A Trial of Dehydroepiandrosterone (DHEA) Treatment for in Vitro Fertilization (IVF)

Specific Aims: The ability of women to respond to ovulation inducing medications also called ovarian reserve, declines with age. (Navot, Bergh et al. 1991; Scott, Leonardi et al. 1993; Toner and Flood 1993 ; Scott and Hofmann 1995; Scott 1996; ASRM 2002) When attempting in-vitro fertilization (IVF), older women produce few oocytes (Chuang, Chen et al. 2003; Orvieto, Bar-Hava et al. 2004) and yield few normal embryos, even when exposed to maximal gonadotropin stimulation.(Orvieto, Bar-Hava et al. 2004) As a result reproductive success for women over 40 years old is significantly reduced compared to younger women. Older ovaries have few antral follicles, high rates of follicular degeneration (atresia)(Faddy 2000) and increased "resistance" to ovulation induction.(Filicori 1999; Chuang, Chen et al. 2003; Kupesic, Kurjak et al. 2003) A delay in onset of atresia could salvage follicles for later ovulation. Our long term goal is to elucidate the role of DHEA on follicular dynamics in the human ovary and to better understand the interaction of DHEA supplementation with other treatments for ovulation induction, especially among older reproductive age women. The specific hypothesis behind the proposed research is that DHEA is a regulator of follicular dynamics acting in the early pre-gonadotropin dependent stage of initial primordial follicle recruitment and growth. That hypothesis is based on the following observations. First, at physiological doses DHEA increases serum levels of the insulin-like growth factor (IGF-l).(Casson, Santoro et al. 1998) DHEA is produced by the ovarian theca,(Burger 2002) increased concentration of follicular DHEA is associated with increased aromatase activity,(Franks, Mason et al. 2000) and DHEA is a prohormone that is converted in peripheral tissues to estrogens.(Haning, Hackett et al. 1993) Second, DHEA exposed rats simulate polycystic ovary syndrome (PCO)(Roy, Mahesh et al. 1962) and have a higher percentage of meiotically active oocytes and less evidence of atresia.(Anderson, Lee et al. 1997) Women chronically exposed to androgens can develop PCO-like ovaries.(Amirikia, Savoy-Moore et al. 1986) Women with anovulatory PCO have less evidence of follicle atresia.(Franks, Mason et al. 2000) Third, Casson et al (Casson, Lindsay et al. 2000) found a small increase in follicle number and E2 response to ovulation induction after two months of DHEA (80 mg/day) administration to five women, with proven ovarian resistance to stimulation. Preliminary data Barad and Gleicher reported a patient with a history of severely decreased ovarian reserve who dramatically increased her oocyte production over nine cycles of treatment while taking DHEA and ovulation induction.(Barad and Gleicher 2005) The dramatic increase in oocyte production seen in this patient did not occur until after four months of DHEA treatment (75 mg/day). This treatment duration is in keeping with the interval required for normal follicular initiation of recruitment and growth(Gougeon 1986) and raises that possibility that the Casson et al. did not treat their subjects long enough to achieve maximum effect. Our case report was followed by a case control study that showed increased oocyte production and improved embryo quality among 25 DHEA treated patients, whose pre-treatment cycle acted as control.(Barad and Gleicher 2005) More recently we showed that DHEA treated patients with significant decreased ovarian reserve have higher pregnancy rates compared to controls.(Barad, Brill et al. 2006) Based on these observations the experimental focus of this project is on the interaction of DHEA adjuvant treatment with gonadotropin treatment during ovulation induction. The specific aims are designed to provide a comprehensive assessment of this effect. 1. DHEA treatment will increase pregnancy rates among women 40 to 45 years old. 2. DHEA treatment will increase antral follicle counts. 3. DHEA will lead to increased anti-mullerian (AMH) hormone levels. 4. DHEA treatment will increase mean and peak follicular phase estradiol. 5. DHEA treatment will increase the number of oocytes retrieved in IVF cycles compared to placebo. Research Plan: Placebo controlled randomized trial of 2 months of DHEA pretreatment prior to ovulation induction for IVF-ET. Hypothesis 1: Two months of DHEA pretreatment will improve the chance of pregnancy and lead to greater oocyte and embryo yields relative to placebo treated control patients. Hypothesis 2: Embryos produced following 2 months of pretreatment with either DHEA alone OR with DHEA plus supplemental FSH 150 units per day will result in embryos with better morphology Hypothesis 3a-c: Two months of DHEA pretreatment will result in: a) increased antral follicle counts, increased AMH, b) increased mean and peak estradiol and c) increased oocyte production Recruitment plan: * New patients presenting for treatment. * Possible print, magazine or Radio advertisement References: Amirikia, H., R. T. Savoy-Moore, et al. (1986). 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