title: Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.
abstract: BACKGROUND
  Infertility is a condition affecting 10% to 15% of couples of reproductive age. It is generally defined as "the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse". The treatment of infertility may involve manipulation of gametes or of the embryos themselves. These techniques are together known as assisted reproductive technology (ART). Practitioners are constantly seeking alternative or adjunct treatments, or both, in the hope that they may improve the outcome of assisted reproductive techniques. This Cochrane review focusses on the adjunct use of synthetic versions of two naturally-produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction.DHEA and its derivative testosterone are steroid hormones proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation, leading to greater oocyte yields and, in turn, increased chance of pregnancy.
  
  
  OBJECTIVE
  To assess the effectiveness and safety of DHEA and testosterone as pre- or co-treatments in subfertile women undergoing assisted reproduction.
  
  
  METHODS
  We searched the following electronic databases, trial registers and websites up to 12 March 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the Web of Science, PubMed and OpenSIGLE. We also carried out handsearches. There were no language restrictions.
  
  
  METHODS
  We included randomised controlled trials (RCTs) comparing DHEA or testosterone as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction.
  
  
  METHODS
  Two review authors independently selected studies, extracted relevant data and assessed them for risk of bias. We pooled studies using fixed-effect models. We calculated odds ratios (ORs) for each dichotomous outcome. Analyses were stratified by type of treatment. There were no data for the intended groupings by dose, mode of delivery or after one/more than one cycle.We assessed the overall quality of the evidence for the main findings using the GRADE working group methods.
  
  
  RESULTS
  We included 17 RCTs with a total of 1496 participants. Apart from two trials, the trial participants were women identified as 'poor responders' to standard IVF protocols. The included trials compared either testosterone or DHEA treatment with placebo or no treatment.When DHEA was compared with placebo or no treatment, pre-treatment with DHEA was associated with higher rates of live birth or ongoing pregnancy (OR 1.88, 95% CI 1.30 to 2.71; eight RCTs, N = 878, I² statistic = 27%, moderate quality evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 15% and 26%. However, in a sensitivity analysis removing trials at high risk of performance bias, the effect size was reduced and no longer reached significance (OR 1.50, 95% CI 0.88 to 2.56; five RCTs, N = 306, I² statistic = 43%). There was no evidence of a difference in miscarriage rates (OR 0.58, 95% CI 0.29 to 1.17; eight RCTs, N = 950, I² statistic = 0%, moderate quality evidence). Multiple pregnancy data were available for five trials, with one multiple pregnancy in the DHEA group of one trial (OR 3.23, 95% CI 0.13 to 81.01; five RCTs, N = 267, very low quality evidence).When testosterone was compared with placebo or no treatment we found that pre-treatment with testosterone was associated with higher live birth rates (OR 2.60, 95% CI 1.30 to 5.20; four RCTs, N = 345, I² statistic = 0%, moderate evidence). This suggests that in women with an 8% chance of live birth with placebo or no treatment, the live birth rate in women using testosterone will be between 10% and 32%. On removal of studies at high risk of performance bias in a sensitivity analysis, the remaining study showed no evidence of a difference between the groups (OR 2.00, 95% CI 0.17 to 23.49; one RCT, N = 53). There was no evidence of a difference in miscarriage rates (OR 2.04, 95% CI 0.58 to 7.13; four RCTs, N = 345, I² = 0%, low quality evidence). Multiple pregnancy data were available for three trials, with four events in the testosterone group and one in the placebo/no treatment group (OR 3.09, 95% CI 0.48 to 19.98; three RCTs, N = 292, very low quality evidence).One study compared testosterone with estradiol and reported no evidence of a difference in live birth rates (OR 2.06, 95% CI 0.43 to 9.87; one RCT, N = 46, very low quality evidence) or miscarriage rates (OR 0.70, 95% CI 0.11 to 4.64; one RCT, N = 46, very low quality evidence).The quality of the evidence was moderate, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in some trials.
  
  
  CONCLUSIONS
  In women identified as poor responders undergoing ART, pre-treatment with DHEA or testosterone may be associated with improved live birth rates. The overall quality of the evidence is moderate. There is insufficient evidence to draw any conclusions about the safety of either androgen. Definitive conclusions regarding the clinical role of either androgen awaits evidence from further well-designed studies.
authors.affiliation: Obstetrics and Gynaecology, University of Auckland, FMHS Park Road, Grafton, Auckland, New Zealand, 1142.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Nagels
authors.forename: Josephine R
authors.initials: JR
authors.lastname: Rishworth
authors.forename: Charalampos S
authors.initials: CS
authors.lastname: Siristatidis
authors.forename: Ben
authors.initials: B
authors.lastname: Kroon
mesh_terms: D000022:Abortion, Spontaneous / Q000453:epidemiology; D000328:Adult; D000728:Androgens / Q000009:adverse effects / Q000627:therapeutic use*; D003687:Dehydroepiandrosterone / Q000009:adverse effects / Q000627:therapeutic use*; D004958:Estradiol / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007247:Infertility, Female / Q000628:therapy*; D050498:Live Birth / Q000453:epidemiology*; D011247:Pregnancy; D018873:Pregnancy Rate; D016032:Randomized Controlled Trials as Topic; D027724:Reproductive Techniques, Assisted; D013739:Testosterone / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000728:Androgens; D013739:Testosterone; D003687:Dehydroepiandrosterone; D004958:Estradiol