by pathologic states such as severe endometriosis and/or chronic pelvic inflammatory disease that directly destroy ovarian tissue or compromise blood flow to the ovaries; post-surgical pelvic scarring and adhesions that strangulate ovarian blood supply can exact a similar toll. Exposure to radiation therapy and/or the use of certain anti-cancer drugs can also destroy ovarian egg bearing tissue resulting in DOR and premature menopause. Finally, genetic/chromosomal factors can sometimes result in the premature onset of DOR and menopause. Presently there is nothing that can be done to slow down or reverse DOR.
The effect of advancing age on egg competency/quality: Advancing age, aside from being responsible for DOR is inevitably and invariably accompanied by progressively declining egg “competency” (quality) which is primarily due a progressive increase in the percentage of eggs that have an irregular number of chromosomes (aneuploidy). Just consider the fact that in women in their early 30’s the incidence of egg aneuploidy is about 50%, but by the time they reach their mid-forties, more than 90% of their eggs will be aneuploid. Aneuploid eggs will, upon fertilization, invariably produce embryos that likewise are aneuploid and thus “incompetent” (incapable of propagating viable, healthy pregnancies). Such aneuploid embryos either arrest during cell division, cause early pregnancy loss, or result in chromosomal birth defects such as Down syndrome.
The role of ovarian male hormones (mainly testosterone) on egg/embryo development and “competency”: A certain concentration of ovarian male hormone (androgens), predominantly testosterone, is absolutely essential for adequate follicle growth and egg development to take place. Complete absence in production of ovarian testosterone will virtually preclude healthy egg production and result in poor quality embryos. Simply stated, some testosterone is necessary for FSH to induce optimal follicle and egg development. However, too much ovarian testosterone can, in my opinion, seriously compromise egg development and increase the likelihood of egg/embryo aneuploidy. There must be a balance.
The importance of controlling ovarian exposure to testosterone during ovarian stimulation: The production of ovarian testosterone is dependent upon the influence of luteinizing hormone (LH) which in turn is primarily derived from pituitary gland production. However, LH can also be found in certain fertility hormones (gonadotropins) such as Menopur and Luveris. Thus in cases where “long” ovarian down-regulation protocols (that involve the administration of GnRH-agonists such as Lupron/Buserelin or GnRH-antagonists such as Ganirelix/Cetrotide that are capable of completely blocking the production or release of LH) are used, along with purified “recombinant” FSH gonadotropins such as Puregon/Gonal-F/Follistim (which contain virtually no LH), it is essential to expose the developing follicles to some testosterone by adding LH activity in the form of Menopur, Luveris or hCG supplementation. Alternatively, a small amount of testosterone may be added to the mix. In so doing, follicle and egg development can be optimized and embryo quality enhanced.
To reiterate, in my opinion, it is essential to understand that the presence of too much ovarian testosterone can be harmful to egg development/quality and follicular development. Accordingly, optimal ovarian stimulation requires that a balance be struck when it comes to exposure to LH or supplementary testosterone. This is especially important when it comes to stimulating the ovaries of older women and those with DOR who already tend to have increased biological LH activity and whose follicles and eggs are particularly vulnerable to the damaging influence of excessive male hormones (testosterone). It is for this reason that when it comes to choosing an ovarian stimulation protocol for my IVF patients, I tend to avoid any/all protocols that cause increased pituitary LH production (“Flare” protocols and use of clomiphene and Letrozole).
How should ovarian stimulation be approached in women with DOR? Since advancing age adversely impacts both egg quality and ovarian reserve, there is a tendency to lump these two variables (DOR and egg quality) together. This misses a critical point: while in most cases, the two variables are tied with age, there are many instances where a younger woman has DOR, but because of her relative youth, those eggs will not necessarily suffer inherent quality deficit brought about primarily by age. Thus, in contrast with an older woman with the same degree of DOR, a younger counterpart would be better capable of yielding “competent” eggs. This is why I tend to recommend egg donation to older women with severe DOR, while I often advise younger women with DOR to opt for “Staggered IVF” with selective “embryo banking” of PGS-selected blastocysts.
What about mini-IVF or Natural Cycle IVF for women with DOR? It is quite understandable that many women with DOR are easily persuaded that less (or no) ovarian stimulation offers a more “natural” and less “stressful” approach on eggs than a robust, high gonadotropin-based, long-pituitary down regulation approach. This, in my opinion is a fallacy and can compromise rather than benefit IVF outcome in such cases. Even in young women in their early or mid-30’s, the IVF success rate per fresh “natural” or “mini” IVF cycle is much lower (<15%) than that which can be achieved through the use of conventional long down-regulation protocols, where the anticipated success is at least double this rate (30%). Mini-IVF is usually conducted using clomiphene or Femara, alone or in combination with Menopur, all of which is associated with the production of excessive LH-induced ovarian testosterone. Furthermore, low dosage stimulation will result in fewer eggs being available, thus further reducing the odds of IVF success per egg retrieval conducted. Natural cycle IVF is in my opinion also not in the best interest of women with DOR, because with such an approach, nothing is done to control the exaggerated production of LH by the woman’s own pituitary gland.
Augmenting ovarian response to gonadotropins in women with DOR:
- There is data to suggest that selective administration of human growth hormone (HGH) to women with DOR and possibly those with egg quality issues, could benefit egg development and maturation by augmenting mitochondrial energy generation that drives DNA synthesis. While the high cost of HGH can be a burden for most women, it is certainly well worth considering in certain cases.
- Estrogen priming before the onset of and during ovarian stimulation is another approach that was pioneered at SIRM. We reported on a distinct benefit using this approach in women with severely diminished ovarian reserve. Estrogen is believed to prime FSH receptors in the follicle granulosa cells and thereby might enhance response to ovarian stimulation.
- Anecdotal evidence suggests that certain nutritional supplements, such as folic acid and antioxidants (especially Coenzyme Q) enhance egg development and maturation. While more data is needed to support this contention, it is also true that such supplements do no harm whatsoever. Also they are low cost, so there is really no harm using them.
- DHEA has been touted as being capable of enhancing egg quality and ovarian response. However, there is no convincing evidence of any such benefit in my opinion. Besides, DHEA is readily metabolized to testosterone in the ovaries and as stated, many older women and those with DOR are more vulnerable to over-exposure to ovarian testosterone, I believe that the indiscriminate use of DHEA in such cases can be potentially harmful to such women.