Controlled Ovarian Stimulation (COS) protocols for women with Diminished Ovarian Reserve (DOR) who are Poor Responders to Ovarian Stimulation

Dr. Geoffrey Sher - June 13, 2016
Controlled Ovarian Stimulation (COS) protocols for women with Diminished Ovarian Reserve (DOR) who are Poor Responders to Ovarian Stimulation

Two main factors determine the quality of a woman’s eggs at ovulation or egg retrieval. First is her age and second is the protocol used for ovarian stimulation. With the possible the exception of cases where there is severe sperm dysfunction, it is the chromosomal integrity of the egg rather than the sperm that will ultimately determine the chromosomal integrity of the embryo (i.e. its “competency”, or its potential to propagate a healthy babies). It therefore follows that the only way by which to influence embryo “competence” is through the selection and implementation of an optimal protocol for ovarian stimulation. Since older women (≥39 years) and those who have diminished ovarian reserve are at greatest risk of yielding “incompetent” eggs, they are the ones that require special attention. This article will highlight the reasons why such women are the ones most prone to produce poor quality eggs and embryos and how best to address ovarian stimulation in an attempt to minimize this risk. Cells that have a full chromosomal component are termed euploid while those that do not, are aneuploid. Most euploid eggs arecompetent”, that is, those that are most likely to propagate euploid, “competent” embryos. Aneuploid, “incompetent” eggs will invariably develop into aneuploid, “incompetent” embryos. There is a progressive increase in the incidence in egg/embryo aneuploidy with advancing age. To put numbers to the equation; by time a woman reaches 35 yrs; about 60% of her eggs are likely to be aneuploid. By the time she reaches her mid 40’s the incidence will be greater than 85%. For example, a woman of 43 years would be fortunate if six (6) or eight (8), of her eggs would upon being fertilized, result in one (1) “competent” embryo. As the woman gets older, the inevitable decline in egg/embryo quality results in her having a reduced ability to conceive naturally, a declining IVF success rates, an increase in miscarriages, and a rising incidence of having her baby affected by chromosomal birth defects such as Trisomy 21 (Down's syndrome). This is why for such a woman, the anticipated IVF birth rate per egg retrieval is less than 10% (i.e. 60% lower than at age 35), the miscarriage rate rises almost by 300% to about 60% and why her risk of having a baby with Down’s Syndrome is about 2% (as compared to 0.1% ). The anticipation of poor IVF outcome statistics for women in their mid-40’s makes IVF with ovum donation the most rational approach. Yet, in spite of this, many older women still elect to use their own eggs as long as there is even the slightest chance of having their own genetic offspring. As a woman approaches and then engages her 40’s, her ability to produce “competent” eggs progressively declines. At the same time she experiences diminishing ovarian reserve that results in a progressive fall-off in the number of eggs she is likely to produce at egg retrieval. As a result, there will be a commensurate drop of in the number of “competent” embryos available for transfer to her uterus. The following are IVF stimulation protocols most often to stimulate the ovaries of women with diminished ovarian reserve:

  • GnRHa Flare (“Short”) protocol: Some IVF physicians advocate the use of gonadotropin releasing hormone-agonist (GnRHa)- flare protocols in which the administration of GnRHa (e.g. Lupron, Buserelin, Nafarelin, Synarel) therapy begins at the same time that ovarian stimulation with gonadotropins is started (usually with the onset of menstruation). The proposed benefit of such an approach is that the GnRHa will cause the woman’s pituitary gland to release large amounts of follicle stimulating hormone (FSH), which would augment the administered dosage of FSH and thereby synergizing the growth of ovarian follicles. The problem associated with this “flare” protocol approach is that concurrent with the GnRHa-induced FSH luteinizing hormone (LH) also surges. In older women and those who have diminished ovarian reserve, the out-pouring of LH can cause the ovarian connective tissue (stroma or theca) which produces male hormones to generate too much testosterone. While a small amount of testosterone is essential for optimal follicle growth, too much testosterone can compromise its development as well as egg/embryo quality. Since older women and women with diminished ovarian reserve often have increased LH production as well as an overgrown of ovarian stroma/theca (i.e. hyperthecosis), a further GnRHa-induced increase in LH can so elevate local ovarian testosterone levels as to severely compromise egg/ embryo “competency”.
  • Combined Clomiphene or Letrozole) /Gonadotropin Stimulation: This approach when used in older women and women with diminished ovarian reserve is also potentially harmful to egg/embryo quality. The reason is that like GnRHa, clomiphene and Letrazole also cause LH to be released in large amounts. Since these medications are given at the start of ovarian stimulation they, as with “flare protocols” can elicit ovarian over-production of testosterone. As such this approach is in my opinion far less than ideal for older women and women who have diminished ovarian reserve.
  • Mid-follicular GnRH-antagonist protocol: With this approach, stimulation with gonadotropins is commenced with the onset of the cycle. Then, several days later, once the majority of follicles have reached about 12mm in size, GnRH antagonist (e.g. Ganirelix, Cetrotide, Cetrorelix, and Orgalutron) is added. The intent in adding the antagonist is to abruptly block pituitary LH release and so prevent a “premature LH surge” with its effect of causing increased ovarian testosterone and impaired follicle and egg development. The problem with such a regime is that women with diminished ovarian reserve already have too much of their own LH around at the beginning of the cycle. Accordingly, blocking LH release only 6-7 days into the stimulation does nothing to prevent the early adverse effects of too much LH-induced ovarian testosterone on early egg/embryo development. It should be borne in mind that eggs are often at their most vulnerable, early on in the cycle. Thus, in my opinion such protocols are also less than optimal for older women and for those with diminished ovarian reserve.
  • GnRHa (“Long”) Pituitary down-Regulation Protocol:
    • The Standard Approach: This protocol, which is the mainstay of ovarian stimulation for IVF, is either initiated about 1 week after natural ovulation (a “luteal phase start”) or is launched off a monophasic birth control pill (a “BCP start”). In the case of the latter, the BCP is taken for at least 8 days before, GnRHa is added daily. Two days after starting the GnRHa, the BCP is stopped. Menstruation usually ensues within 3-5 days. GnRHa administration is continued and FSHr stimulation is initiated. Both daily Gonadotropin stimulation and GnRHa are continued until the day of the “hCG trigger”. The initial administration of agonist serves to rapidly expunge pituitary FSH and LH causing an immediate rise in the blood levels of both hormones. Then, within a few days, having virtually exhausted/depleted pituitary gonadotropin stores, the blood levels of FSH and LH both rapidly decline, such that by the time menstruation occurs, the levels are very low. The initial premenstrual GnRHa-induced rise in FSH helps recruit ovarian antral follicles for the upcoming cycle, while the ultimate virtual depletion of LH serves to prevent excessive ovarian testosterone production and protects egg quality. I prefer to use pure FSHr (Folistim, Puregon, Gonal F) for ovarian stimulation for IVF with the initial dosage being reduced by about 25% within a few days. Thereupon a very small amount of daily LHr (Luveris) or Menopur (menotropins) is added.
    • Agonist/Antagonist Conversion protocol (A/ACP): Agonists are believed to competitively inhibit follicle response to FSH. Therefore, in an attempt to improve follicle response to FSH we modified the “standard approach” (a- above) as follows: Rather than continuing to give GnRHa throughout the stimulation protocol, we here supplant GnRHa with low dosage GnRH antagonist starting with the initiation of menstruation, continuing throughout stimulation until the day of the “hCG trigger” at which point both the antagonist and gonadotropins are discontinued. We have had very good results using the A/ACP modification of the “standard long pituitary down-regulation protocol”. In fact it has become my preferred approach for most women with a normal ovarian reserve, who undergo ovarian stimulation for IVF.

Augmenting ovarian response to gonadotropins in women with DOR:

  • The administration of human growth hormone (HGH), as an adjunct to ovarian stimulation might enhance follicle and egg development in older women, women with DOR, those with PCOS and women with a past history of producing poor quality eggs at ER. This effect of HGH is thought to be mediated by HGH promoting production’/activity of insulin-like growth factor 1 (IGF-1). Two basic mechanisms have been proposed: 1) improving the response to gonadotropin therapy by up-regulating the FSH receptors on the granulosa cells that form the inner lining of follicles and, 2) through a direct enhancing effect of HGH on the egg’s mitochondrial activity.  While human eggs do have HGH receptors, those retrieved from older women show decreased expression of such receptors (as well as a reduction in the number of functional mitochondria) as compared with those derived from younger women. In fact, it has recently been shown that older women treated with HGH showed a marked increase in functional mitochondria in their eggs along with improved egg quality.
  • Agonist/Antagonist Conversion Protocol (A/ACP) with “Estrogen Priming”: Estrogen primes follicle FSH receptors, thereby enhancing response to FSH. This forms the basis of the “estrogen priming” approach in women with diminished ovarian response. The approach involves administering estradiol by daily injection, or by skin patch starting about 10 days prior to initiating high dosage gonadotropin stimulation. As with the A/ACP, the estrogen priming protocol is initiated a week post-ovulation (luteal phase start) or is launched off a birth control pill. It also starts with GnRHa administration for about 5 days whereupon menstruation ensues and the agonist is supplanted by an antagonist. But this is where things change slightly such that instead of directly initiating FSHr injections, the patient, while continuing to take the GnRH antagonist now receives twice weekly estradiol valerate injections or daily estradiol skin patches (I prefer the former) for a period of about 10 days. Thereupon, daily high dosage FSHr (750U) is administered once daily. Four to five days later dosage of FSHr is reduced to 600U daily and a small daily dose (75U) of LHr (Luveris) or Menopur is added. “Estrogen priming” is continued until more than 50% of the follicles are at least 12mm in size whereupon it is discontinued.
  • 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 in recent times 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.

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