9 Mar 2012
BACKGROUND: It has been twelve years since the first report suggesting that exogenous androgens could improve ovarian response in those women classified as having diminished ovarian reserve (DOR) . Despite the argument as to the definition of ovarian reserve (OR) , it is generally accepted that women over the age of 40 will have declining ovarian reserve and that this is the major limiting factor to their success with assisted reproductive technology. It is important to understand DOR as women over 40 represent the most rapidly growing group of patients seeking fertility treatment .
It has been suggested that ovarian reserve is not static but rather dynamic from cycle to cycle, and that the diagnostic indicators of OR, basal follicle stimulating hormone (FSH), anti-Mullerian hormone (AMH) and antral follicle count (AFC) are age-specific and change in parallel with OR . FSH and AMH seem to be less reliable prognosticators of success. In our hands AFC and a trial of stimulation with maximum doses of gonadotrophins have proved to be the best markers of ovarian response.
Interestingly, a survey of 196 IVF units worldwide has shown that 26% of IVF units utilize dehydroepiandrosterone (DHEA) for patients with DOR . Since 2005 reports from Gleicher and Barad [6-8]have shown that DHEA supplementation improves ovarian response in terms of both quantity and quality of oocytes and embryos, leading to increased pregnancy rates. In addition, Gleicher and our group have shown decreased miscarriage rates from over 50% in women over age 40 undergoing IVF to 25% and less with DHEA pre-treatment. . There is now direct evidence from preimplantation genetic screening that DHEA reduces embryo aneuploidy to explain these results [10,11].
At the 14th World Congress of Gynecological Endocrinology in 2010 our group presented data to show that pre-treatment of older women with DHEA followed by controlled ovarian hyperstimulation and intrauterine insemination (COH-IUI) resulted in an excellent clinical pregnancy rate of 23% per cycle. The current study was undertaken to evaluate the efficacy of DHEA pre-treatment in the same age group of older women who had failed to conceive with COH-IUI and proceeded to in vitro fertilization (IVF).
METHODS: A retrospective cohort study was conducted in a private university affiliated fertility centre. Despite a large intake of appropriate patients, we have been unable to conduct prospective randomized trials (RCT) with DHEA as women in this age range refuse to be randomized. From a total of over 600 patients who began treatment with DHEA from Feb. 2006 to Nov. 2011 we have ongoing data on over 400patients, a significant number having been lost to follow up.
84 IVF cycles were performed in women between ages 40 and 46 who had been pretreated with at least 3 months of oral micronized DHEA 25 mg three times daily. We included all patients up to age 46 for analysis and then repeated the analysis after excluding patients who were age 43 and older at the time of commencing the IVF cycle. This was done in order to compare our results with those of the only RCT in the literature that also excluded patients over age 43 .
Our inclusion criteria were based upon patients with late maternal age who demonstrated poor ovarian follicular response to an oral aromatase inhibitor, or to COH-IUI with high-dose gonadotrophins, elevated cycle day 3 FSH levels, very low AMH levels, low antral follicle counts, and previous failed or poor stimulation for IVF at other institutions.
Informed consent for the use of DHEA was obtained through physician discussion and patient review of all published data on DHEA with respect to fertility treatment.
Side effects such as acne, hirsutism, hair loss, weight gain and sleep difficulties were rare and seldom necessitated discontinuation of DHEA (less than 2% of patients).
All patients had an endometrial biopsy in the mid-luteal phase of the immediately pre-IVF menstrual cycle in order to increase the implantation rate . Stimulation protocols were either a microdose GnRH agonist flare with FSH and FSH/hMG combined as described by Schoolcraft , or maximal dose (450 IU) rec-FSH and the addition of a GnRH antagonist. Intracytoplasmic sperm injection (ICSI) was used in all cases.
We had a significant male factor component in 33% of cases. Embryo transfer was performed by one of two operators at 72 hr. post-oocyte retrieval utilizing a double-lumen, bulb-tipped catheter assisted by transabdominal ultrasound guidance.
RESULTS: We had 16 IVF cycles cancelled due to failure to stimulate with maximal doses of gonadotrophins and 52 cycles were completed to embryo transfer. Table I summarizes the results of the 52 cycles with respect to measured parameters in the Non-pregnant group and the Pregnant group. Unfortunately AMH (data not shown) was only obtained in 10 patients due to the recent availability and high cost of the test in Canada.
The analysis of the 52 completed IVF cycles show 18 pregnancies (35%) and 34 cycles with no pregnancy (65%). There were 6 early pregnancy losses, including one chemical (33%), and 12 patients delivered as of November 2011 (67%). The clinical pregnancy rate per embryo transfer was 33% and the live birth rate per embryo transfer was 21%. One baby was stillborn and excluded from the analysis. There were 4 multiple pregnancies including one twin loss.
CONCLUSION: U.S. national IVF success rates, as reported by the CDC/SART for 2009, cite 4 to 12% live birth rates in women over age 41. Pre-treatment with DHEA followed by IVF in our study resulted in an improved live birth rate of 21% per embryo transfer which is the ultimate marker of oocyte quality. Furthermore our results are in keeping with the small prospectively randomized controlled trial of Wiser and Shulman that reported a 23% live birth rate in the DHEA group as compared with 4% in the control group .
The mechanism of action of DHEA is still unclear. As discussed by Gleicher in his excellent review of ovarian aging, a direct effect of DHEA in rescuing or rejuvenating aged oocytes seems unlikely . New research with androgen receptor knockout mice has shown that ovarian androgens are essential to folliculogenesis , and a more plausible concept of DHEA action may be that of follicular conditioning resulting from an improvement in the ovarian environment leading to improved oocyte quality. This may be in addition to the beneficial effect of DHEA on mitochondrial function . Our centre has recently added the mitochondrial nutrient coenzyme Q10 in a dose of 600 mg per day as an additional supplement for older women and others with DOR in response to the positive results from mouse studies reported by Bentov and Casper .
In summary, androgen supplementation with DHEA in older women represents a safe, effective, low cost therapeutic modality to improve the ovarian environment and decrease aneuploidy that leads to excellent clinical pregnancy and live birth rates with IVF in this worst prognosis group of women who have failed to conceive by other means. Although we have had babies born to DHEA-treated patients up to age 46, both spontaneously and with COH-IUI, this study and the Shulman RCT strongly suggest that women age 43 and over who have failed to conceive despite treatment with DHEA, should not be offered IVF. They should instead be counselled with regard to the greater success of donor oocyte programmes.
Acknowledgement: We thank Dr. Karen Cross for her help with the statistical analysis.
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