OVARIAN STIMULATION: OPTIMIZING RESPONSE IN WOMEN WITHELEVATED BASAL BLOOD LH LEVELS(I.E; 40Y, DIMINISHED OVARIAN RESERVE, PCOS).
Geoffrey Sher MD
Women, who are over 40 years and/or those who have diminished ovarian reserve requiring ovarian stimulation, are traditionally labeled as being producers of “poor quality eggs and embryos, often leading them to resort to ovum donation prematurely. In fact, such is not inevitable, provided thatthe “recipe” or “one size fits all” attitude towards ovarian stimulation is supplanted by one that embraces a customized approach that addresses specific individualized needs on a case by case basis. This article addresses several concepts that must be considered in order to arrive at a rational and individualized approach to ovarian stimulation.
Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) are both produced by the pituitary gland. Upon reaching the ovaries, LH produced by the pituitary gland elicits the production of Testosterone and other androgens by ovarian connective tissue known as stroma or theca. The testosterone is delivered to the follicle where it is converted by FSH to estrogen (estradiol/E2). Accordingly some LH is essential for testosterone “fueling” of follicle and egg development. However, too much testosterone represents an “overdose” and is very prejudicial to normal follicle and egg development, leading to poor embryo quality and failed ART.
Women who have diminished ovarian reserve (elevated FSH, low Inhibin B, abnormal clomiphene challenge tests, history of poor response to gonadotropins), older women (>40 years tend to produce increased amounts of LH (with increased biological potency) and also often have an overgrowth of testosterone producing ovarian stroma ( the ovarian “LH target”). Such women accordingly have a higher susceptibility to LH-mediated ovarian testosterone production. Unless their ovarian exposure to LKH is regulated through the application of very individualized ovarian stimulation protocols, they will be predisposed to producing poor quality eggs and embryos and to having poor IVF birth rates.
1. Use of Agonist- “Flare protocols” in women who have diminished ovarian and/or and some women who are high responders (.those with polycystic ovarian syndrome) .
With “Flare Protocols” agonist (e.g Lupron, Buserelin, Superfact, Nafarelin, Synarel etc) therapy is initiated with the onset of menstruation (cycle day 1-3) and synchronous with the commencement of gonadotropin administration. Agonists, upon administration, immediately elicit an expunging of stared LH reservoir in the pituitary gland. Upon reaching the ovary, the excessive LH causes an immediate release of testosterone and other androgens by the ovarian stroma (theca). Older women, women with “diminished ovarian reserve (“poor responders”) and women with polycystic ovarian syndrome-PCOS (often high responders)tend to have elevated LH production and ovarian stromal hyperplasia. Accordingly over-exposure to excessive testosterone adversely impacts both follicle and egg development.Since egg quality determines embryo quality, it should not come as a surprise that in such cases the woman ends up with poor quality eggs and embryos and that pregnancy rates are usually very low.
2. Use of “Late follicular phase Antagonist suppression protocols in older women and women and in “poor responders” who have diminished ovarian reserve”.
The conventional use of GnRH antagonists (e.g Antagon, Ganarelix, Cetrotide, Orgalutron, Cetrorelix etc) involves the administration of 250mcg Antagonist daily from the 6or 7th day of stimulation until the day of the hCG trigger. This is problematic, for women with high LHand stromal hyperplasia (i.e. women with diminished ovarian reserve (“poor responders”), women over 40yrs. In such cases the “late” initiation of pituitary suppression with GnRH antagonists fails to suppress pituitary LH in the early stages of follicular development which could well be the most vulnerable and most critical stage of egg development. This will often result in compromised egg/embryo quality and failure to conceive.
3. Use of protocols that prescribe large amounts of LH-containing gonadotropins in older women and women and in “poor responders” who have diminished ovarian reserve”.
LH-containing gonadotropins [e.g Repronex, Menopur, Humagon, Niken HMG and Luveris ( LHr) etc] should be administered sparingly and only in small amounts to older women, and to women with diminished ovarian reserve (poor responders) because by further contributing LH the likelihood of excessive testosterone exposure and poor outcomes will increase.
4.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 rise in LH –induced ovarian androgens (male hormones ….mainly testosterone) will adversely influence egg development, resulting in compromised embryo quality. However, prolonged administration of GnRH agonists starting several days prior to the initiation of gonadotropin therapy and then continued through the gonadotropin stimulation phase (until the day of the hCG trigger) has one possible down side, i.e the agonist can compete for FSH binding sites on follicle cell FSH receptors and thereby blunt response to stimulation. Obviously this is the last thing that a “poor responder “needs. It is for this reason that about 7 years ago, the author introduced the Agonist/Antagonist Conversion Protocol (A/ACP)
With the A/ACP, a 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 (usually Antagon). Commencing within a few days of initiating antagonist therapy, daily FSH-gonadotropins (usually Folistim) injections are commenced. A few days later daily injections of LH 37U, (Luveris) is added. Gonadotropin and antagonist therapy are both discontinued on the day of the hCG trigger. Frankly, the author currently prescribes the A/ACP for most of his IVF patients regardless of whether they are “normal responders” or “poor responders”. Preliminary results suggest a significant improvement in egg number, egg/embryo quality as well as in implantation and viable IVF pregnancy rates.
5. Estrogen “priming”:
The author has shown that the addition of estradiol for about a week following the initiation of the 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 (E2V/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.
It is remarkable, that while using the A/ACP + "estrogen priming " in “poor responders “ whose FSH levels have often been markedly elevated ( 9-44 MIU/ml) the authors cycle cancellation is very low (6-8%).. Many such patients who previously had been advised to give up and switch to ovum donation have subsequently achieved viable pregnancies at SIRM using the A/ACP with “estrogen priming”.
“When designing an individualized ovarian stimulation protocol women 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 FSH-dominant medications, limiting the administration of LH-containing gonadotropins, and accurately timing the hCG trigger to coincide wit optimal egg development.