Effect of Testosterone Treatment on Embryo Quality

• Clinical and Ongoing Pregnancy [ Time Frame: 8 weeks post treatment initiation ] [ Designated as safety issue: No ]
  Clinical pregnancy is defined as the presence of a viable gestational sac visible in the uterus 4 weeks after embryo transfer. Clinical ongoing pregnancy is defined as intrauterine pregnancy with evidence of an active fetal heart at 6 weeks after embryo transfer.
  
  

• Measures of Atresia [ Time Frame: 8 weeks after intervention initiation ] [ Designated as safety issue: No ]
  1. Follicular fluid will be collected separately for the first 5 follicles aspirated that are at least 18mm diameter for each patient.
  2. Granulosa cell counts will be performed on each follicle fluid. Granulosa cell counts of <10,000 per follicle will be considered atretic.
  3. Aliquots of follicular fluid will be analyzed for Testosterone, androstenedoine and estradiol using standard immuno assay. Healthy follicles should be capable of metabolizing testosterone to estradiol and should have a higher concentration estradiol (in nmol/ml) compared to testosterone
  
  
• Oocytes number [ Time Frame: 8 weeks after initiation of intervention ] [ Designated as safety issue: No ]
  The number of oocytes retrieved at oocyte retrieval for in-vitro fertilization will be compared between the treatment group and placebo.
  
  

At CHR the investigators have been using DHEA supplementation to improve ovarian response to ovulation induction for in vitro fertilization for about five years (Barad, Brill et al. 2007; Barad, Weghofer et al .2009; Gleicher, Ryan et al. 2009; Gleicher, Weghofer et al. 2010; Gleicher and Barad 2011). Our views on the effect of androgens on the follicular environment have recently been reviewed (Gleicher, Weghofer et al. 2011). A recent analysis of androgen metabolites of DHEA in our patients suggested that women who successfully respond to DHEA supplementation with increased egg production and clinical pregnancy had testosterone above the normal median values for reproductive age women. There also appears to be a cohort of women who did not respond to DHEA and who had very low serum testosterone. The investigators decided to investigate if supplementing those women with testosterone to the normal female range would improve ovarian function and possibly increase pregnancy rates.

Recruitment & Experimental Plan

• A baseline blood draw following completion of 6 weeks of DHEA supplementation will determine eligibility for the study. The baseline blood determinations are part of the standard pre cycle screening at CHR for all patients.
• After signing informed consent subjects will be randomly assigned to either active testosterone cream treatment or placebo.
• Active treatment will consist of a testosterone delivery system that will deliver transdermal testosterone cream(0.5 mg per gram of cream.) The cream and placebo cream will be compounded by Metro Drugs (New York, NY) and dispensed in calibrated pump that will deliver one gram of cream per stroke. Transdermal absorption is about 10% so 2 grams (1.0 mg) per day applied to the skin will deliver about 100 ug per day. In preliminary analysis we have determined that a 2 gram dose of this preparation will raise total testosterone to our target range of between 50 and 100 ng/dL.
• The dose of testosterone cream will be 2 grams of cream per day applied to the left inner forearm. The study medication will continue to be applied for 6 weeks.
• All patients with evidence of diminished ovarian reserve in our practice are treated with DHEA. Thus, patients in this study will be receiving DHEA + testosterone or DHEA + Placebo. Patients who achieve a level of serum testosterone in the desired range using DHEA alone will not be eligible for this study.