Optimizing Response to Ovarian Stimulation in Women Who Have Compromised Ovarian Reserve: A Personal Approach.

Dr. Geoffrey Sher - July 8, 2016
Optimizing Response to Ovarian Stimulation in Women Who Have Compromised Ovarian Reserve: A Personal Approach.

Older women, and those who have diminished ovarian reserve (DOR) with resistance to ovarian stimulation (“poor responders” are often labeled as being producers of “poor quality" eggs and embryos, and advised to seek IVF with egg donation. In fact, in my opinion such “recipe” or “one size fits all” attitude towards ovarian stimulation is not always justified. In my opinion it should be replaced by a customized approach that addresses specific individualized needs on a case by case basis. This article addresses my personal preference in selecting a stimulation protocol in such cases. The older a woman becomes, the more likely it is that her eggs will be chromosomally/genetically "incompetent" (not have the potential upon being fertilized and transferred, to result in a viable pregnancy). That is why, the likelihood of failure to conceive, miscarrying and of giving birth to a chromosomally defective child (e.g. with Down Syndrome) increases with the woman’s advancing age. In addition, as women age beyond 35Y there is commonly a progressive diminution in the number of eggs left in the ovaries, i.e. diminished ovarian reserve (DOR). So it is that older women as well as those who (regardless of age) have DOR have a reduced potential for IVF success. Much of this is due to the fact that such women tend to have increased production of LH biological activity which can result in excessive LH-induced ovarian male hormone (predominantly testosterone) production which in turn can have a deleterious effect on egg/embryo “competency”. While it is presently not possible by any means, to reverse the age-related effect on the woman’s “biological clock," certain ovarian stimulation regimes, by promoting excessive LH production (e.g. short agonist/Lupron- “flare” protocols, clomiphene and Letrozole), can make matters worse. Similarly, the amount/dosage of certain fertility drugs that contain LH/hCG (e.g. Menopur) can have a negative effect on the development of the eggs of older women and those who have DOR and should be limited. I try to avoid using such protocols/regimes (especially) in older women and those with DOR, favoring instead the use of the agonist/antagonist conversion protocol (A/ACP), a modified, long pituitary down-regulation regime, augmented by adding supplementary human growth hormone (HGH).

  • The Agonist/Antagonist Conversion Protocol Women who have a tendency to overproduce LH (i.e poor responders, older women) require a form of pituitary blockade (with GnRH agonist or an antagonist) throughout the stimulation period to prevent the progressive and excessive rise in LH –induced ovarian male hormones, (mainly testosterone) can adversely influence egg development, resulting in compromised embryo quality. However, prolonged administration of GnRH agonists (e.g. Lupron/Lucrin/Buserelin/Superfact/Decapeptyl) starting several days prior to the initiation of gonadotropin therapy (the long protocol) and then continued through the gonadotropin stimulation phase (until the day of the hCG trigger) has one possible down side, namely that the agonist can compete for FSH binding sites on follicle cell FSH receptors and thereby blunt the response to gonadotropin stimulation. Obviously this is the last thing that women who have DOR (“poor responders”) need. It is for this reason that I, some time back developed the Agonist/Antagonist Conversion Protocol (A/ACP) With this protocol, the women starts by taking a combined BCP for 8 or more days, whereupon a GnRH agonist is overlapped with the pill for two days. The BCP is then stopped and daily agonist administration continues until the onset of menstruation (usually within 3-6 days). At this point the agonist is completely supplanted with daily injections of 125mcg, antagonist (Ganirelix/Cetrotide/Orgalutron). Commencing within a few days of initiating antagonist therapy, daily FSH-gonadotropins (usually Folistim) injections are commenced. A few days later daily injections of Menopur 75U daily is added. Gonadotropin and antagonist therapy are both discontinued on the day of the hCG trigger
  • Agonist/antagonist conversion protocol combinred with Estrogen “priming”: The addition of parenteral estradiol valerate (E2V) for about a week following the initiation of the agonist/antagonist conversion protocol (A/ACP), prior to commencing FSH-dominant gonadotropin stimulation appears to further enhance ovarian response, presumably by up-regulating ovarian FSH-receptors. Accordingly, for women with severely diminished ovarian reserve (“very poor responders”) he adds “estrogen priming” by administering of estradiol valerate (Delestrogen) during the 1st week of antagonist therapy. This appears to enhance ovarian follicular response to gonadotropins. Following one week of “estrogen priming”, gonadotropin therapy is commenced and is this is continued along with antagonist therapy (as above) until the day of the hCG trigger. In my opinion, in cases of severe DOR with very poor response to stimulation, the use of A/ACP + "estrogen priming " there is in my experience a relatively low (<15%) cycle cancellation rate. In fact , a significant number of patients who previously had been advised to give up and switch to egg donation subsequently achieved viable pregnancies using the A/ACP with “estrogen priming”.
  • Augmentation of ovarian stimulation with Human Growth Hormone (HGH) Several researchers have shown that the administration of human growth hormone (HGH), as an adjunct to ovarian stimulation, enhances follicle response in older women and those with DOR and so can help optimize egg quality. It is thought that HGH hormone by increasing the production of insulin-like growth factor 1 (IGF-1), improves follicle development, estrogen hormone production and egg maturation. 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. My personal experience in selectively prescribing HGH as an adjuvant to women with DOR, older women and those with unexplained egg quality deficits, is that if used in combination with the A/ACP it seems to indeed enhance egg quality and ovarian response, culminating in improved IVF outcome.
  • Embryo Banking: I further recommend that such women be offered access to embryo banking of PGS (next generation gene sequencing/NGS)-selected normal blastocysts, the subsequent selective transfer of which by allowing them to to capitalize on whatever residual ovarian reserve and egg quality might still exist and thereby “make hay while the sun still shines” could significantly enhance the opportunity to achieve a viable pregnancy

“When designing an individualized ovarian stimulation protocol woman with diminished ovarian reserve and/or older women the primary objective is to optimally regulate the intraovarian testosterone environment by: 1. avoiding protocols of stimulation that cause increased LH exposure, using predominantly FSH-dominant medications such as Follistim/Gonal-F and Puregon, limiting the administration of LH-containing gonadotropins, augmenting the protocol by adding HGH accurately timing the hCG trigger to coincide wit optimal follicle/egg development and offering such women access to “Embryo Banking with the selective transfer of PGS-selected embryos.


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