Effect of Testosterone Treatment on Embryo Quality

• ClinicalTrials.gov Identifier: NCT01662466
• Recruitment Status: Recruiting
• First Posted: August 10, 2012
• Last Update Posted: November 12, 2020
• Sponsor: Center for Human Reproduction
• Collaborator: Foundation for Reproductive Medicine
• Information provided by (Responsible Party): Center for Human Reproduction

Tracking Information

• First Submitted Date: August 2, 2012
• First Posted Date: August 10, 2012
• Last Update Posted Date: November 12, 2020
• Study Start Date: July 1, 2012
• Estimated Primary Completion Date: June 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 11, 2012)

Clinical and Ongoing Pregnancy [ Time Frame: 8 weeks post treatment initiation ]

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.

Original Primary Outcome Measures (submitted: August 9, 2012)

Clinical and Ongoing Pregnancy [ Time Frame: 12 weeks post treatment initiation ]

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.

Current Secondary Outcome Measures (submitted: August 9, 2012)

• Measures of Atresia [ Time Frame: 8 weeks after intervention initiation ]
  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 ]
  The number of oocytes retrieved at oocyte retrieval for in-vitro fertilization will be compared between the treatment group and placebo.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effect of Testosterone Treatment on Embryo Quality
• Official Title: A Randomized Double Blind Control Trial of Transdermal Testosterone Supplementation vs Placebo on Follicular Development and Atresia, Oocyte and Embryo Quality Among Women With Diminished Ovarian Reserve Undergoing in Vitro Fertilization
• Brief Summary: The purpose of this study is to determine the effect of treatment with trans-dermal testosterone cream compared to placebo on measures of ovarian reserve, oocyte and embryo quality, and pregnancy rates among women with evidence of diminished ovarian reserve that have persistently low serum testosterone and free testosterone after completing six previous weeks of DHEA supplementation.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Primary Ovarian Insufficiency
• Female Infertility Due to Diminished Ovarian Reserve

Intervention

• Drug: Testosterone cream (0.5mg per gram)
  Testosterone cream 2 gms per day applied transdermally to the left wrist to deliver 1.mg daily dose with estimated absorption of 100 ug per day testosterone
  Other Name: Testosterone
• Dietary Supplement: DHEA
  DHEA 25mg tid
  Other Name: Dehydroepiandrosterone
• Drug: Placebo
  Carrier cream without added testosterone in the identical type of pump
  Other Name: Carrier cream without added testosterone

Study Arms

• Active Comparator: DHEA+Testosterone
  These patients will be administered the testosterone cream along with standard DHEA supplements
  Interventions:

  • Drug: Testosterone cream (0.5mg per gram)
  • Dietary Supplement: DHEA
• Placebo Comparator: DHEA+Placebo
  These patients will receive the placebo cream along with her DHEA supplements. In other words, no testosterone will be administered.
  Interventions:

  • Dietary Supplement: DHEA
  • Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 9, 2012): 180
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2022
• Estimated Primary Completion Date: June 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Women with 38 to 44 years old planning to undergo ovulation induction for IVF who are willing to sign an informed consent.
• BMI > 18 and <= 30 kg/m^2
• FSH > 10 mIU/mL
• AMH =< 1.05 ng/mL
• Using DHEA for treatment of DOR/POA.
• Baseline Total Testosterone less than 30 ng per deciliter (1.0 nmol per liter) or serum free testosterone concentrations of less than 3.5 pg per milliliter (12.1 pmol per liter), which are below the median values for normal premenopausal women (Endocrine Sciences, Calabasas Hills, Calif.).

Exclusion Criteria:

• History of hormone dependent neoplasm
• History of severe acne or hirsutism.
• Hyperlipidemia.
• Pre existing cardiac, renal or hepatic disease

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 38 Years to 44 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jolanta Tapper, MD MS; 212 994-4400 ext 4406; jtapper@theCHR.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01662466
• Other Study ID Numbers: 072312-01; CHR-DHEA-testosterone-2012 ( Other Identifier: Center for Human Reproduction )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: We do not plan to share IPD

• Responsible Party: Center for Human Reproduction
• Study Sponsor: Center for Human Reproduction
• Collaborators: Foundation for Reproductive Medicine

Investigators

• Study Chair: Norbert Gleicher, MD; Center for Human Reproduction
• Principal Investigator: David H Barad, MD, MS; Center for Human Reproduction

• PRS Account: Center for Human Reproduction
• Verification Date: February 2020