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Higher live birth rate following transdermal testosterone pretreatment in poor responders: a systematic review and meta-analysis

Published:October 06, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.09.022

      Abstract

      A systematic review and meta-analysis was performed aiming to identify good-quality randomized controlled trials (RCT) evaluating testosterone pretreatment in poor responders. Eight RCTs were analysed, evaluating 797 women. Transdermal testosterone gel was used in all studies, with a dose ranging from 10 to 12.5 mg/day for 10–56 days. The main outcome measure was achievement of pregnancy, expressed as clinical pregnancy or live birth. Testosterone pretreatment was associated with a significantly higher live birth (risk ratio [RR] 2.07, 95% confidence interval [CI] 1.09–3.92) and clinical pregnancy rate (RR 2.25, 95% CI 1.54–3.30), as well as a significant increase in the number of cumulus–oocyte complexes retrieved. Significantly fewer days to complete ovarian stimulation, a lower total dose of gonadotrophins, a lower cancellation rate due to poor ovarian response and a thicker endometrium on the day of triggering of final oocyte maturation were observed. No significant differences were observed in oestradiol concentration, the numbers of follicles ≥17 mm, metaphase II oocytes, two-pronuclear oocytes and embryos transferred, and the proportion of patients with embryo transfer. The current study suggests that the probability of pregnancy is increased in poor responders pretreated with transdermal testosterone who are undergoing ovarian stimulation for IVF.

      Keywords

      Introduction

      A significant proportion of women undergoing ovarian stimulation for IVF, ranging from 9% to 24% (
      • Kyrou D.
      • Kolibianakis E.M.
      • Venetis C.A.
      • Papanikolaou E.G.
      • Bontis J.
      • Tarlatzis B.C.
      How to improve the probability of pregnancy in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis.
      ;
      • Patrizio P.
      • Vaiarelli A.
      • Levi Setti P.E.
      • Tobler K.J.
      • Shoham G.
      • Leong M.
      • Shoham Z.
      How to define, diagnose and treat poor responders? Responses from a worldwide survey of IVF clinics.
      ;
      • Surrey E.S.
      • Schoolcraft W.B.
      Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques.
      ), show poor ovarian response and are characterized by severely diminished pregnancy rates (
      • Li F.
      • Lu R.
      • Zeng C.
      • Li X.
      • Xue Q.
      Development and Validation of a Clinical Pregnancy Failure Prediction Model for Poor Ovarian Responders During IVF/ICSI.
      ;

      Liu, Y., Su, R., & Wu, Y. (2021). Cumulative Live Birth Rate and Cost-Effectiveness Analysis of Gonadotropin Releasing Hormone-Antagonist Protocol and Multiple Minimal Ovarian Stimulation in Poor Responders [Original Research]. 11(1047). https://doi.org/10.3389/fendo.2020.605939

      ). Among the numerous interventions evaluated in these women, androgen supplementation appears to be associated with an increased probability of live birth (

      Jeve, Y., & Bhandari, H. (2016). Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis [Review Article]. 9(2), 70-81. https://doi.org/10.4103/0974-1208.183515

      ;
      • Nagels H.E.
      • Rishworth J.R.
      • Siristatidis C.S.
      • Kroon B.
      Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction.
      ;
      • Noventa M.
      • Vitagliano A.
      • Andrisani A.
      • Blaganje M.
      • Viganò P.
      • Papaelo E.
      • Scioscia M.
      • Cavallin F.
      • Ambrosini G.
      • Cozzolino M.
      Testosterone therapy for women with poor ovarian response undergoing IVF: a meta-analysis of randomized controlled trials.
      ;
      • Richardson A.
      • Jayaprakasan K.
      The Use of Androgen Priming in Women with Reduced Ovarian Reserve Undergoing Assisted Reproductive Technology.
      ).
      Androgens have been shown to stimulate the early stages of follicular growth (
      • Vendola K.A.
      • Zhou J.
      • Adesanya O.O.
      • Weil S.J.
      • Bondy C.A.
      Androgens stimulate early stages of follicular growth in the primate ovary.
      ;
      • Weil S.J.V.
      • Zhou K.
      • Adesanya J.
      • Wang O.O.
      • Okafor J.
      • Bondy J.
      Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations.
      ), and to increase the number of primary, pre-antral and antral follicles (
      • Hillier S.G.
      • Tetsuka M.
      3 Role of androgens in follicle maturation and atresia.
      ;
      • Weil S.J.V.
      • Zhou K.
      • Adesanya J.
      • Wang O.O.
      • Okafor J.
      • Bondy J.
      Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations.
      ;
      • Weil S.
      • Vendola K.
      • Zhou J.
      • Bondy C.A.
      Androgen and Follicle-Stimulating Hormone Interactions in Primate Ovarian Follicle Development.
      ) as well as ovarian sensitivity to FSH (
      • Hillier S.G.
      • De Zwart F.A.
      Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro.
      ).
      Androgen supplementation has so far been evaluated in several randomized controlled trials (RCT) and meta-analysed in seven systematic reviews (
      • Bosdou J.K.
      • Venetis C.A.
      • Kolibianakis E.M.
      • Toulis K.A.
      • Goulis D.G.
      • Zepiridis L.
      • Tarlatzis B.C.
      The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: A systematic review and meta-analysis [Article].
      ;
      • González-Comadran M.
      • Durán M.
      • Solà I.
      • Fábregues F.
      • Carreras R.
      • Checa M.A.
      Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta-analysis.
      ;

      Jeve, Y., & Bhandari, H. (2016). Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis [Review Article]. 9(2), 70-81. https://doi.org/10.4103/0974-1208.183515

      ;
      • Noventa M.
      • Vitagliano A.
      • Andrisani A.
      • Blaganje M.
      • Viganò P.
      • Papaelo E.
      • Scioscia M.
      • Cavallin F.
      • Ambrosini G.
      • Cozzolino M.
      Testosterone therapy for women with poor ovarian response undergoing IVF: a meta-analysis of randomized controlled trials.
      ;
      • Sunkara S.K.
      • Pundir J.
      • Khalaf Y.
      Effect of androgen supplementation or modulation on ovarian stimulation outcome in poor responders: a meta-analysis.
      ;
      • Zhang Y.
      • Zhang C.
      • Shu J.
      • Guo J.
      • Chang H.M.
      • Leung P.C.K.
      • Sheng J.Z.
      • Huang H.
      Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.
      ), but no solid conclusions can currently be drawn regarding its effectiveness.
      In the latest systematic review and meta-analysis, an increased probability of live birth was present in women undergoing IVF after testosterone pretreatment (
      • Neves A.R.
      • Montoya-Botero P.
      • Polyzos N.P.
      Androgens and diminished ovarian reserve: The long road from basic science to clinical implementation. A comprehensive and systematic review with meta-analysis.
      ). However, in that meta-analysis, a literature search did not identify two RCT examining testosterone pretreatment (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ;
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      ), although it included an RCT with co-intervention (
      • Fábregues F.
      • Peñarrubia J.
      • Creus M.
      • Manau D.
      • Casals G.
      • Carmona F.
      • Balasch J.
      Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: A randomized, clinical trial [Article].
      ). Furthermore, no distinction was made between testosterone pretreatment and testosterone administration during ovarian stimulation (
      • Saharkhiz N.
      • Zademodares S.
      • Salehpour S.
      • Hosseini S.
      • Nazari L.
      • Tehrani H.G.
      The effect of testosterone gel on fertility outcomes in women with a poor response in in vitro fertilization cycles: A pilot randomized clinical trial.
      ). For these reasons, the accuracy and precision of the estimates in that meta-analysis could be significantly improved.
      The aim of the current meta-analysis was to evaluate the association between testosterone pretreatment and achievement of pregnancy, expressed as clinical pregnancy or live birth, in poor responders undergoing ovarian stimulation for IVF.

      Materials and methods

      The current systematic review and meta-analysis was registered in the PROSPERO International Prospective Register of Systematic Reviews (registration number CRD42021262098, date of registration 22 August 2021).

      Search strategy

      A computerized literature search in the MEDLINE, EMBASE, CENTRAL, ISI Web of Science and SCOPUS databases covering the period until July 2022 was performed independently by two reviewers (E.T.K. and J.K.B.), aiming to identify published RCT that evaluated the following research question: does pretreatment with testosterone increase the probability of pregnancy in poor responders undergoing ovarian stimulation with gonadotrophin-releasing hormone (GnRH) analogues and gonadotrophins for IVF? The search terms used are shown in Table 1. Various synonyms describing each term were entered as free-text terms in the electronic databases in an attempt to maximize the sensitivity of the search strategy. Additionally, the citation lists of all relevant publications and review articles were hand-searched. No language limitations were applied.
      Table 1Search terms used for the identification of eligible studies
      InterventionPopulationSetting
      (testosteron*)AND [(poor) OR (low) OR (slow) OR (inadequate) OR (suboptimal) OR (decreas*) OR (diminish*)] AND (respon*) OR (reserve)(in-vitro fertilization) OR (in vitro fertilization) OR (IVF) OR (intracytoplasmic sperm injection) OR (ICSI) OR (IVF/ICSI)

      Selection of studies

      Criteria for the inclusion/exclusion of studies were established prior to the literature search. Studies had to fulfil the following criteria for eligibility: (i) women characterized as poor responders irrespective of the definition; (ii) testosterone pretreatment in the intervention group irrespective of the dose and protocol used; (iii) ovarian stimulation for IVF using gonadotrophins and GnRH analogues; and (iv) a parallel design using a random allocation of patients in the groups compared. Studies with asymmetrical interventions (co-interventions) were excluded (Table 2). Selection of the studies was performed independently by two of the reviewers (E.T.K. and J.K.B.). Any disagreement was resolved by discussion.
      Table 2Excluded studies and reasons for exclusion
      StudyReason for exclusion
      Sipe et al. (1986)Case report
      Balasch et al. (2006)Prospective, self-controlled trial
      • Fábregues F.
      • Peñarrubia J.
      • Creus M.
      • Manau D.
      • Casals G.
      • Carmona F.
      • Balasch J.
      Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: A randomized, clinical trial [Article].
      Co-intervention
      Sipe et al. (2010)Prospective, randomized, crossover trial
      • Saharkhiz N.
      • Zademodares S.
      • Salehpour S.
      • Hosseini S.
      • Nazari L.
      • Tehrani H.G.
      The effect of testosterone gel on fertility outcomes in women with a poor response in in vitro fertilization cycles: A pilot randomized clinical trial.
      Testosterone administration during ovarian stimulation
      Hassan et al. (2019)Crossover trial
      Erin Ahart et al. (2019)Prospective, cohort, non-randomized trial
      Padmashri et al. (2019)Not performed in poor responders
      Andreeva et al. (2020)Observational, pilot study

      Data extraction

      Data extraction was performed independently by two of the reviewers (E.T.K. and J.K.B.). The following data were recorded from each of the eligible studies: demographic (citation data, country, study period and number of patients included), methodological (method of randomization, and allocation concealment) and procedural (whether financial support was declared, type of GnRH analogue and protocol used for LH surge inhibition, dose and protocol of the intervention proposed, type and starting dose of gonadotrophin administered for ovarian stimulation, type and dose of medication used for triggering final oocyte maturation, criteria used for triggering final oocyte maturation, type of fertilization, day of embryo transfer, type of luteal support and adverse events associated with the type of intervention) (Tables 3 and 4). When a study provided data on different protocols of testosterone administration, all the available information was extracted, resulting in multiple datasets.
      Table 3Methodological characteristics of eligible RCT
      Authors (year), journalITT (n)Per protocol (n)Testosterone pretreatmentNo pretreatmentDefinition of poor ovarian responseRandomization methodBlindingPrimary outcomeFinancial support
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      , Human Reproduction
      53492425Oestradiol <1200 pg/ml on day of HCG and ≤ 5 COC retrieved, and day 3 FSH >12 IU/l, oestradiol >70 pg/ml and inhibin B <45 pg/mlComputer-generated randomization listDouble blindCOC retrievedYes
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      , Fertility and Sterility
      1101105555≤3 COC retrieved despite the use of a high total gonadotrophin dose (>2500 IU)Computer-generated randomization listNoMature oocytes retrievedNot reported
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      , Development and Reproduction
      12012030, 30, 30
      Testosterone was applied for different durations in different groups of patients. AFC, antral follicle count; AMH, anti-Müllerian hormone; COC, cumulus–oocyte complex; HCG, human chorionic gonadotrophin; ITT, intention-to-treat; RCT, randomized controlled trial.
      30≤3 COC retrieved despite the use of a high total gonadotrophin dose (>2500 IU)Computer-generated randomization listNoMature oocytes retrievedNot reported
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      , Human Reproduction
      50502624Bologna criteriaComputer-generated randomization listSingle blindCOC retrievedPartially funded by a scholarship
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      , Gynecological Endocrinology
      1101105555AFC <5–7 follicles or AMH ≤1.26 ng/mlNot reportedNot reportedNot reportedNot reported
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      , Annals of Tropical Medicine and Public Health
      1321327161POSEIDON criteriaNot reportedNot reportedNumber of retrieved and mature oocytes and pregnancy rateNo
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      , Reproductive Medicine and Biology
      15912242, 38
      Testosterone was applied for different durations in different groups of patients. AFC, antral follicle count; AMH, anti-Müllerian hormone; COC, cumulus–oocyte complex; HCG, human chorionic gonadotrophin; ITT, intention-to-treat; RCT, randomized controlled trial.
      42Bologna criteriaManual lotterySingleTotal number of retrieved mature oocytesNot reported
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      , Reproductive BioMedicine Online
      634917, 16
      Testosterone was applied for different durations in different groups of patients. AFC, antral follicle count; AMH, anti-Müllerian hormone; COC, cumulus–oocyte complex; HCG, human chorionic gonadotrophin; ITT, intention-to-treat; RCT, randomized controlled trial.
      16Bologna criteriaComputer-generated randomization listSingleMature oocytes retrievedYes
      a Testosterone was applied for different durations in different groups of patients.AFC, antral follicle count; AMH, anti-Müllerian hormone; COC, cumulus–oocyte complex; HCG, human chorionic gonadotrophin; ITT, intention-to-treat; RCT, randomized controlled trial.
      Table 4Cycle characteristics of eligible RCT
      Authors (year)GnRH analogueType of analogue protocolGonadotrophin type/starting doseGonadotrophin adjustmentsSignal for triggering oocyte maturationCriteria for HCG administrationOPUFertilizationEmbryo transferType of luteal supportEmbryo quality studiedAdverse effects
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      Triptorelin or cetrorelixMainly long GnRH agonist but also short GnRH agonist and antagonist (proportions of GnRH analogue protocols were not statistically different between the two arms)rFSH/300–450 IUYes, no further information provided10,000 IU uHCGAt least three follicles 17 mm in diameter36 h after HCGIVF/ICSIDay 2/3Micronized progesterone 200 mg/b.i.d. vaginally and 2500 IU HCG at 3, 6 and 9 days after HCG for triggering final oocyte maturationNot reportedNone
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      Cetrorelix 0.25 mg/dayFlexible protocol (when lead follicle reached 13–14 mm in diameter)r(h)FSH/300IUYes, every 3–4 days according to ovarian response250 mg rHCGAt least one follicle of at least 18 mm in diameter36 h after HCGIVF/ICSIDay 3Vaginal progesterone gel 90 mg/dayNumber of grade 1 and 2 embryosNone
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      Cetrorelix 0.25 mg/dayFlexible protocol (when lead follicle reached 13–14 mm in diameter)r(h)FSH/300 IUYes, every 3–4 days according to ovarian response250 mg rHCGAt least one follicle of at least 18 mm in diameter35–36 h after HCGIVF/ICSIDay 3Vaginal progesterone gel 90 mg/dayNumber of grade 1 and 2 embryosNone
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      Triptorelin 3.75 mg depot, followed by daily injections of triptorelin 0.1 mg, if necessaryLong GnRH agonist protocolFollitropin alpha/–Not reported250 mg rHCGAt least two follicles reached 17 mm in diameter or, if this was not possible, the maximum number of follicles were present36 h after HCGICSIDay 2Vaginal micronized progesterone 600 mg/dayQuality of embryos on day 2 of in-vitro culture (top/medium/low)None
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      Not reportedGnRH antagonist protocolNot reportedNot reported5000 or 10,000 IU HCGAt least two follicles of more than 17 mm size35–40 h after HCGIVFNot reportedNot reportedNot reportedNot reported
      Al-Jeborry et al. (2019)Cetrotide 0.25 mg/dayFlexible protocol (when lead follicle reached 13–14 mm in diameter)r(h)FSH/300–4500 IU with or without addition of Menogon 75–150 IU dailyYes, every few days according to ovarian response/measuring serial serum oestradiol levels5000–10,000 IU uHCGTwo or three follicles more than 17–18 mm size34–35 h after HCGICSIDay 3Cyclogest progesterone suppository vaginally in dose of 400 mg twice dailyNot reportedNot reported
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      Cetrotide 0.25 mg/dayGnRH antagonist protocolrFSH/300 IUYes, based on patient's condition and individual ovarian response6500 IU HCGAt least two follicles reached at least 18 mm36–37 h after HCGIVFDay 3Micronized progesterone 800 mg/dayNumber of good-quality embryos according to Istanbul consensusLight itching
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      Not reportedConventional short antagonist protocolHuman menopausal gonadotrophin/300 IUNoNot reportedAt least one follicle measured over 16 mm36 h after HCGICSIDay 2 or 3Not reportedNumber of day 3 embryosNone
      b.i.d., twice daily; GnRH, gonadotrophin-releasing hormone; HCG, human chorionic gonadotrophin; ICSI, intracytoplasmic sperm injection; OPU, Oocyte pick up; RCT, randomized controlled trials; rFSH, recombinant FSH; r(h)FSH, recombinant (human) FSH; rHCG, recombinant human chorionic gonadotrophin; uHCG, urinary human chorionic gonadotrophin.
      In the majority of studies, the duration of testosterone pretreatment was 21 days; therefore when studies with protocols of different duration were included, data were extracted to datasets with a similar duration. For example, when a study included groups with different durations of testosterone administration, the group with a duration nearest to 21 days was included in the data extraction. Any disagreement between the two reviewers responsible for the data extraction was resolved by discussion.

      Assessment of risk of bias

      For the assessment of risk of bias, Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria (risk of bias, inconsistency of the effect, indirectness, imprecision and publication bias) were applied, using GRADEpro GDT in order to assess the quality of the evidence (

      GRADEpro, G. (2022). GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. Available fromgradepro.org.

      ). The overall quality of the body of evidence was assessed for the primary outcomes included in the meta-analysis. Two authors (E.T.K. and J.K.B.) independently made judgements about the quality of the evidence (high, moderate, low or very low) and any disagreement was resolved by discussion (Supplementary Table I).

      Outcomes

      The results were interpreted based on an intention-to-treat analysis (defined as the inclusion of all randomized patients). The main outcome measure was the achievement of pregnancy per patient randomized, expressed as clinical pregnancy (evidence of an intrauterine sac with fetal heart activity at 6–8 weeks of gestation) or as live birth. Secondary outcome measures included the following: the duration of gonadotrophin stimulation, total dose of gonadotrophins required for ovarian stimulation, oestradiol concentrations, endometrial thickness and number of follicles ≥17 mm on the day of triggering of final oocyte maturation, cancellation rate due to poor ovarian response, number of cumulus–oocyte complexes (COC) retrieved, number of embryos transferred, number of metaphase II (MII) and two-pronuclear (2pn) oocytes, miscarriage rate and proportion of patients having an embryo transfer. Where information was missing, the study authors were contacted in order to retrieve the relevant data.

      Quantitative data synthesis

      Estimates for dichotomous data were expressed as the risk ratio (RR) with 95% confidence intervals (CI), using the Mantel–Haenszel approach (
      • Mantel N.
      • Haenszel W.
      Statistical Aspects of the Analysis of Data From Retrospective Studies of Disease.
      ) when using the fixed effects method, and the DerSimonian and Laird approach (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ) when using the random effects method. When the outcome of interest was continuous in nature, the differences were pooled across the studies, resulting in a weighted mean difference (WMD) with 95% CI. The inverse variance method (
      • Hedges L.V.
      • Olkin I
      CHAPTER 9 - Random Effects Models for Effect Sizes.
      ) and the DerSimonian and Laird method (
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      ) were used when the fixed or random effects method, respectively, was applied.
      All results were combined for meta-analysis with STATA/MP Software (Version 14.1; Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, 2011). Study-to-study variation was assessed by using the chi-squared statistic (the hypothesis tested was that the studies were all drawn from the same population, i.e. from a population with the same effect size). A fixed effects model was used where no statistically significant heterogeneity was present (I2 < 40%), whereas in the presence of statistically significant heterogeneity, a random effects model was applied. Statistical significance was set at a P-level of 0.05. The presence of a publication bias was tested using Harbord–Egger's test (
      • Harbord R.M.
      • Egger M.
      • Sterne J.A.
      A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints.
      ).

      Qualitative data synthesis

      The methodological quality and risk of bias of the studies included in the current systematic review and meta-analysis was assessed using the Risk of Bias (RoB) 2 tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions (
      • Sterne J.A.C.
      • Savović J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • Cates C.J.
      • Cheng H.-Y.
      • Corbett M.S.
      • Eldridge S.M.
      • Emberson J.R.
      • Hernán M.A.
      • Hopewell S.
      • Hróbjartsson A.
      • Junqueira D.R.
      • Jüni P.
      • Kirkham J.J.
      • Lasserson T.
      • Li T.
      • McAleenan A.
      • Reeves B.C.
      • Shepperd S.
      • Shrier I.
      • Stewart L.A.
      • Tilling K.
      • White I.R.
      • Whiting P.F.
      • Higgins J.P.T.
      RoB 2: a revised tool for assessing risk of bias in randomised trials.
      ). Two authors (E.T.K. and J.K.B.) assessed each study's risk of bias and any disagreement was resolved by discussion (Supplementary Figure I).

      Results

      Identification of literature

      The literature search yielded 2012 publications. After removing 801 duplicates, screening of the remaining publications by title and abstract resulted in 17 studies, further examined in full text, leading finally to eight eligible trials (Figure 1).
      Figure 1
      Figure 1PRISMA flow diagram detailing the selection of studies for inclusion.

      Systematic review

      Eight RCT (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ;
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      ;
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ;
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      ;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ) published between 2006 and 2021 were eligible for the systematic review, including a total of 797 women. The number of included patients ranged from 50 to 132. The characteristics of the studies included in the systematic review are presented in Table 3.
      The randomization method and allocation concealment were reported in six (
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      , 2014;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ) and in three (
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ;
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      ) out of the eight studies, respectively. The definition of poor ovarian response, as well as the primary outcome, varied among the studies. A power analysis was performed in three studies (
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ) and financial support was also declared in three out of the eight studies (
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ) (Table 3).
      To inhibit a premature LH surge, GnRH antagonists were used in six studies (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ;
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      ;
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ;
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ), whereas in one study a GnRH agonist protocol was applied (
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ). In the study by Massin and colleagues (
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ) both GnRH agonists and GnRH antagonists were used (Table 4), although the proportions of the different GnRH analogue protocols were not statistically different between the two groups compared.
      Ovarian stimulation was performed with using recombinant FSH in six of the studies (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ;
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      , 2014;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ). Gonadotrophin adjustments were reported in five studies (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ;
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ;
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      ;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ). Human chorionic gonadotrophin (HCG) was used to trigger final oocyte maturation in all the studies, while the criteria for HCG administration and the dose for signalling final oocyte maturation varied across studies (Table 4).
      The time of oocyte retrieval varied from 35 to 40 h after HCG administration in all studies, whereas in half of them it was performed strictly 36 h after HCG administration (
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ). Fertilization methods included IVF (
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      ;
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ), IVF/intracytoplasmic sperm injection (ICSI) (
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ;
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      ;
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ) and ICSI (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ;
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ).
      Embryo transfers were performed on day 2 or 3 after oocyte retrieval and luteal support varied among the studies, although two studies did not provide details about the type of luteal support used (
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ). No systemic or local adverse effects attributed to transdermal testosterone gel were reported (Table 4).

      Intervention

      Regarding the type of intervention performed, pretreatment with transdermal testosterone gel was performed in all studies, with a daily dose ranging from 10 to 12.5 mg/day. The duration of testosterone pretreatment ranged from 10 to 56 days (Table 5).
      Table 5Protocols used for testosterone pretreatment
      Authors (year), journalTestosterone administration
      TypeRouteDoseDuration
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ,

      Human Reproduction
      Testosterone

      gel 1%
      Transdermal10 mg/day15–20 days
      • Kim C.H.
      • Howles C.M.
      • Lee H.A.
      The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders [Journal Article; Randomized Controlled Trial].
      ,

      Fertility and Sterility
      Testosterone

      gel 1%
      Transdermal12.5 mg/day21 days
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      , Development and Reproduction
      Testosterone

      gel 1%
      Transdermal12.5 mg/daySubgroup a: 14 days

      Subgroup b: 21 days

      Subgroup c: 28 days
      • Bosdou J.K.
      • Venetis C.A.
      • Dafopoulos K.
      • Zepiridis L.
      • Chatzimeletiou K.
      • Anifandis G.
      • Mitsoli A.
      • Makedos A.
      • Messinis I.E.
      • Tarlatzis B.C.
      • Kolibianakis a.E.M
      Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial.
      , Human Reproduction
      Testosterone gel 1%

      Transdermal10 mg/day21 days
      • Doan H.T.
      • Quan L.H.
      • Nguyen T.T.
      The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization [Article].
      , Gynecological Endocrinology
      Testosterone gel 1%Transdermal12.5 mg/dayFrom day 6 of previous menstrual period to day 2 of stimulated menstrual period
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      , Annals of Tropical Medicine and Public Health
      Testosterone gel 1%Transdermal10 mg/day21 days
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      , Reproductive Medicine and Biology
      Testosterone gel 1%Transdermal12.5 mg/daySubgroup a: 28 days

      Subgroup b: 42 days
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      , Reproductive BioMedicine Online
      Testosterone gel 1%Transdermal12.5 mg/daySubgroup a (long testosterone): 56 days

      Subgroup b (short testosterone): 10 days

      Risk of bias assessment results

      Among the eight RCT included in the present systematic review and meta-analysis, all studies (100%) had a low risk of bias on random sequence generation, and three of them (37.5%) had a low risk of bias on allocation concealment; therefore there were some concerns regarding the randomization process for the remaining five studies (62.5%). No study had a high risk of bias on random sequence generation and allocation concealment. Regarding the deviations from the intended outcomes, four studies (50%) were low risk and only one study was high risk (12.5%). Three studies (37.5%) were considered as high risk for missing outcomes and five (62.5%) were low risk. In terms of measurement of the outcomes, two studies (25%) were low risk, one study (12.5%) was considered as creating ‘some concerns’ and the rest were considered as high risk, according to RoB2. Finally, 7 out of 8 studies (87.5%) were low risk regarding the selection of the reported result.
      In conclusion, the current systematic review and meta-analysis included three ‘low-risk’ studies (37.5%), three studies with ‘some concerns’ (37.5%) and two ‘high-risk’ studies (25%). Supplementary Table I and Supplementary Figure I show the results obtained from the risk of bias assessment.

      Meta-analysis

      Primary outcome

      The primary outcome was achievement of pregnancy expressed as clinical pregnancy or live birth. The probability of pregnancy was significantly increased in women pretreated with transdermal testosterone compared with those who were not, regarding both live birth (RR 2.07, 95% CI 1.09–3.92; Risk Difference 10%, 95% CI 2–17; fixed effects model I2 0%, four studies, 333 women) and clinical pregnancy (RR 2.25, 95% CI 1.54–3.30; RD 11%, 95% CI 4–18%; fixed effects model I2 0%, eight studies, 797 women) (Figure 2, Figure 3).
      Figure 2
      Figure 2Risk ratio (RR) with 95% confidence interval (CI) for live birth in patients with poor ovarian response pretreated or not pretreated with testosterone (T). When the studies were evaluating testosterone pretreatments of different durations, subgroups a–c were created in each study for more precise results. Therefore, a, b or c in brackets next to the study authors represents the particular subgroup from the total sample size evaluating testosterone pretreatment of different durations.
      Figure 3
      Figure 3Risk ratio (RR) with 95% confidence interval (CI) for clinical pregnancy in patients with poor ovarian response pre-treated or not pretreated with testosterone (T). When the studies were evaluating testosterone pretreatments of different durations, subgroups a–c were created in each study for more precise results. Therefore, a, b or c in brackets next to the study authors represents the particular subgroup from the total sample size evaluating testosterone pretreatment of different durations.

      Secondary outcomes that improved following testosterone pretreatment (Table 6)

      Duration of ovarian stimulation

      Significantly fewer days were required to complete ovarian stimulation in women pretreated with transdermal testosterone compared with those who were not (WMD –0.81, 95% CI –1.46 to –0.16, random effects model I2 92%, seven studies, 744 women).
      Table 6Secondary outcomes following testosterone pretreatment
      StudiesSample sizeMethod appliedEffect(95% CI)
      Outcomes improved following testosterone pretreatment
       Duration of ovarian stimulation (days)7744Random effects model,

      I2: 92%
      WMD: –0.81

      (–1.46 to –0.16)
       Total dose of gonadotrophins required for ovarian stimulation (IU)8797Random effects model,

      I2: 87%
      WMD: –368.8

      (–612.4 to –125.2)
       Endometrial thickness on the day of triggering final oocyte maturation (mm)5561Random effects model,

      I2: 77.6%
      WMD: 0.83

      (0.13 to 1.53)
       Cancellation rate due to poor ovarian response6681Fixed effects model,

      I2: 0%
      RR: 0.37

      (0.20 to 0.71)
       No. of cumulus–oocyte complexes retrieved8797Random effects model,

      I2: 78.7%
      WMD: 0.88

      (0.22 to 1.54)
      Outcomes not significantly different following testosterone pretreatment
       Oestradiol concentration on the day of triggering final oocyte maturation (pg/ml)4394Fixed effects model,

      I2: 0%
      WMD: –8.12 (–118.2 to 101.96)
       No. of follicles ≥17 mm on the day of triggering final oocyte maturation5386Random effects model,

      I2: 85.7%
      WMD: 0.82

      (–0.11 to 1.74)
       No. of metaphase II oocytes3245Fixed effects model,

      I2: 0%
      WMD: 0.48(–0.16 to 1.13)
       No. of 2pn oocytes7665Random effects model,

      I2: 80.3%
      WMD: 0.49

      (–0.11 to 1.10)
       No. of embryos transferred8797Random effects model,

      I2: 70.5%
      WMD: 0.21

      (–0.07 to 0.49)
       No. of miscarriages3202Fixed effects model,

      I2: 0%
      RR: 1.12

      (0.30 to 4.22)
       Proportion of patients having an embryo transfer8797Fixed effects model,

      I2: 15.9%
      RR: 1.00

      (0.96 to 1.04)
      2pn, two-pronuclear; CI, confidence interval; I2, heterogeneity; RR, risk ratio; WMD, weighted mean difference.

      Total dose of gonadotrophins required for ovarian stimulation

      A significantly lower total dose of gonadotrophins was required in women pretreated with transdermal testosterone compared with those who were not (WMD –368.8 IU, 95% CI –612.4 to –125.2 IU, random effects model I2 87%, eight studies, 797 women).

      Endometrial thickness on the day of triggering of final oocyte maturation

      A significantly thicker endometrium on the day of triggering of final oocyte maturation was present in women pretreated with transdermal testosterone compared with those who were not (WMD 0.83 mm, 95% CI 0.13–1.53 mm, random effects model I2 77.6%, five studies, 561 women).

      Cancellation rate due to poor ovarian response

      A significantly lower cancellation rate was present in women pretreated with transdermal testosterone compared with those who were not (RR 0.37, 95% CI 0.20–0.71, fixed effects model I2 0%, six studies, 681 women).

      COC retrieved

      Significantly more COC were retrieved in women pretreated with transdermal testosterone compared with women who were not (WMD 0.88, 95% CI 0.22–1.54, random effects model I2 78.7%, eight studies, 797 women).

      Secondary outcomes not significantly different following testosterone pretreatment (Table 6)

      Oestradiol concentrations on the day of triggering final oocyte maturation

      No significant difference in oestradiol concentrations on the day of triggering of final oocyte maturation was present between women who were pretreated with transdermal testosterone and those who were not (WMD –8.12 pg/ml, 95% CI –118.2 to 101.96 pg/ml, fixed effects model I2 0%, four studies, 394 women).

      Number of follicles ≥17 mm on the day of triggering final oocyte maturation

      No difference in the number of follicles ≥17 mm on the day of triggering of final oocyte maturation was present between women pretreated with transdermal testosterone and those who were not (WMD 0.82, 95% CI –0.11 to 1.74, random effects model I2 85.7%, five studies, 386 women).

      MII oocytes

      No difference in the number of MII oocytes was present between women pretreated with transdermal testosterone and those who were not (WMD 0.48, 95% CI –0.16 to 1.13, fixed effects model I2 0%, three studies, 245 women).

      2pn oocytes

      No difference in the number of 2pn oocytes was present between women pretreated with transdermal testosterone and those who were not (WMD 0.49, 95% CI –0.11 to 1.10, random effects model I2 80.3%, seven studies, 665 women).

      Embryos transferred

      No significant difference in the number of embryos transferred was present between women pretreated with transdermal testosterone and those who were not (WMD 0.21, 95% CI –0.07 to 0.49, random effects model I2 70.5%, eight studies, 797 women).

      Miscarriage

      A significant difference in the probability of miscarriage was present between women pretreated with transdermal testosterone and those who were not (RR 1.12, 95% CI 0.30–4.22, fixed effects model I2 0%, three studies, 202 women).

      Proportion of patients with embryo transfer

      No significant difference in the proportion of women with embryo transfer was present between those who were pretreated with transdermal testosterone and those who were not (RR 1.00, 95% CI 0.96–1.04, fixed effects model I2 15.9%, eight studies, 797 women).

      Discussion

      The present systematic review and meta-analysis summarizes the best available evidence regarding testosterone pretreatment in poor responders undergoing ovarian stimulation for IVF, using gonadotrophins and GnRH analogues. Pretreatment with transdermal testosterone significantly improved the probability of live birth, as well as that of clinical pregnancy. This was accompanied by a significant increase in the number of COC retrieved and in endometrial thickness on the day of triggering of final oocyte maturation. Concomitantly, testosterone pretreatment significantly decreased the duration of ovarian stimulation, the total dose of gonadotrophins required for ovarian stimulation and the probability of cycle cancellation.
      In the present systematic review and meta-analysis the administration of testosterone via the percutaneous route appears to be safe, as no adverse effects following transdermal testosterone administration were reported in the studies analysed, with the exception of itching at the application site in one case (
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ). However, the long-term effects of testosterone pretreatment have not currently been studied. Similarly, no data are currently available on children born after testosterone pretreatment.
      To the best of the authors’ knowledge, this is the largest systematic review and meta-analysis evaluating the effect of testosterone pretreatment in poor responders undergoing IVF, including eight RCT and 797 patients (a 28.1% increase patients compared with the study by Noventa et al. [2019], with 573 patients). Applying strict inclusion criteria, studies with co-intervention or those available only in abstract form were excluded, leading to more precise estimates.
      The review is, however, characterized by certain limitations that should be considered when interpreting its findings. The definition of poor ovarian response varied among studies, limiting the extrapolation of the results obtained. Despite the use of the Bologna criteria (
      • Ferraretti A.P.
      • La Marca A.
      • Fauser B.C.
      • Tarlatzis B.
      • Nargund G.
      • Gianaroli L.
      ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.
      ) in three out of the eight eligible studies, the Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number (POSEIDON) criteria (
      • Al-Jeborry M.M.
      Efficacy of transdermal testosterone in assisted reproduction outcome of poor responders.
      ), as well as arbitrary definitions of poor ovarian response, were also used. In addition, considerable heterogeneity regarding the type, dose and duration of testosterone pretreatment was present in the studies analysed. Thus, although the present study is currently the largest meta-analysis evaluating testosterone pretreatment, additional relevant trials are still necessary and are certainly justified.
      The findings of the current meta-analysis are in line with those of previous meta-analyses on the same subject (
      • Neves A.R.
      • Montoya-Botero P.
      • Polyzos N.P.
      Androgens and diminished ovarian reserve: The long road from basic science to clinical implementation. A comprehensive and systematic review with meta-analysis.
      ;
      • Noventa M.
      • Vitagliano A.
      • Andrisani A.
      • Blaganje M.
      • Viganò P.
      • Papaelo E.
      • Scioscia M.
      • Cavallin F.
      • Ambrosini G.
      • Cozzolino M.
      Testosterone therapy for women with poor ovarian response undergoing IVF: a meta-analysis of randomized controlled trials.
      ). However, the increase in the number of patients/studies and the avoidance of methodological flows allows the confident highlighting of the importance of this intervention in patients with poor ovarian response, in whom numerous other interventions do not appear to be beneficial (

      Song, D., Shi, Y., Zhong, Y., Meng, Q., Hou, S., & Li, H. (2016). Efficiency of mild ovarian stimulation with clomiphene on poor ovarian responders during IVF\ICSI procedures: a meta-analysis. https://doi.org/10.1016/j.ejogrb.2016.07.498

      ;
      • Zhang Y.
      • Zhang C.
      • Shu J.
      • Guo J.
      • Chang H.M.
      • Leung P.C.K.
      • Sheng J.Z.
      • Huang H.
      Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.
      ).
      The current study suggests that the probability of pregnancy is increased in poor responders pretreated with transdermal testosterone. For each 10 poor responders pretreated with transdermal testosterone, one additional live birth is expected compared with no pretreatment. This is probably attributed to the fact that testosterone pretreatment increases the number of COC retrieved and therefore the probability of pregnancy.
      With regard to the pathophysiological role of testosterone, it is known that testosterone and dihydrotestosterone (DHT) are the only bioactive forms that can bind directly to the androgen receptor, whereas the other androgens require conversion to the bioactive hormones in order to become effective (
      • Walters K.A.
      • Handelsman D.J.
      Role of androgens in the ovary.
      ;
      • Walters K.A.
      • Paris V.R.
      • Aflatounian A.
      • Handelsman D.J.
      Androgens and ovarian function: translation from basic discovery research to clinical impact.
      ). Observations from in-vivo investigations in primates revealed that testosterone and DHT treatment increased the number pre-antral and antral follicles, and had an overall positive impact on follicle development (
      • Vendola K.
      • Zhou J.
      • Wang J.
      • A.Bondy C
      Androgens promote insulin-like growth factor-I and insulin-like growth factor-I receptor gene expression in the primate ovary.
      ;
      • Vendola K.A.
      • Zhou J.
      • Adesanya O.O.
      • Weil S.J.
      • Bondy C.A.
      Androgens stimulate early stages of follicular growth in the primate ovary.
      ).
      Following that, several studies in animals have confirmed the importance of the role of testosterone. In primate ovaries, testosterone or DHT raises the transcript levels of insulin-like growth 1 (IGF-1) and IGF-1 receptors. Given that IGF-1 reduces follicular apoptosis and is present in the granulosa cells, theca, interstitial cells and oocytes, testosterone may exert a variety of functions on ovarian function through IGF-1, directly influencing the quality of oocytes and generated embryos (
      • Prizant H.
      • Gleicher N.
      • Sen A.
      Androgen actions in the ovary: balance is key.
      ).
      Furthermore, androgen support is crucial for overall follicle survival as it lowers follicle atresia and granulosa cell apoptosis, and increases granulosa cells proliferation and differentiation. Some of these findings may be explained by how the FSH receptor (FSHR) and androgen receptor interact as research on primates has revealed a significant correlation between FSHR and androgen receptor mRNA levels in granulosa cells (
      • Franks S.
      • Hardy K.
      Androgen Action in the Ovary.
      ;
      • Sen A.
      • Prizant H.
      • Light A.
      • Biswas A.
      • Hayes E.
      • Lee H.-J.
      • Barad D.
      • Gleicher N.
      • Hammes S.R.
      Androgens regulate ovarian follicular development by increasing follicle stimulating hormone receptor and microRNA-125b expression.
      ). Additionally, it has been demonstrated that testosterone treatment increases FSHR expression throughout the entire follicular development, whereas FSH increases androgen receptor expression in primary follicles (

      Fujibe Y, Baba T, Nagao S, et al. Androgen potentiates the expression of FSH receptor and supports preantral follicle development in mice. J Ovarian Res. 2019; 12(1): 31. Published 2019 Apr 4. doi:10.1186/s13048-019-0505-5

      ;
      • Laird M.
      • Thomson K.
      • Fenwick M.
      • Mora J.
      • Franks S.
      • Hardy K.
      Androgen Stimulates Growth of Mouse Preantral Follicles In Vitro: Interaction With Follicle-Stimulating Hormone and With Growth Factors of the TGFβ Superfamily.
      ;
      • Weil S.
      • Vendola K.
      • Zhou J.
      • Bondy C.A.
      Androgen and Follicle-Stimulating Hormone Interactions in Primate Ovarian Follicle Development.
      ).
      With human data, there has been controversy regarding testosterone administration before assisted reproduction techniques. In 2006, Massin and colleagues were not able to demonstrate any beneficial effect of testosterone administration on ovarian response (
      • Massin N.
      • Cedrin-Durnerin I.
      • Coussieu C.
      • Wolf J.P.
      • Hugues J.N
      Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique–a prospective, randomized, double-blind study [Journal Article; Randomized Controlled Trial].
      ). However, in 2009, a randomized clinical trial demonstrated that pretreatment with transdermal testosterone decreased the percentage of cycles with a low response in low-responder IVF patients (
      • Fábregues F.
      • Peñarrubia J.
      • Creus M.
      • Manau D.
      • Casals G.
      • Carmona F.
      • Balasch J.
      Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: A randomized, clinical trial [Article].
      ). Clinical trials to investigate the effects of testosterone supplementation for poor responders have recently been attempted, but the results have been limited.
      Future studies on testosterone pretreatment should in addition focus on its duration of administration, which was evaluated in three studies in the current meta-analysis (
      • Hoang Q.H.
      • Ho H.S.
      • Do H.T.
      • Nguyen T.V.
      • Nguyen H.P.
      • Le M.T.
      Therapeutic effect of prolonged testosterone pretreatment in women with poor ovarian response: A randomized control trial [Article].
      ;
      • Kim
      • Ahn C.-H.
      • Moon J.-W.
      • Kim J.-W.
      • Chae S.-H.
      • Kang H.-D.
      • Byung-Moon
      Ovarian Features after 2 Weeks, 3 Weeks and 4 Weeks Transdermal Testosterone Gel Treatment and Their Associated Effect on IVF Outcomes in Poor Responders.
      ;
      • Subirá J.
      • Algaba A.
      • Vázquez S.
      • Taroncher Dasí R.
      • Mollá Robles G.
      • Monzó Fabuel S.
      • Baydal V.
      • Ruiz Herreros A.
      • García Camuñas N.
      • Rubio Rubio J.M.
      Testosterone does not improve ovarian response in Bologna poor responders: a randomized controlled trial (TESTOPRIM).
      ) albeit with controversial results. Moreover, a prerequisite for accurately evaluating testosterone pretreatment is that relevant RCT are performed in well-defined populations of poor responders (
      • Ferraretti A.P.
      • La Marca A.
      • Fauser B.C.
      • Tarlatzis B.
      • Nargund G.
      • Gianaroli L.
      ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.
      ).
      In conclusion, based on the currently available evidence, testosterone pretreatment increases clinical pregnancy and live birth rates in poor responders undergoing ovarian stimulation for IVF.

      Acknowledgements

      The authors would like to express their gratitude to the following colleagues for providing data for the purposes of this research: Q. H. Hoang (Vietnam), M.T. Le (Vietnam) and J. Subirá (Spain)

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      Biography

      Evangelia Katsika graduated from the Medical School of Aristotle University of Thessaloniki, Greece, in 2018 and received her Masterʼs degree in Human Reproduction in 2022. She currently is an Obstetrics and Gynecology Resident at University College London Hospital, London, UK, with an interest in infertility and gynaecological endocrinology.
      Key message
      Testosterone pretreatment increases both live birth and clinical pregnancy rates in women with poor ovarian response undergoing ovarian stimulation for IVF. These findings confidently highlight the importance of this intervention in women with a poor ovarian response, in whom numerous other interventions do not appear to be beneficial