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Effect of oestrogen modulation on semen parameters in men with secondary hypogonadism: Systematic review and meta‐analysis

Effect of oestrogen modulation on semen parameters in men with secondary hypogonadism: Systematic... INTRODUCTIONReduced semen quality (male infertility) is one of the most common reasons a couple cannot conceive within 12 months of regular unprotected intercourse. Male infertility may result from secondary hypogonadism, in which gonadotropin levels are low or inappropriately normal. Secondary hypogonadism may result from organic (irreversible) or functional (potentially reversible) hypothalamic–pituitary factors.1–4 Accordingly, unlike primary hypogonadism, gonadotrophin therapy (GnT) has been proven to restore fertility as well as normal testosterone levels in men with secondary hypogonadism.5 Unfortunately, GnT is quite expensive and therefore unaffordable in most healthcare systems worldwide.Selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) can increase endogenous gonadotrophin‐releasing hormone (GnRH), gonadotrophin and testosterone secretion in men by reducing oestrogenic negative feedback on the hypothalamic–pituitary axis even regardless of a man's age.6–10 Due to their putative mechanism of action, SERMs/AIs require the presence of an intact hypothalamic–pituitary–testis axis and they should be considered unsuitable in patients with irreversible damage at the central level or in those with primary hypogonadism.1–4 These agents can potentially improve semen quality as well as the likelihood of paternity in men with idiopathic infertility.11–13 These agents have also been shown to be beneficial in improving testosterone deficiency in men with secondary hypogonadism, mostly data limited to men with dysmetabolic conditions with functional hypogonadism such as obesity, metabolic syndrome and functional hypogonadism.8,14,15 Nevertheless, it remains unresolved whether SERMs/AIs might have utility in men with infertility associated with milder cases of secondary hypogonadism, or cases of functional, secondary hypogonadism unresponsive to lifestyle intervention. In addition, these drugs are not approved for the treatment of male hypogonadism and their use must be considered an ‘off‐label’ approach. Finally, SERM agonistic effect on venous vessels could facilitate the development of venous thromboembolic diseases in predisposed men.16If SERMs/AIs could be used to improve semen quality in a subset of men with secondary hypogonadism‐related infertility, this would enable many affected couples to access fertility treatment, otherwise unaffordable because of the high costs of GnT. There currently exists no consensus on the effectiveness of SERMs/AIs to treat men with secondary hypogonadism‐related infertility. We conducted a systematic review and meta‐analysis investigating the effect of monotherapy or a combination of SERMs/AIs on sperm parameters and/or fertility in men with secondary hypogonadism, and to identify predictors of successful treatment if observed.MATERIALS AND METHODSWe followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines in conducting this systematic review. The study was registered in PROSPERO under the registration number CRD42022306535.Search strategyWe performed an electronic search in the Cochrane Library, MEDLINE and PubMed in January 2022. We searched using the search strategy (‘hypogonadotropic hypogonadism’ OR ‘secondary hypogonadism’) AND (‘selective estrogen receptor modulator’ OR SERM OR clomiphene OR tamoxifen OR enclomiphene OR aromatase inhibitor OR anastrozole OR letrozole) in PubMed and MEDLINE from inception to 11 January 2022 without additional filters. All search results were exported into EndNote, and duplicates were removed before screening. The search was updated on 11 November 2022.To identify additional papers, we performed citation searching by manually screening references of selected articles. We performed an electronic search in ClinicalTrials.gov for registered studies of potential relevance, but without publications. We contacted the principal investigator for data; studies were excluded if the results were not available or there was no response from the investigators. The detailed search strategy is available in Supporting Information S1.Study selectionTitles and abstracts of all records were screened independently by two reviewers (N. L. de S. and H. D.) to identify publications eligible for full‐text review. The same reviewers screened selected full‐text articles independently to identify eligible studies to include in the review. When there were discrepancies in selected full‐text articles, two reviewers discussed and reached a consensus. Conflicts were resolved by a third reviewer (C. J.).All randomised‐controlled trials (RCTs) and non‐randomised studies of intervention (NRSIs; prospective or retrospective) reporting the effect of SERMs/AI as monotherapy or in combination on semen parameters in men with secondary hypogonadism of any aetiology (defined as hypogonadism with low or inappropriately normal gonadotrophins)1 irrespective of fertility history were included in the analysis. We included any RCT reporting semen parameters (sperm concentration/motility/total motile sperm count/morphology/volume) compared to placebo or other treatment modalities for secondary hypogonadism. We also included NRSIs reporting semen parameters before and after the intervention with SERMs and/or AIs. Additionally, our inclusion criteria included RCTs and NRSIs reporting conception or live birth. We searched for full‐text original articles published in English. We excluded case reports.When available data in the full‐text article were inadequate to define eligibility, corresponding authors were contacted for clarification. If there was no response, the studies were excluded.Data extractionTwo reviewers (N. L. de S. and H. D.) independently extracted data from all selected full‐text articles on study details (year of publication, country), design, participant characteristics (age at commencement, cause of secondary hypogonadism, body mass index [BMI], co‐morbidities, hormone profile, baseline semen parameters), intervention (agent, dose, duration) and control, outcomes, data analysis and any additional concerns. Funding details and conflicts of interest were assessed to determine if there was a notable concern.Primary outcomes were the effects of SERMs/AIs on semen parameters either in RCTs or NRSIs. Secondary outcomes included clinical pregnancy and live birth rates. We assessed serious adverse effects as safety outcomes. The data extraction form is available in Supporting Information S2. We have not analysed outcomes related to reproductive hormone levels because they have been addressed in previous systematic reviews8,14 and because it is beyond the review's primary focus.Risk of bias analysis and assessment of the quality of evidenceThe risk of bias (ROB) in RCTs was assessed using a revised version of the Cochrane risk of bias (ROB2) tool.17 When assessing ‘the bias because of deviations from intended interventions’, we were interested in the effect of the assignment to the intervention at baseline (intention‐to‐treat effect) rather than the effect of adhering to the intervention (per‐protocol effect). We reviewed the published articles and records from Clinicaltrials.gov to obtain information on reporting bias.The ROBINS‐I tool was used to assess the ROB in NRSIs.18 Potential confounders considered were as follows: severity and cause of hypogonadism; baseline sperm concentration; previous testosterone replacement therapy (TRT) stopped at the time of intervention; other interventions that could have improved the underlying secondary hypogonadism.The quality of evidence was assessed according to the ‘GRADE’ approach using GRADEproGDT software. The certainty of evidence was graded based on five main considerations: ROB, consistency of effect, imprecision, indirectness and publication bias.19Data analysisThe planned meta‐analysis of effect estimates from the available studies could not be performed for RCTs because outcome measures differed across studies and there was incomplete reporting of effect estimates. Therefore, we adapted the vote counting method to determine the direction of effect.20 Vote counting was performed without considering the statistical significance as per the standard method in data synthesis. The benefit or harm of the intervention was defined based on the direction of the effect.Available NRSIs were pre‐ and post‐intervention studies with critical ROB. The statistical heterogeneity was calculated using I2 statistics. Even when low heterogeneity was detected, a random‐effect model was applied because the validity of tests of heterogeneity can be limited with a small number of component studies.While acknowledging the limitation in synthesising data from NRSIs with a critical ROB, we decided to conduct a meta‐analysis because available NRSIs and their data were directly relevant in answering the research question of the review. Meta‐analysis was performed in Comprehensive Meta‐Analysis V4, with single‐group pre‐ and post‐intervention data calculation and random effect model.RESULTSDatabase searches yielded 1157 records. After removing duplicates, 1008 records remained for screening. After excluding 949 abstracts, 59 full‐text articles were screened for eligibility. After excluding 51 studies, eight studies were selected for the systematic review. The updated search did not yield any additional eligible studies. One additional study was identified through citation searching. Two studies identified through ClinicalTrials.gov were included using the results published in the database. Attempts to obtain published full‐text articles of these studies by contacting the investigators were unsuccessful. Other studies were excluded because they were either already included through database search (n = 4) or had no published results and could not be accessed even after contacting the principal investigators (n = 2). Details of studies excluded after full‐text review are summarised in Supporting Information S3. PRISMA flow diagram summarising the search strategy is given in Figure 1.1FIGUREPreferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram for the study selection. Source: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:71. https://doi.org/10.1136/bmj.n71. For more information, visit: http://www.prisma‐statement.org/. Database search yielded 1157 studies, which was reduced to 1008 after removing duplicates. Fifty‐nine studies were selected to review full‐text articles. Eight studies from the database search were included in the review. Three additional studies were included through citation searching and ClinicalTrials.gov.Randomised controlled studiesSix RCTs including 747 participants were eligible for inclusion: among included studies, two compared the effects of SERMs versus placebo versus TRT (n = 377),21,22 or just with placebo (n = 332).23,24 In addition, one study investigated the role of SERMs compared to TRT (n = 12),25 or AIs (n = 26).26 The characteristics of the included studies are summarised in Table 1. All studies recruited participants with mean serum testosterone <300 ng/dL and mean serum luteinising hormone (LH) within the reference range; however, the minimum levels of serum LH were reported only in one study.26 Three of the six studies were restricted to men with overweight/obesity22–24; the aetiology of secondary hypogonadism was not specified in the remaining studies.21,25,26 However, the mean BMI of participants in two other studies was >30 kg/m2,21,26 and the mean weight was 105 kg in the other study.25 Normospermia was an inclusion criterion for two studies,23,24 and another study excluded men with a sperm concentration <1 million/mL.26 All participants had previously received TRT in one study,25 whereas in another study, 23% of the participants had received TRT.22 TRT within the last 326 or 6 months23,24 was an exclusion criterion in three studies. Data on TRT were not available in one.21 Semen analyses were performed 3–6 months after starting treatment in all included studies. All included studies, except one, had a high ROB, as summarised in Figure 2.1TABLECharacteristics of selected randomised controlled studies.Participant baseline characteristicsStudy (country)Inclusion criteriaExclusion criteriaGroupNumber (number with semen parameters)AetiologyMean age (SD) [years]Mean BMI (SD) (kg/m2)Mean testosterone (SD) [ng/dl]Mean FSH (SD) [IU/L]Mean LH (SD) [IU/L]Mean spermconcent ration (SD) [million/mL]InterventionControlDurationOutcomeFunding, conflict of interestNotesSelective oestrogen receptor modulators versus placebo versus testosterone gelWiehle, 2014 (USA)Diagnosis of secondary hypogonadism, morning testosterone <250 ng/dLNREnclomiphene 12.5 mg27 (16)NR49.7 (11.6)32.6 (5.17)217.2 (58.8)6.4 (4.2)4 (1.8)3/16aEnclomiphene 12.5, 25 mg1% testosterone gel, placebo6 months (semen analysis at 3 months)Sperm concentration < 15 million/mL (p values for total sperm count, volume, motility)Repros therapeutics, notable concernsNo details on previous testosterone useEnclomiphene 25 mg33 (19)49.2 (10.9)31.7 (4.9)209.8 (55.4)9.4 (10.9)5.3 (4)1/19aTestosterone gel33 (19)52 (10.6)33.1 (5.87)210 (54)6 (2.9)3.9 (1.8)3/19aPlacebo28 (13)51.6 (11.7)30.9 (4.17)213.7 (74.9)6.1 (4.8)3.9 (2.6)1/13aKim, 2016 (USA)Overweight men, aged 18–60 years, with secondaryhypogonadism (morning serum TT of <300 ng/dL and LH <9.4 IU/L)NREnclomiphene41 + 44Possible overweight/obesity49.1 (7.4), 47.3 (8.8)33.1 (4.4), 33.8 (4.6)203.3 (52.4), 212.9 (48)4.9–6.13.3–3.898.3 (87.2), 79 (55.2)Enclomiphene 12.5 mg/day increased to 25 mg/day if TT did not increase >450 ng/dL after 4 weeks1.62% testosterone gel adjusted according to the manufacturer, placebo16 weeksSperm concentration percentage change from the baseline, adverse effectsRepros therapeutics, notable concernsCombination of two studies, previous testosterone use 21–23%. Study complete by 217.Testosterone gel43 + 4247.4 (7.2), 45 (8.2)34 (4.4), 33.1 (4.6)208.6 (54), 229.8 (44)4.9–6.13.3–3.878.9 (68.5), 75.1 (45.8)Placebo45 + 4147.2 (9), 47.5 (8.9)32.6 (4.3), 33.5 (4.4)200 (43.1), 206 (48.2)4.9–6.13.3–3.895 (90.8), 80.5 (62.3)Selective oestrogen receptor modulators versus testosterone gelKaminetsky, 2013 (USA)Secondary hypogonadism, TT <300 mg/dLKallman syndrome, primary hypogonadism, testicular failure, significant medical illness.Unwilling to stop testosterone or other hormones for ?30 days (not clear)Enclomiphene7 (6)NR46 years (range 41–59 years)Mean weight 105 kg165 (66)NRNRNREnclomiphene 25 mg dailyTestosterone gel (dose NR)6 monthsPost‐intervention sperm concentration difference between groupsRepros therapeutics, notable concernsAll used topical testosterone for at least 6 months, stopped for 7−14 days before baseline assessmentTestosterone gel5Selective oestrogen receptor modulators versus placeboNCT01739595 (USA)Overweight/obese men with secondary hypogonadism (TT <300 ng/dL, LH <9.4 mIU/L) and sperm concentration >15 million/mLPrior use of testosterone treatments within the last 6 monthsIrreversibly infertile or compromised fertility (cryptorchism, Kallman syndrome, primary hypogonadism, vasectomy, or tumours of the pituitary)Enclomiphene 12.5 mg112 (99)Possible overweight/obesity44.6 (9.6)NRNRNRNRNREnclomiphene 12.5 mg daily, dose increase to 25 if TT not increased to 300 in 6 weeksPlacebo12 weeks, extended to 18 weeks if dose increasedProportion of subjects with a 50% or greater decrease in sperm concentration from baseline after 12 weeks of treatment, adverse eventsRepros therapeutics, notable concernsPublished article not availableEnclomiphene 25 mg22 (21)45.8 (8.6)Placebo47 (45)43.6 (10.5)NCT01532414 (USA)Same as aboveSame as aboveEnclomiphene 12.5 mg92 (85)Possible overweight/obesity47.2 (9.6)NRNRNRNRNRSame as aboveSame as aboveSame as aboveSame as aboveRepros therapeutics, notable concernsProtocol similar to the study described above. Published article not available. Possible overlapping population.Enclomiphene 25 mg21 (19)43.6 (10.1)Placebo38 (35)47.8 (9.5)Selective oestrogen receptor modulator versus aromatase inhibitorsHelo, 2015 (USA)Men 18–50 years, infertility, testosterone 150–350 ng/dL (average of two consecutive samples), LH 1.2–8.6 mIU/LSperm concentration 1 million/mL, BMI >40, haematocrit <36 or >52, previous oral or inhaled steroid use, opioid use.Known pituitary or testicular diseaseAnastrozole13 (12)NR35 (6.5)33 (9.8)248 (18)9.9 (1.9)4.8 (0.48)32.7 (12)Anastrozole 1 mg dailyClomiphene 25 mg daily12 weeksSemen volume, concentration and motility before and after intervention, fertility, adverse eventsNot reported, no notable concernsSix participants with secondary subfertilityClomiphene13 (12)33 (3.9)32 (7.5)253 (17)4.2 (1.7)3.9 (0.45)32 (12)Abbreviations: BMI, body mass index; FSH, follicle‐stimulating hormone; LH, luteinising hormone; NR, not reported; TT, total testosterone.aNumber of men with sperm concentration <15 million/mL out of the participants with semen parameters.2FIGURESummary of risk of bias assessment of randomised controlled studies. Based on the overall assessment, the first five studies a have high risk of bias and the other study has some concerns on the risk of bias.The main RCT results related to semen outcome are summarised in Table 2. Outcomes and reporting differed across studies, so it was not possible to compute summary statistics. Therefore, we adapted the vote counting method to adjudicate the overall direction of effect. Table 5 summarises findings, including the assessment of the certainty of evidence using the GRADE tool. Four RCTs with 591 participants compared SERMs against placebo. Two published studies showed evidence towards the benefit; however, two unpublished studies suggested that SERMs were inferior to placebo (possible overlap of patients not excluded). Overall, the certainty of evidence was very low because of the high ROB and imprecision because of the small total sample size.2TABLESummary of results from randomised controlled trials.StudyOutcomeOverall ROB judgmentAvailable dataSummary statisticsVote counting (without considering statistical significance)Selective oestrogen receptor modulators versus placeboWiehle, 2014Sperm concentration <15 million/mLHigh riskIntervention 2/35Control 2/13OR 0.33 (95% CI 0.04–2.66)BenefitSperm concentration (million/mL)EC 12.5 mg: p = 0.95EC 25 mg: p = 0.78NRSperm motilityNSNRTotal sperm countEC 12.5 mg: p = 0.45EC 25 mg: p = 0.77NRKim, 2016Percentage change of the sperm concentration from the baselineHigh riskIntervention 11.7 (80.3), 15.2 (55.8)Control 4.1 (57.2), 7.6 (89.6)MD 7.60 (–22.12, 37.32),MD 7.60 (–24.40, 39.60)BenefitNCT01739595Proportion of subjects with a 50% or greater decrease in sperm concentrationHigh riskIntervention 19/134Control 2/47OR 3.72 (0.83, 16.61)HarmNCT01532414 (? Overlapping population)Proportion of subjects with a 50% or greater decrease in sperm concentrationHigh riskIntervention 16/113Control 1/38OR 6.10 (0.78, 47.67)HarmSelective oestrogen receptor modulator versus aromatase inhibitorsHelo, 2015Sperm concentration (million/mL)Some concernsAZ 26 (13)CC 41 (13)MD –15.00 (–25.40, –4.60)CC benefitSemen volume (mL)AZ 3.15 (0.51)CC 2.2 (0.54)MD 0.95 (0.53, 1.37)AZ benefitSperm motility (%)AZ 35 (5.4)CC 41 (5.4)MD –6.00 (–10.32, –1.68)CC benefitFertilityAZ 1/12CC 2/12Inadequate dataAbbreviations: AZ, anastrozole; CC, clomiphene citrate; CI, confidence interval; EC, enclomiphene citrate; MD, mean difference; NR, not reported; NS, not significant; OR, odds ratio; ROB, risk of bias.Three RCTs comparing SERMs against testosterone gel (n = 275) showed higher sperm concentration with SERMs compared to testosterone gel in men with secondary hypogonadism. Further statistical analyses were not carried out because exogenous testosterone is already known to suppress spermatogenesis.The study comparing anastrozole to clomiphene suggested better sperm concentration outcomes with clomiphene (mean difference –15.00 [–25.40, –4.60]).26Only the study by Helo et al. mentioned fertility outcomes reporting the conception of one and two partners of men on anastrozole and clomiphene, respectively, conceiving during the study period. However, its intervention period was only 12 weeks.Two studies did not report safety data,21,25 and one study reported that there were no serious adverse effects in participants.23 One study reported one fatal stroke in a participant on enclomiphene, although causality was not established.22 One serious adverse event with enclomiphene was reported in another study; however, the adverse effect was not specified.24 In the remaining study, anastrozole treatment was associated with skin rash in one patient, and deep vein thrombosis in another patient (who had a previous episode of deep vein thrombosis).26Non‐randomised studiesWe identified five NRSIs including 105 participants reporting semen parameters with SERMs.27–31 Four studies were uncontrolled retrospective observational, while the study by Lima et al. was uncontrolled prospective. Although details of patients treated with human chorionic gonadotropin (hCG) are also reported in two studies29,31 the authors did not consider this a comparator group. There were no eligible studies reporting data on AIs. Characteristics of included studies are summarised in Table 3.3TABLECharacteristics of selected non‐randomised studies of intervention with selective oestrogen receptor modulators.ParticipantsParticipant characteristicsStudy (country)DesignInclusionExclusionNumber of participantsAetiologyMean age (SD) (years)Mean BMI (SD) (kg/m2)Mean TT (SD) (ng/dL)Mean FSH (SD) (IU/L)Mean LH (SD) (IU/L)Mean sperm concentration (SD) (million/mL)Intervention, durationOutcome of interestFunding, conflicts of interestNotesLima,2021(USA)ProspectiveMen with primary infertility, morning TT <300 ng/dL on two occasions, abnormal semen parameters in two occasions (TMSC <9)IHH being on testosterone/hCG/CC at the time of baseline assessment (stopped for 8 weeks)16NR40.9 (4.3)34.7 (7.9)190.7 (63.7)6.1 (4.6)4.5 (2.6)3.1 (3.8)CC 25 mg every other day, 3 monthsSperm concentration, TMSC, semen volume and sperm motility before and after interventionNR, no notable concernsAdditional group received CC + hCGPrimary objective was to assess 17‐OHP as a predictor of successSharma,2019(USA)RetrospectiveHypogonadism (TT <300 ng/dL) and/or infertilityPrevious treatment with testosteroneOpted varicocele repair57NRMediana 35, IQR 31–40Mediana 28, IQR 26–32Mediana 242, IQR 191–317Mediana 3, IQR 2–6Mediana 4, IQR 2–615 (27)CC 25 mg/day titrated to 50 mg/day (if TT <300 mg/dL after 4 weeks), median 2.8 months (IQR 1.8–4.4)Semen volume, sperm concentration, motile percentage, TMC before and after interventionNR, notable concernsHypogonadotropic hypogonadism not mentioned as an inclusion criteria, but participant characteristics suggestiveSurbone,2019(Switzerland)RetrospectiveMen with infertility, low plasma TT, low or normal FSH and LH, sperm concentration >0.1 million/mLSecondary causes of hypogonadism like Kallman, cranial surgery, tumour, radiotherapy18NR36 (6.8)28.2 (3.9)8.5 (2.3)4.2 (2.3)4.8 (3.3)14.7 (18.2)CC 50 mg every 48 h, at least 3 monthsSperm concentration, progressive motility before and after, spontaneous pregnancy, adverse effectsNR, no notable concernsPatel,2015(USA)RetrospectiveMen aged 18–55 years with hypogonadism and/or subfertilityTT <300 ng/dL and/or bioavailable testosterone <155 ng/dLPrevious testosterone/tamoxifen/hCG/anastrozole use47 (baseline sperm parameters only in 27, 3 month data only in 10)NR34.5 (NR)30.2 (NR)246.8 (97.6)5.8 (4.8)9.6 (10.7)50.7 (71.6)CC 50 mg every other day, increased to daily if testosterone rise <50 ng/dL in 2 weeks, median follow‐up 3 months (IQR 2.3–3.7)Semen volume, sperm concentration, progressive motile percentage, total motile count, percentage normal morphology before and after, adverse effectsAmerican medical systems, no notable concernsWhitten,2006(England)RetrospectiveMen with hypogonadotropic hypogonadismNR4 (six other patients treated with hCG)IHH‐3, panhypopituitarism‐131, 30, 28, 33NR194, 117, 41, 14771, 0.8, 0.9, 0.6NR0.6, 0, 0, 0CC 50 mg 3 times a week for 3 monthsSperm concentration before and after, fertilityNR, no notable concernPatient with panhypopituitarism was on testosterone replacement. One additional patient (IHH) had taken clomiphene and remained azoospermic before the studyAbbreviations: 17–OHP, 17–hydroxyprogesterone; BMI, body mass index; CC, clomiphene citrate; FSH, follicle‐stimulating hormone; hCG, human chorionic gonadotropin; IHH, idiopathic hypogonadotropic hypogonadism; IQR, interquartile range; LH, luteinising hormone; NR, not reported; TMC, total motile count; TMSC, total motile sperm count; TT, total testosterone.aMixed with 20 eugonadal men.All studies included men with infertility. Whitten et al. included men with idiopathic secondary hypogonadism (n = 3) or panhypopituitarism (n = 1).29 The aetiology of secondary hypogonadism was not reported in the other four studies. The mean/median BMI of participants in all four studies reporting BMI was >28 kg/m2.27,28,30,31 In two studies, previous TRT was an exclusion criterion,27,28 whereas in one study, previous TRT was not reported,30 and in the other, one patient had been on TRT.29 In one study, patients who had been on TRT were given a washout period of 8 weeks.31 Except in the study by Patel et al.,28 mean/median sperm concentration at baseline was low or close to the lower limit of the normal. The approximate follow‐up duration was 3 months for all the studies.All five studies had a critical ROB because of the risk of confounding because all of them had a single pre‐intervention outcome measurement and a single post‐intervention outcome measurement. Other domains of bias were variable between the studies (Figure 3). The publication bias could not be assessed because less than 10 studies were included in the quantitative analysis. The main results of the studies in relation to semen parameters and the overall ROB judgment are summarised in Table 4.3FIGURESummary of risk of bias assessment of non‐randomised studies of intervention on selective oestrogen receptor modulators. All included studies have a critical risk of bias in the overall assessment with bias of confounding been critical in all the studies.4TABLESummary of results from non‐randomised studies of intervention on selective oestrogen receptor modulators.StudyOutcomeOverall risk of bias judgementPre‐interventionPost‐interventionMean difference (95% confidence interval)SignificanceLima, 2021Sperm concentration (million/mL)Critical3.1 (3.8)10.14 (14.27)7.04 (–0.20, 14.28)0.006Semen volume (mL)2.7 (1.6)2.61 (1.31)–0.09 (–1.1, 0.2)0.43Total motile sperm count (million)3.75 (6.6)13.33 (18.45)9.58 (–0.02, 19.18)0.03Sharma, 2019Sperm concentration (million/mL)Critical15 (27)21 (25)6 (–3.55, 15.55)0.22Semen volume (mL)2.4 (1.5)2.4 (1.2)0.00 (–0.50, 0.50)1Total motility (%)31 (21)35 (26)–4.00 (–12.68, 4.68)0.37Total motile sperm count (million)14 (26)30 (112)16.00 (–13.85, 45.85)0.29Surbone, 2019Sperm concentration (million/mL)Critical14.7 (18.2)19.3 (16.6)4.60 (–6.78, 15.98)0.024Progressive motility (%)20.5 (17.5)22.2 (18.5)1.70 (–10.06, 13.46)0.395Patel, 2015Sperm concentration (million/mL)Critical50.7 (71.6)72.4 (60.1)21.70 (–24.31, 67.71)0.009Semen volume (mL)3.3 (1.9)3.2 (1.3)–0.10 (–1.18, 0.98)0.28Sperm motility (%)33.1 (20.5)38.5 (24.3)5.40 (–11.53, 22.33)0.53Total motile sperm count (million)59.7 (110.8)90.99 (92.9)31.29 (–39.86, 102.44)0.09Sperm morphology (normal %)8.6 (17.2)8.8 (16.8)0.20 (–12.07, 12.47)0.45Whitten, 2006Sperm concentration (million/mL)Critical0.6, 0, 0, 010, 33, 163, 051.35 (–22.74, 125.44)0.17All five studies (n = 105) reported changes in sperm concentration. Mean differences were suggestive of benefit (6.64 [95% confidence interval, CI 1.54, 11.74], I2 = 0%) (Table 5). Semen volume and total motile sperm count were reported in three studies with a total population of 83. The overall mean differences were –0.03 (95% CI –0.44, 0.38), I2 = 0% and 10.52 (95% CI 1.46–19.59), I2 = 0%, respectively. The certainty of evidence was very low because of the critical ROB in these studies.5TABLESummary of findings for effects of selective oestrogen receptor modulators/aromatase inhibitors in men with hypogonadotropic hypogonadism.OutcomeNumber of studiesNumber of participantsSummary of resultsaCertainty of evidence (GRADE)Selective oestrogen receptor modulators versus placeboSperm concentration4591Benefit: 2 studiesHarm: 2 studies (? overlapping population)Very lowbOther sperm parameters188No benefitVery lowbSelective oestrogen receptor modulators versus aromatase inhibitorsSperm concentration126Clomiphene benefitVery lowcNon‐randomised studies of selective oestrogen receptor modulators reporting before and after intervention dataSperm concentration51056.64 (1.54, 11.74), p = 0.01Very lowdSemen volume383–0.03 (–0.44, 0.38), p = 0.89Very lowdTotal motile sperm count38310.52 (1.46, 19.59), p = 0.02Very lowdAll studiesFertility3Inadequate dataSerious adverse events6Only few eventsVery lowaFor randomised‐controlled trials (RCTs)—summary according to vote counting; for non‐randomised studies of intervention (NRSIs)—summary is pooled mean difference.bStudies with high risk of bias, imprecision because of small sample size.cSome concern in risk of bias, small sample size.dVery serious risk of bias because of critical risk of bias in all non‐randomised studies of intervention.Surbone et al. reported fertility data, with three female partners becoming pregnant during the study period out of 57. In the study by Whitten et al., female partners of two study participants (out of four) conceived. The other three studies did not report fertility data.Safety data were not reported in three studies.27,29,31 Surbone et al. reported that there were no significant adverse effects.30 In the other study, three patients had a paradoxical drop in total testosterone and switched to hCG.28 One patient had fatigue and mood swings.Overall, little AI data were found; specifically, neither RCTs comparing AI with placebo nor NRSIs of AI were identified. There were inadequate data on fertility because only three studies reported fertility outcomes, and all were of short follow‐up. It was not possible to analyse determinants of response to SERM or AI because of the limited number of studies, low total numbers of participants, and unavailability of disaggregated data from subgroups of interest. Safety data were not reported in many studies. Few major adverse events were observed, but causality could not be attributed to SERM/AI treatment.DISCUSSIONOur systematic review was conducted to appraise for the first time whether SERMs/AIs might improve semen quality in men with secondary hypogonadism. Non‐comparative cohort studies suggest that SERM treatment is associated with improved sperm concentration and total motile sperm count in men with low testosterone with low/normal gonadotrophins and infertility; however, RCTs show heterogeneous effects of SERMs compared with placebo. Although studies comparing SERMs to testosterone gel were also summarised in our review, we have not pursued to draw any conclusions using their data because of known suppressive effects of exogenous testosterone on spermatogenesis.Although we aimed to review studies including men with secondary hypogonadism of diverse aetiology, there was an overrepresentation of men with low testosterone with low/normal gonadotrophins in the background of obesity. From a pathophysiological point of view, a greater response is expected with SERMs in men with obesity‐related low testosterone because oestradiol produced through increased aromatase activity from adipose tissue is thought to mediate suppression of the hypothalamus and pituitary.32 There remains controversy on whether this can be strictly defined as a type of hypogonadism because their hypothalamic–pituitary–gonadal axis has no pathology and this is considered an adaptive response to another illness.33–35 In contrast, if there are symptoms of hypogonadism and low testosterone with low/normal gonadotrophins, making a diagnosis of secondary hypogonadism in these men may be recommended.36 Additionally, hypogonadism associated with obesity or type 2 diabetes is considered an increasingly prevalent cause of male infertility.37,38 Considering these factors, we included these studies in our review acknowledging the limitation in generalising these data to men with organic secondary hypogonadism and we have identified the broad patient population in our review as having low testosterone with low/normal gonadotrophins.There is a gap in the evidence between the androgenic and spermatogenic effects of oestrogen modulators among men considered in our review because the evidence on the improvement of testosterone seems to be more robust.8,14 It is not clear whether this is because of the true inefficacy of these agents to promote spermatogenesis or the lack of high‐quality studies. This ambiguity is further intensified by some data that suggest that SERMs enhance Leydig cell function but not Sertoli cell action.39 Another important factor is the possible short duration of intervention and follow‐up in the studies. The total duration for spermatogenesis and delivery of spermatozoa to ejaculatory ducts is approximately 120 days.40 Therefore, follow‐up of about 3 months is likely to miss the slow response of spermatogenesis even if the Sertoli cells are responding. On the other hand, spermatogenesis is an intricate process dependent on many factors other than hormone regulation.41 This could limit the spermatogenic response despite the rise of intra‐testicular testosterone synthesis. Oestrogen signalling is implicated in the regulation of spermatogenesis,6 so its blockade might negatively impact semen quality. In keeping with this, paradoxical declines of spermatogenesis have been reported in a minority of men treated with SERMs.42 However, some studies have suggested that SERMs/AIs may improve semen parameters in men with idiopathic infertility.9,11,13It is important to consider the limitations of the current analysis and its constituent studies. Most studies, particularly RCTs, did not consider fertility history in the inclusion criteria. Additionally, several studies had enrolled normospermic men with normal fertility. Measures to optimise results of semen analysis and assessment of patient adherence to drug treatment during the follow‐up were underreported in the available studies. Safety data and pregnancy rates were not reported adequately. The lack of disaggregated data and small numbers limited any subgroup analysis. Due to the heterogeneity in the methods used in reporting outcomes within the included studies, we did not conduct a formal meta‐analysis to synthesise available RCT data. Of the available options, we used vote counting because that was the only method that could be used across studies. However, we have summarised effect estimates wherever possible. Vote counting has a few inherent limitations, such as disregarding the magnitude of the effect and differences in the relative sizes of the studies.20 Ideally, vote counting would be better suited to a larger number of studies than identified by our review. Multiple studies have reported the effects of AIs on semen parameters in men with low testosterone:oestradiol ratio. However, gonadotrophin levels in these studies were not clearly consistent with secondary hypogonadism,43–45 so these studies did not meet the inclusion criteria of our review.SERMs have been used off‐label in clinical practice for men with secondary hypogonadism, especially when fertility is a concern. According to the findings of our review, it seems that this practice is not supported by high‐quality evidence. Therefore, we believe that high‐quality studies on men with secondary hypogonadism and abnormal semen parameters should be performed with an adequate follow‐up duration to clarify this dilemma. It is also important to define standardised objective outcome measures to determine improvement in semen parameters and assess clinically relevant outcomes such as pregnancy rate in future studies evaluating the role of SERMs and/or AIs in the treatment of male subfertility because of secondary hypogonadism.CONCLUSIONSAlthough low‐quality evidence suggests a possible improvement of semen parameters with selective oestrogen receptor modulators in men with low testosterone associated with low/normal gonadotrophins, there is inadequate evidence on its efficacy to improve semen parameters compared to placebo or other fertility options. The available evidence is mostly limited to men with overweight/obesity. There is no evidence on the role of aromatase inhibitors. Data on the effects of selective oestrogen receptor modulators/aromatase inhibitors on fertility in the population of interest are limited. Larger randomised‐controlled trials with well‐defined inclusion criteria on the aetiology of secondary hypogonadism, cut‐off values for testosterone, gonadotrophin and semen parameters and fertility status are required to ascertain the effects of selective oestrogen receptor modulators/aromatase inhibitors on the fertility of these men. Outcomes such as semen parameters and fertility should be assessed with a longer follow‐up considering the time taken to normalise spermatogenesis before these agents can be recommended for clinical practice, even for off‐label use.AUTHOR CONTRIBUTIONSChanna N. Jayasena conceived and Nipun Lakshitha de Silva and Ranga Eshaka Wickramarachchi planned the review. Giovanni Corona and Suks Minhas supervised the methodological aspects of the review. Nipun Lakshitha de Silva and Harsha Dissanayake performed the search, screening and study selection. Nipun Lakshitha de Silva, Harsha Dissanayake and Camila Suarez performed data extraction and analysis. Channa N. Jayasena, Waljit S. Dhillo and Ranjith Ramasamy guided and supervised data extraction and analysis. Nipun Lakshitha de Silva drafted the initial manuscript. All authors revised and edited the manuscript.ACKNOWLEDGEMENTSThe Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, NIHR and is supported by the NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The following authors are also funded by: Channa N. Jayasena—NIHR Post‐Doctoral Fellowship; WSD—NIHR Senior Investigator Award.CONFLICT OF INTEREST STATEMENTThe authors declare they have no conflicts of interest.FUNDING INFORMATIONThe authors received no specific funding for this work.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available in the Supporting Information.REFERENCESBhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715‐1744.Minhas S, Bettocchi C, Boeri L, et al. European Association of Urology Guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol. 2021;80(5):603‐620.Isidori AM, Aversa A, Calogero A, et al. Adult‐ and late‐onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE). J Endocrinol Investig. 2022;45(12):2385‐2403.Ferlin A, Calogero AE, Krausz C, et al. Management of male factor infertility: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS). J Endocrinol Investig. 2022;45(5):1085‐1113.Rastrelli G, Corona G, Mannucci E, Maggi M. Factors affecting spermatogenesis upon gonadotropin‐replacement therapy: a meta‐analytic study. Andrology. 2014;2(6):794‐808.Russell N, Grossmann M. Mechanisms in endocrinology: estradiol as a male hormone. Eur J Endocrinol. 2019;181(1):R23‐R43.Rastrelli G, Maggi M, Corona G. Pharmacological management of late‐onset hypogonadism. Expert Rev Clin Pharmacol. 2018;11(4):439‐458.Awouters M, Vanderschueren D, Antonio L. Aromatase inhibitors and selective estrogen receptor modulators: unconventional therapies for functional hypogonadism? Andrology. 2020;8(6):1590‐1597.del Giudice F, Busetto G, de Berardinis E, et al. A systematic review and meta‐analysis of clinical trials implementing aromatase inhibitors to treat male infertility. Asian J Androl. 2020;22(4):360.T'Sjoen GG, Giagulli VA, Delva H, Crabbe P, De Bacquer D, Kaufman JM. Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab. 2005;90(10):5717‐5722.Chua ME, Escusa KG, Luna S, Tapia LC, Dofitas B, Morales M. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: a meta‐analysis. Andrology. 2013;1(5):749‐757.Shahid MN, Khan TM, Neoh CF, Lean QY, Bukhsh A, Karuppannan M. Effectiveness of pharmacological intervention among men with infertility: a systematic review and network meta‐analysis. Front Pharmacol. 2021;12:1879.Cannarella R, Condorelli RA, Mongioì LM, Barbagallo F, Calogero AE, La Vignera S. Effects of the selective estrogen receptor modulators for the treatment of male infertility: a systematic review and meta‐analysis. Expert Opin Pharmacother. 2019;20(12):1517‐1525.Huijben M, Lock MTWT, de Kemp VF, de Kort LMO, van Breda HMK. Clomiphene citrate for men with hypogonadism: a systematic review and meta‐analysis. Andrology. 2022;10(3):451‐469.Pelusi C, Giagulli VA, Baccini M, et al. Clomiphene citrate effect in obese men with low serum testosterone treated with metformin due to dysmetabolic disorders: a randomized, double‐blind, placebo‐controlled study. PLoS One. 2017;12(9):e0183369.Daly E, Vessey MP, Hawkins MM, Carson JL, Gough P, Marsh S. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet North Am Ed. 1996;348(9033):977‐980.Higgins JPT, Savović J, Page MJ, Elbers RG, Sterne JAC. Assessing risk of bias in a randomized trial. Cochrane Handbook for Systematic Reviews of Interventions. 2019:205‐228.Sterne JA, Hernán MA, Reeves BC, et al. ROBINS‐I: a tool for assessing risk of bias in non‐randomised studies of interventions. BMJ. 2016;355:i4919.GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490.McKenzie JE, Brennan SE. Synthesizing and presenting findings using other methods. Cochrane Handbook for Systematic Reviews of Interventions. 2019:321‐347.Wiehle RD, Fontenot GK, Wike J, Hsu K, Nydell J, Lipshultz L. Enclomiphene citrate stimulates testosterone production while preventing oligospermia: a randomized phase II clinical trial comparing topical testosterone. Fertil Steril. 2014;102(3):720‐727.Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement. BJU Int. 2016;117(4):677‐685.Phase III Study to Evaluate Morning Testosterone Normalization in Men With Secondary Hypogonadism. Full Text View. ClinicalTrials.gov. January 12, 2023. https://clinicaltrials.gov/ct2/show/NCT01532414Phase III Study to Evaluate Morning Testosterone Normalization in Overweight Men With Secondary Hypogonadism. Full Text View. ClinicalTrials.gov. January 12, 2023. https://clinicaltrials.gov/ct2/show/NCT01739595Kaminetsky J, Werner M, Fontenot G, Wiehle RD. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med. 2013;10(6):1628‐1635.Helo S, Ellen J, Mechlin C, et al. A randomized prospective double‐blind comparison trial of clomiphene citrate and anastrozole in raising testosterone in hypogonadal infertile men. J Sex Med. 2015;12(8):1761‐1769.Sharma D, Zillioux J, Khourdaji I, et al. Improvements in semen parameters in men treated with clomiphene citrate—a retrospective analysis. Andrologia. 2019;51(5):e13257.Patel DP, Brant WO, Myers JB, et al. The safety and efficacy of clomiphene citrate in hypoandrogenic and subfertile men. Int J Impotence Res. 2015;27(6):221‐224.Whitten SJ, Nangia AK, Kolettis PN. Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate. Fertil Steril. 2006;86(6):1664‐1668.Surbone A, Vaucher L, Primi MP, et al. Clomiphene citrate effect on testosterone level and semen parameters in 18 infertile men with low testosterone level and normal/low gonadotropines level. Eur J Obstet Gynecol Reprod Biol. 2019;238:104‐109.Lima TFN, Rakitina E, Blachman‐Braun R, Ramasamy R. Evaluation of a serum 17‐hydroxyprogesterone as a predictor of semen parameter improvement in men undergoing medical treatment for infertility. Can Urol Assoc J. 2021;15(7):E340.Fernandez CJ, Chacko EC, Pappachan JM. Male obesity‐related secondary hypogonadism—pathophysiology, clinical implications and management. Eur Endocrinol. 2019;15(2):83.Handelsman DJ. The illusory case for treatment of an invented disease. Front Endocrinol. 2022;12:1579.Handelsman DJ. Androgen misuse and abuse. Endocr Rev. 2021;42(4):457‐501.Perls T. Pseudohypogonadism—making men believe they need testosterone. Today Geriatr Med. 2015;8(5):30.Corona G, Goulis DG, Huhtaniemi I, et al. European Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of functional hypogonadism in males. Andrology. 2020;8(5):970‐987.Hammoud AO, Meikle AW, Reis LO, Gibson M, Peterson CM, Carrell DT. Obesity and male infertility: a practical approach. Semin Reprod Med. 2012;30(6):486‐495.Phillips KP, Tanphaichitr N. Mechanisms of obesity‐induced male infertility. Expert Rev Endocrinol Metab. 2010;5(2):229‐251.Pelusi C, Fanelli F, Baccini M, et al. Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels. Clin Endocrinol. 2020;92(1):38‐45.Chen H, Mruk D, Xiao X, Cheng CY. Human spermatogenesis and its regulation. Contemporary Endocrinology. Humana Press Inc.; 2017:49‐72.de Kretser DM, Loveland KL, Meinhardt A, Simorangkir D, Wreford N. Spermatogenesis. Hum Reprod. 1998;13(1):1‐8.Gundewar T, Kuchakulla M, Ramasamy R. A paradoxical decline in semen parameters in men treated with clomiphene citrate: a systematic review. Andrologia. 2021;53(1):e13848.Shoshany O, Abhyankar N, Mufarreh N, Daniel G, Niederberger C. Outcomes of anastrozole in oligozoospermic hypoandrogenic subfertile men. Fertil Steril. 2017;107(3):589‐594.Gregoriou O, Bakas P, Grigoriadis C, Creatsa M, Hassiakos D, Creatsas G. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril. 2012;98(1):48‐51.Saylam B, Efesoy O, Ayan S. The effect of aromatase inhibitor letrozole on body mass index, serum hormones, and sperm parameters in infertile men. Fertil Steril. 2011;95(2):809‐811. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Andrology Wiley

Effect of oestrogen modulation on semen parameters in men with secondary hypogonadism: Systematic review and meta‐analysis

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© 2023 American Society of Andrology and European Academy of Andrology.
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Abstract

INTRODUCTIONReduced semen quality (male infertility) is one of the most common reasons a couple cannot conceive within 12 months of regular unprotected intercourse. Male infertility may result from secondary hypogonadism, in which gonadotropin levels are low or inappropriately normal. Secondary hypogonadism may result from organic (irreversible) or functional (potentially reversible) hypothalamic–pituitary factors.1–4 Accordingly, unlike primary hypogonadism, gonadotrophin therapy (GnT) has been proven to restore fertility as well as normal testosterone levels in men with secondary hypogonadism.5 Unfortunately, GnT is quite expensive and therefore unaffordable in most healthcare systems worldwide.Selective oestrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) can increase endogenous gonadotrophin‐releasing hormone (GnRH), gonadotrophin and testosterone secretion in men by reducing oestrogenic negative feedback on the hypothalamic–pituitary axis even regardless of a man's age.6–10 Due to their putative mechanism of action, SERMs/AIs require the presence of an intact hypothalamic–pituitary–testis axis and they should be considered unsuitable in patients with irreversible damage at the central level or in those with primary hypogonadism.1–4 These agents can potentially improve semen quality as well as the likelihood of paternity in men with idiopathic infertility.11–13 These agents have also been shown to be beneficial in improving testosterone deficiency in men with secondary hypogonadism, mostly data limited to men with dysmetabolic conditions with functional hypogonadism such as obesity, metabolic syndrome and functional hypogonadism.8,14,15 Nevertheless, it remains unresolved whether SERMs/AIs might have utility in men with infertility associated with milder cases of secondary hypogonadism, or cases of functional, secondary hypogonadism unresponsive to lifestyle intervention. In addition, these drugs are not approved for the treatment of male hypogonadism and their use must be considered an ‘off‐label’ approach. Finally, SERM agonistic effect on venous vessels could facilitate the development of venous thromboembolic diseases in predisposed men.16If SERMs/AIs could be used to improve semen quality in a subset of men with secondary hypogonadism‐related infertility, this would enable many affected couples to access fertility treatment, otherwise unaffordable because of the high costs of GnT. There currently exists no consensus on the effectiveness of SERMs/AIs to treat men with secondary hypogonadism‐related infertility. We conducted a systematic review and meta‐analysis investigating the effect of monotherapy or a combination of SERMs/AIs on sperm parameters and/or fertility in men with secondary hypogonadism, and to identify predictors of successful treatment if observed.MATERIALS AND METHODSWe followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines in conducting this systematic review. The study was registered in PROSPERO under the registration number CRD42022306535.Search strategyWe performed an electronic search in the Cochrane Library, MEDLINE and PubMed in January 2022. We searched using the search strategy (‘hypogonadotropic hypogonadism’ OR ‘secondary hypogonadism’) AND (‘selective estrogen receptor modulator’ OR SERM OR clomiphene OR tamoxifen OR enclomiphene OR aromatase inhibitor OR anastrozole OR letrozole) in PubMed and MEDLINE from inception to 11 January 2022 without additional filters. All search results were exported into EndNote, and duplicates were removed before screening. The search was updated on 11 November 2022.To identify additional papers, we performed citation searching by manually screening references of selected articles. We performed an electronic search in ClinicalTrials.gov for registered studies of potential relevance, but without publications. We contacted the principal investigator for data; studies were excluded if the results were not available or there was no response from the investigators. The detailed search strategy is available in Supporting Information S1.Study selectionTitles and abstracts of all records were screened independently by two reviewers (N. L. de S. and H. D.) to identify publications eligible for full‐text review. The same reviewers screened selected full‐text articles independently to identify eligible studies to include in the review. When there were discrepancies in selected full‐text articles, two reviewers discussed and reached a consensus. Conflicts were resolved by a third reviewer (C. J.).All randomised‐controlled trials (RCTs) and non‐randomised studies of intervention (NRSIs; prospective or retrospective) reporting the effect of SERMs/AI as monotherapy or in combination on semen parameters in men with secondary hypogonadism of any aetiology (defined as hypogonadism with low or inappropriately normal gonadotrophins)1 irrespective of fertility history were included in the analysis. We included any RCT reporting semen parameters (sperm concentration/motility/total motile sperm count/morphology/volume) compared to placebo or other treatment modalities for secondary hypogonadism. We also included NRSIs reporting semen parameters before and after the intervention with SERMs and/or AIs. Additionally, our inclusion criteria included RCTs and NRSIs reporting conception or live birth. We searched for full‐text original articles published in English. We excluded case reports.When available data in the full‐text article were inadequate to define eligibility, corresponding authors were contacted for clarification. If there was no response, the studies were excluded.Data extractionTwo reviewers (N. L. de S. and H. D.) independently extracted data from all selected full‐text articles on study details (year of publication, country), design, participant characteristics (age at commencement, cause of secondary hypogonadism, body mass index [BMI], co‐morbidities, hormone profile, baseline semen parameters), intervention (agent, dose, duration) and control, outcomes, data analysis and any additional concerns. Funding details and conflicts of interest were assessed to determine if there was a notable concern.Primary outcomes were the effects of SERMs/AIs on semen parameters either in RCTs or NRSIs. Secondary outcomes included clinical pregnancy and live birth rates. We assessed serious adverse effects as safety outcomes. The data extraction form is available in Supporting Information S2. We have not analysed outcomes related to reproductive hormone levels because they have been addressed in previous systematic reviews8,14 and because it is beyond the review's primary focus.Risk of bias analysis and assessment of the quality of evidenceThe risk of bias (ROB) in RCTs was assessed using a revised version of the Cochrane risk of bias (ROB2) tool.17 When assessing ‘the bias because of deviations from intended interventions’, we were interested in the effect of the assignment to the intervention at baseline (intention‐to‐treat effect) rather than the effect of adhering to the intervention (per‐protocol effect). We reviewed the published articles and records from Clinicaltrials.gov to obtain information on reporting bias.The ROBINS‐I tool was used to assess the ROB in NRSIs.18 Potential confounders considered were as follows: severity and cause of hypogonadism; baseline sperm concentration; previous testosterone replacement therapy (TRT) stopped at the time of intervention; other interventions that could have improved the underlying secondary hypogonadism.The quality of evidence was assessed according to the ‘GRADE’ approach using GRADEproGDT software. The certainty of evidence was graded based on five main considerations: ROB, consistency of effect, imprecision, indirectness and publication bias.19Data analysisThe planned meta‐analysis of effect estimates from the available studies could not be performed for RCTs because outcome measures differed across studies and there was incomplete reporting of effect estimates. Therefore, we adapted the vote counting method to determine the direction of effect.20 Vote counting was performed without considering the statistical significance as per the standard method in data synthesis. The benefit or harm of the intervention was defined based on the direction of the effect.Available NRSIs were pre‐ and post‐intervention studies with critical ROB. The statistical heterogeneity was calculated using I2 statistics. Even when low heterogeneity was detected, a random‐effect model was applied because the validity of tests of heterogeneity can be limited with a small number of component studies.While acknowledging the limitation in synthesising data from NRSIs with a critical ROB, we decided to conduct a meta‐analysis because available NRSIs and their data were directly relevant in answering the research question of the review. Meta‐analysis was performed in Comprehensive Meta‐Analysis V4, with single‐group pre‐ and post‐intervention data calculation and random effect model.RESULTSDatabase searches yielded 1157 records. After removing duplicates, 1008 records remained for screening. After excluding 949 abstracts, 59 full‐text articles were screened for eligibility. After excluding 51 studies, eight studies were selected for the systematic review. The updated search did not yield any additional eligible studies. One additional study was identified through citation searching. Two studies identified through ClinicalTrials.gov were included using the results published in the database. Attempts to obtain published full‐text articles of these studies by contacting the investigators were unsuccessful. Other studies were excluded because they were either already included through database search (n = 4) or had no published results and could not be accessed even after contacting the principal investigators (n = 2). Details of studies excluded after full‐text review are summarised in Supporting Information S3. PRISMA flow diagram summarising the search strategy is given in Figure 1.1FIGUREPreferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) flow diagram for the study selection. Source: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:71. https://doi.org/10.1136/bmj.n71. For more information, visit: http://www.prisma‐statement.org/. Database search yielded 1157 studies, which was reduced to 1008 after removing duplicates. Fifty‐nine studies were selected to review full‐text articles. Eight studies from the database search were included in the review. Three additional studies were included through citation searching and ClinicalTrials.gov.Randomised controlled studiesSix RCTs including 747 participants were eligible for inclusion: among included studies, two compared the effects of SERMs versus placebo versus TRT (n = 377),21,22 or just with placebo (n = 332).23,24 In addition, one study investigated the role of SERMs compared to TRT (n = 12),25 or AIs (n = 26).26 The characteristics of the included studies are summarised in Table 1. All studies recruited participants with mean serum testosterone <300 ng/dL and mean serum luteinising hormone (LH) within the reference range; however, the minimum levels of serum LH were reported only in one study.26 Three of the six studies were restricted to men with overweight/obesity22–24; the aetiology of secondary hypogonadism was not specified in the remaining studies.21,25,26 However, the mean BMI of participants in two other studies was >30 kg/m2,21,26 and the mean weight was 105 kg in the other study.25 Normospermia was an inclusion criterion for two studies,23,24 and another study excluded men with a sperm concentration <1 million/mL.26 All participants had previously received TRT in one study,25 whereas in another study, 23% of the participants had received TRT.22 TRT within the last 326 or 6 months23,24 was an exclusion criterion in three studies. Data on TRT were not available in one.21 Semen analyses were performed 3–6 months after starting treatment in all included studies. All included studies, except one, had a high ROB, as summarised in Figure 2.1TABLECharacteristics of selected randomised controlled studies.Participant baseline characteristicsStudy (country)Inclusion criteriaExclusion criteriaGroupNumber (number with semen parameters)AetiologyMean age (SD) [years]Mean BMI (SD) (kg/m2)Mean testosterone (SD) [ng/dl]Mean FSH (SD) [IU/L]Mean LH (SD) [IU/L]Mean spermconcent ration (SD) [million/mL]InterventionControlDurationOutcomeFunding, conflict of interestNotesSelective oestrogen receptor modulators versus placebo versus testosterone gelWiehle, 2014 (USA)Diagnosis of secondary hypogonadism, morning testosterone <250 ng/dLNREnclomiphene 12.5 mg27 (16)NR49.7 (11.6)32.6 (5.17)217.2 (58.8)6.4 (4.2)4 (1.8)3/16aEnclomiphene 12.5, 25 mg1% testosterone gel, placebo6 months (semen analysis at 3 months)Sperm concentration < 15 million/mL (p values for total sperm count, volume, motility)Repros therapeutics, notable concernsNo details on previous testosterone useEnclomiphene 25 mg33 (19)49.2 (10.9)31.7 (4.9)209.8 (55.4)9.4 (10.9)5.3 (4)1/19aTestosterone gel33 (19)52 (10.6)33.1 (5.87)210 (54)6 (2.9)3.9 (1.8)3/19aPlacebo28 (13)51.6 (11.7)30.9 (4.17)213.7 (74.9)6.1 (4.8)3.9 (2.6)1/13aKim, 2016 (USA)Overweight men, aged 18–60 years, with secondaryhypogonadism (morning serum TT of <300 ng/dL and LH <9.4 IU/L)NREnclomiphene41 + 44Possible overweight/obesity49.1 (7.4), 47.3 (8.8)33.1 (4.4), 33.8 (4.6)203.3 (52.4), 212.9 (48)4.9–6.13.3–3.898.3 (87.2), 79 (55.2)Enclomiphene 12.5 mg/day increased to 25 mg/day if TT did not increase >450 ng/dL after 4 weeks1.62% testosterone gel adjusted according to the manufacturer, placebo16 weeksSperm concentration percentage change from the baseline, adverse effectsRepros therapeutics, notable concernsCombination of two studies, previous testosterone use 21–23%. Study complete by 217.Testosterone gel43 + 4247.4 (7.2), 45 (8.2)34 (4.4), 33.1 (4.6)208.6 (54), 229.8 (44)4.9–6.13.3–3.878.9 (68.5), 75.1 (45.8)Placebo45 + 4147.2 (9), 47.5 (8.9)32.6 (4.3), 33.5 (4.4)200 (43.1), 206 (48.2)4.9–6.13.3–3.895 (90.8), 80.5 (62.3)Selective oestrogen receptor modulators versus testosterone gelKaminetsky, 2013 (USA)Secondary hypogonadism, TT <300 mg/dLKallman syndrome, primary hypogonadism, testicular failure, significant medical illness.Unwilling to stop testosterone or other hormones for ?30 days (not clear)Enclomiphene7 (6)NR46 years (range 41–59 years)Mean weight 105 kg165 (66)NRNRNREnclomiphene 25 mg dailyTestosterone gel (dose NR)6 monthsPost‐intervention sperm concentration difference between groupsRepros therapeutics, notable concernsAll used topical testosterone for at least 6 months, stopped for 7−14 days before baseline assessmentTestosterone gel5Selective oestrogen receptor modulators versus placeboNCT01739595 (USA)Overweight/obese men with secondary hypogonadism (TT <300 ng/dL, LH <9.4 mIU/L) and sperm concentration >15 million/mLPrior use of testosterone treatments within the last 6 monthsIrreversibly infertile or compromised fertility (cryptorchism, Kallman syndrome, primary hypogonadism, vasectomy, or tumours of the pituitary)Enclomiphene 12.5 mg112 (99)Possible overweight/obesity44.6 (9.6)NRNRNRNRNREnclomiphene 12.5 mg daily, dose increase to 25 if TT not increased to 300 in 6 weeksPlacebo12 weeks, extended to 18 weeks if dose increasedProportion of subjects with a 50% or greater decrease in sperm concentration from baseline after 12 weeks of treatment, adverse eventsRepros therapeutics, notable concernsPublished article not availableEnclomiphene 25 mg22 (21)45.8 (8.6)Placebo47 (45)43.6 (10.5)NCT01532414 (USA)Same as aboveSame as aboveEnclomiphene 12.5 mg92 (85)Possible overweight/obesity47.2 (9.6)NRNRNRNRNRSame as aboveSame as aboveSame as aboveSame as aboveRepros therapeutics, notable concernsProtocol similar to the study described above. Published article not available. Possible overlapping population.Enclomiphene 25 mg21 (19)43.6 (10.1)Placebo38 (35)47.8 (9.5)Selective oestrogen receptor modulator versus aromatase inhibitorsHelo, 2015 (USA)Men 18–50 years, infertility, testosterone 150–350 ng/dL (average of two consecutive samples), LH 1.2–8.6 mIU/LSperm concentration 1 million/mL, BMI >40, haematocrit <36 or >52, previous oral or inhaled steroid use, opioid use.Known pituitary or testicular diseaseAnastrozole13 (12)NR35 (6.5)33 (9.8)248 (18)9.9 (1.9)4.8 (0.48)32.7 (12)Anastrozole 1 mg dailyClomiphene 25 mg daily12 weeksSemen volume, concentration and motility before and after intervention, fertility, adverse eventsNot reported, no notable concernsSix participants with secondary subfertilityClomiphene13 (12)33 (3.9)32 (7.5)253 (17)4.2 (1.7)3.9 (0.45)32 (12)Abbreviations: BMI, body mass index; FSH, follicle‐stimulating hormone; LH, luteinising hormone; NR, not reported; TT, total testosterone.aNumber of men with sperm concentration <15 million/mL out of the participants with semen parameters.2FIGURESummary of risk of bias assessment of randomised controlled studies. Based on the overall assessment, the first five studies a have high risk of bias and the other study has some concerns on the risk of bias.The main RCT results related to semen outcome are summarised in Table 2. Outcomes and reporting differed across studies, so it was not possible to compute summary statistics. Therefore, we adapted the vote counting method to adjudicate the overall direction of effect. Table 5 summarises findings, including the assessment of the certainty of evidence using the GRADE tool. Four RCTs with 591 participants compared SERMs against placebo. Two published studies showed evidence towards the benefit; however, two unpublished studies suggested that SERMs were inferior to placebo (possible overlap of patients not excluded). Overall, the certainty of evidence was very low because of the high ROB and imprecision because of the small total sample size.2TABLESummary of results from randomised controlled trials.StudyOutcomeOverall ROB judgmentAvailable dataSummary statisticsVote counting (without considering statistical significance)Selective oestrogen receptor modulators versus placeboWiehle, 2014Sperm concentration <15 million/mLHigh riskIntervention 2/35Control 2/13OR 0.33 (95% CI 0.04–2.66)BenefitSperm concentration (million/mL)EC 12.5 mg: p = 0.95EC 25 mg: p = 0.78NRSperm motilityNSNRTotal sperm countEC 12.5 mg: p = 0.45EC 25 mg: p = 0.77NRKim, 2016Percentage change of the sperm concentration from the baselineHigh riskIntervention 11.7 (80.3), 15.2 (55.8)Control 4.1 (57.2), 7.6 (89.6)MD 7.60 (–22.12, 37.32),MD 7.60 (–24.40, 39.60)BenefitNCT01739595Proportion of subjects with a 50% or greater decrease in sperm concentrationHigh riskIntervention 19/134Control 2/47OR 3.72 (0.83, 16.61)HarmNCT01532414 (? Overlapping population)Proportion of subjects with a 50% or greater decrease in sperm concentrationHigh riskIntervention 16/113Control 1/38OR 6.10 (0.78, 47.67)HarmSelective oestrogen receptor modulator versus aromatase inhibitorsHelo, 2015Sperm concentration (million/mL)Some concernsAZ 26 (13)CC 41 (13)MD –15.00 (–25.40, –4.60)CC benefitSemen volume (mL)AZ 3.15 (0.51)CC 2.2 (0.54)MD 0.95 (0.53, 1.37)AZ benefitSperm motility (%)AZ 35 (5.4)CC 41 (5.4)MD –6.00 (–10.32, –1.68)CC benefitFertilityAZ 1/12CC 2/12Inadequate dataAbbreviations: AZ, anastrozole; CC, clomiphene citrate; CI, confidence interval; EC, enclomiphene citrate; MD, mean difference; NR, not reported; NS, not significant; OR, odds ratio; ROB, risk of bias.Three RCTs comparing SERMs against testosterone gel (n = 275) showed higher sperm concentration with SERMs compared to testosterone gel in men with secondary hypogonadism. Further statistical analyses were not carried out because exogenous testosterone is already known to suppress spermatogenesis.The study comparing anastrozole to clomiphene suggested better sperm concentration outcomes with clomiphene (mean difference –15.00 [–25.40, –4.60]).26Only the study by Helo et al. mentioned fertility outcomes reporting the conception of one and two partners of men on anastrozole and clomiphene, respectively, conceiving during the study period. However, its intervention period was only 12 weeks.Two studies did not report safety data,21,25 and one study reported that there were no serious adverse effects in participants.23 One study reported one fatal stroke in a participant on enclomiphene, although causality was not established.22 One serious adverse event with enclomiphene was reported in another study; however, the adverse effect was not specified.24 In the remaining study, anastrozole treatment was associated with skin rash in one patient, and deep vein thrombosis in another patient (who had a previous episode of deep vein thrombosis).26Non‐randomised studiesWe identified five NRSIs including 105 participants reporting semen parameters with SERMs.27–31 Four studies were uncontrolled retrospective observational, while the study by Lima et al. was uncontrolled prospective. Although details of patients treated with human chorionic gonadotropin (hCG) are also reported in two studies29,31 the authors did not consider this a comparator group. There were no eligible studies reporting data on AIs. Characteristics of included studies are summarised in Table 3.3TABLECharacteristics of selected non‐randomised studies of intervention with selective oestrogen receptor modulators.ParticipantsParticipant characteristicsStudy (country)DesignInclusionExclusionNumber of participantsAetiologyMean age (SD) (years)Mean BMI (SD) (kg/m2)Mean TT (SD) (ng/dL)Mean FSH (SD) (IU/L)Mean LH (SD) (IU/L)Mean sperm concentration (SD) (million/mL)Intervention, durationOutcome of interestFunding, conflicts of interestNotesLima,2021(USA)ProspectiveMen with primary infertility, morning TT <300 ng/dL on two occasions, abnormal semen parameters in two occasions (TMSC <9)IHH being on testosterone/hCG/CC at the time of baseline assessment (stopped for 8 weeks)16NR40.9 (4.3)34.7 (7.9)190.7 (63.7)6.1 (4.6)4.5 (2.6)3.1 (3.8)CC 25 mg every other day, 3 monthsSperm concentration, TMSC, semen volume and sperm motility before and after interventionNR, no notable concernsAdditional group received CC + hCGPrimary objective was to assess 17‐OHP as a predictor of successSharma,2019(USA)RetrospectiveHypogonadism (TT <300 ng/dL) and/or infertilityPrevious treatment with testosteroneOpted varicocele repair57NRMediana 35, IQR 31–40Mediana 28, IQR 26–32Mediana 242, IQR 191–317Mediana 3, IQR 2–6Mediana 4, IQR 2–615 (27)CC 25 mg/day titrated to 50 mg/day (if TT <300 mg/dL after 4 weeks), median 2.8 months (IQR 1.8–4.4)Semen volume, sperm concentration, motile percentage, TMC before and after interventionNR, notable concernsHypogonadotropic hypogonadism not mentioned as an inclusion criteria, but participant characteristics suggestiveSurbone,2019(Switzerland)RetrospectiveMen with infertility, low plasma TT, low or normal FSH and LH, sperm concentration >0.1 million/mLSecondary causes of hypogonadism like Kallman, cranial surgery, tumour, radiotherapy18NR36 (6.8)28.2 (3.9)8.5 (2.3)4.2 (2.3)4.8 (3.3)14.7 (18.2)CC 50 mg every 48 h, at least 3 monthsSperm concentration, progressive motility before and after, spontaneous pregnancy, adverse effectsNR, no notable concernsPatel,2015(USA)RetrospectiveMen aged 18–55 years with hypogonadism and/or subfertilityTT <300 ng/dL and/or bioavailable testosterone <155 ng/dLPrevious testosterone/tamoxifen/hCG/anastrozole use47 (baseline sperm parameters only in 27, 3 month data only in 10)NR34.5 (NR)30.2 (NR)246.8 (97.6)5.8 (4.8)9.6 (10.7)50.7 (71.6)CC 50 mg every other day, increased to daily if testosterone rise <50 ng/dL in 2 weeks, median follow‐up 3 months (IQR 2.3–3.7)Semen volume, sperm concentration, progressive motile percentage, total motile count, percentage normal morphology before and after, adverse effectsAmerican medical systems, no notable concernsWhitten,2006(England)RetrospectiveMen with hypogonadotropic hypogonadismNR4 (six other patients treated with hCG)IHH‐3, panhypopituitarism‐131, 30, 28, 33NR194, 117, 41, 14771, 0.8, 0.9, 0.6NR0.6, 0, 0, 0CC 50 mg 3 times a week for 3 monthsSperm concentration before and after, fertilityNR, no notable concernPatient with panhypopituitarism was on testosterone replacement. One additional patient (IHH) had taken clomiphene and remained azoospermic before the studyAbbreviations: 17–OHP, 17–hydroxyprogesterone; BMI, body mass index; CC, clomiphene citrate; FSH, follicle‐stimulating hormone; hCG, human chorionic gonadotropin; IHH, idiopathic hypogonadotropic hypogonadism; IQR, interquartile range; LH, luteinising hormone; NR, not reported; TMC, total motile count; TMSC, total motile sperm count; TT, total testosterone.aMixed with 20 eugonadal men.All studies included men with infertility. Whitten et al. included men with idiopathic secondary hypogonadism (n = 3) or panhypopituitarism (n = 1).29 The aetiology of secondary hypogonadism was not reported in the other four studies. The mean/median BMI of participants in all four studies reporting BMI was >28 kg/m2.27,28,30,31 In two studies, previous TRT was an exclusion criterion,27,28 whereas in one study, previous TRT was not reported,30 and in the other, one patient had been on TRT.29 In one study, patients who had been on TRT were given a washout period of 8 weeks.31 Except in the study by Patel et al.,28 mean/median sperm concentration at baseline was low or close to the lower limit of the normal. The approximate follow‐up duration was 3 months for all the studies.All five studies had a critical ROB because of the risk of confounding because all of them had a single pre‐intervention outcome measurement and a single post‐intervention outcome measurement. Other domains of bias were variable between the studies (Figure 3). The publication bias could not be assessed because less than 10 studies were included in the quantitative analysis. The main results of the studies in relation to semen parameters and the overall ROB judgment are summarised in Table 4.3FIGURESummary of risk of bias assessment of non‐randomised studies of intervention on selective oestrogen receptor modulators. All included studies have a critical risk of bias in the overall assessment with bias of confounding been critical in all the studies.4TABLESummary of results from non‐randomised studies of intervention on selective oestrogen receptor modulators.StudyOutcomeOverall risk of bias judgementPre‐interventionPost‐interventionMean difference (95% confidence interval)SignificanceLima, 2021Sperm concentration (million/mL)Critical3.1 (3.8)10.14 (14.27)7.04 (–0.20, 14.28)0.006Semen volume (mL)2.7 (1.6)2.61 (1.31)–0.09 (–1.1, 0.2)0.43Total motile sperm count (million)3.75 (6.6)13.33 (18.45)9.58 (–0.02, 19.18)0.03Sharma, 2019Sperm concentration (million/mL)Critical15 (27)21 (25)6 (–3.55, 15.55)0.22Semen volume (mL)2.4 (1.5)2.4 (1.2)0.00 (–0.50, 0.50)1Total motility (%)31 (21)35 (26)–4.00 (–12.68, 4.68)0.37Total motile sperm count (million)14 (26)30 (112)16.00 (–13.85, 45.85)0.29Surbone, 2019Sperm concentration (million/mL)Critical14.7 (18.2)19.3 (16.6)4.60 (–6.78, 15.98)0.024Progressive motility (%)20.5 (17.5)22.2 (18.5)1.70 (–10.06, 13.46)0.395Patel, 2015Sperm concentration (million/mL)Critical50.7 (71.6)72.4 (60.1)21.70 (–24.31, 67.71)0.009Semen volume (mL)3.3 (1.9)3.2 (1.3)–0.10 (–1.18, 0.98)0.28Sperm motility (%)33.1 (20.5)38.5 (24.3)5.40 (–11.53, 22.33)0.53Total motile sperm count (million)59.7 (110.8)90.99 (92.9)31.29 (–39.86, 102.44)0.09Sperm morphology (normal %)8.6 (17.2)8.8 (16.8)0.20 (–12.07, 12.47)0.45Whitten, 2006Sperm concentration (million/mL)Critical0.6, 0, 0, 010, 33, 163, 051.35 (–22.74, 125.44)0.17All five studies (n = 105) reported changes in sperm concentration. Mean differences were suggestive of benefit (6.64 [95% confidence interval, CI 1.54, 11.74], I2 = 0%) (Table 5). Semen volume and total motile sperm count were reported in three studies with a total population of 83. The overall mean differences were –0.03 (95% CI –0.44, 0.38), I2 = 0% and 10.52 (95% CI 1.46–19.59), I2 = 0%, respectively. The certainty of evidence was very low because of the critical ROB in these studies.5TABLESummary of findings for effects of selective oestrogen receptor modulators/aromatase inhibitors in men with hypogonadotropic hypogonadism.OutcomeNumber of studiesNumber of participantsSummary of resultsaCertainty of evidence (GRADE)Selective oestrogen receptor modulators versus placeboSperm concentration4591Benefit: 2 studiesHarm: 2 studies (? overlapping population)Very lowbOther sperm parameters188No benefitVery lowbSelective oestrogen receptor modulators versus aromatase inhibitorsSperm concentration126Clomiphene benefitVery lowcNon‐randomised studies of selective oestrogen receptor modulators reporting before and after intervention dataSperm concentration51056.64 (1.54, 11.74), p = 0.01Very lowdSemen volume383–0.03 (–0.44, 0.38), p = 0.89Very lowdTotal motile sperm count38310.52 (1.46, 19.59), p = 0.02Very lowdAll studiesFertility3Inadequate dataSerious adverse events6Only few eventsVery lowaFor randomised‐controlled trials (RCTs)—summary according to vote counting; for non‐randomised studies of intervention (NRSIs)—summary is pooled mean difference.bStudies with high risk of bias, imprecision because of small sample size.cSome concern in risk of bias, small sample size.dVery serious risk of bias because of critical risk of bias in all non‐randomised studies of intervention.Surbone et al. reported fertility data, with three female partners becoming pregnant during the study period out of 57. In the study by Whitten et al., female partners of two study participants (out of four) conceived. The other three studies did not report fertility data.Safety data were not reported in three studies.27,29,31 Surbone et al. reported that there were no significant adverse effects.30 In the other study, three patients had a paradoxical drop in total testosterone and switched to hCG.28 One patient had fatigue and mood swings.Overall, little AI data were found; specifically, neither RCTs comparing AI with placebo nor NRSIs of AI were identified. There were inadequate data on fertility because only three studies reported fertility outcomes, and all were of short follow‐up. It was not possible to analyse determinants of response to SERM or AI because of the limited number of studies, low total numbers of participants, and unavailability of disaggregated data from subgroups of interest. Safety data were not reported in many studies. Few major adverse events were observed, but causality could not be attributed to SERM/AI treatment.DISCUSSIONOur systematic review was conducted to appraise for the first time whether SERMs/AIs might improve semen quality in men with secondary hypogonadism. Non‐comparative cohort studies suggest that SERM treatment is associated with improved sperm concentration and total motile sperm count in men with low testosterone with low/normal gonadotrophins and infertility; however, RCTs show heterogeneous effects of SERMs compared with placebo. Although studies comparing SERMs to testosterone gel were also summarised in our review, we have not pursued to draw any conclusions using their data because of known suppressive effects of exogenous testosterone on spermatogenesis.Although we aimed to review studies including men with secondary hypogonadism of diverse aetiology, there was an overrepresentation of men with low testosterone with low/normal gonadotrophins in the background of obesity. From a pathophysiological point of view, a greater response is expected with SERMs in men with obesity‐related low testosterone because oestradiol produced through increased aromatase activity from adipose tissue is thought to mediate suppression of the hypothalamus and pituitary.32 There remains controversy on whether this can be strictly defined as a type of hypogonadism because their hypothalamic–pituitary–gonadal axis has no pathology and this is considered an adaptive response to another illness.33–35 In contrast, if there are symptoms of hypogonadism and low testosterone with low/normal gonadotrophins, making a diagnosis of secondary hypogonadism in these men may be recommended.36 Additionally, hypogonadism associated with obesity or type 2 diabetes is considered an increasingly prevalent cause of male infertility.37,38 Considering these factors, we included these studies in our review acknowledging the limitation in generalising these data to men with organic secondary hypogonadism and we have identified the broad patient population in our review as having low testosterone with low/normal gonadotrophins.There is a gap in the evidence between the androgenic and spermatogenic effects of oestrogen modulators among men considered in our review because the evidence on the improvement of testosterone seems to be more robust.8,14 It is not clear whether this is because of the true inefficacy of these agents to promote spermatogenesis or the lack of high‐quality studies. This ambiguity is further intensified by some data that suggest that SERMs enhance Leydig cell function but not Sertoli cell action.39 Another important factor is the possible short duration of intervention and follow‐up in the studies. The total duration for spermatogenesis and delivery of spermatozoa to ejaculatory ducts is approximately 120 days.40 Therefore, follow‐up of about 3 months is likely to miss the slow response of spermatogenesis even if the Sertoli cells are responding. On the other hand, spermatogenesis is an intricate process dependent on many factors other than hormone regulation.41 This could limit the spermatogenic response despite the rise of intra‐testicular testosterone synthesis. Oestrogen signalling is implicated in the regulation of spermatogenesis,6 so its blockade might negatively impact semen quality. In keeping with this, paradoxical declines of spermatogenesis have been reported in a minority of men treated with SERMs.42 However, some studies have suggested that SERMs/AIs may improve semen parameters in men with idiopathic infertility.9,11,13It is important to consider the limitations of the current analysis and its constituent studies. Most studies, particularly RCTs, did not consider fertility history in the inclusion criteria. Additionally, several studies had enrolled normospermic men with normal fertility. Measures to optimise results of semen analysis and assessment of patient adherence to drug treatment during the follow‐up were underreported in the available studies. Safety data and pregnancy rates were not reported adequately. The lack of disaggregated data and small numbers limited any subgroup analysis. Due to the heterogeneity in the methods used in reporting outcomes within the included studies, we did not conduct a formal meta‐analysis to synthesise available RCT data. Of the available options, we used vote counting because that was the only method that could be used across studies. However, we have summarised effect estimates wherever possible. Vote counting has a few inherent limitations, such as disregarding the magnitude of the effect and differences in the relative sizes of the studies.20 Ideally, vote counting would be better suited to a larger number of studies than identified by our review. Multiple studies have reported the effects of AIs on semen parameters in men with low testosterone:oestradiol ratio. However, gonadotrophin levels in these studies were not clearly consistent with secondary hypogonadism,43–45 so these studies did not meet the inclusion criteria of our review.SERMs have been used off‐label in clinical practice for men with secondary hypogonadism, especially when fertility is a concern. According to the findings of our review, it seems that this practice is not supported by high‐quality evidence. Therefore, we believe that high‐quality studies on men with secondary hypogonadism and abnormal semen parameters should be performed with an adequate follow‐up duration to clarify this dilemma. It is also important to define standardised objective outcome measures to determine improvement in semen parameters and assess clinically relevant outcomes such as pregnancy rate in future studies evaluating the role of SERMs and/or AIs in the treatment of male subfertility because of secondary hypogonadism.CONCLUSIONSAlthough low‐quality evidence suggests a possible improvement of semen parameters with selective oestrogen receptor modulators in men with low testosterone associated with low/normal gonadotrophins, there is inadequate evidence on its efficacy to improve semen parameters compared to placebo or other fertility options. The available evidence is mostly limited to men with overweight/obesity. There is no evidence on the role of aromatase inhibitors. Data on the effects of selective oestrogen receptor modulators/aromatase inhibitors on fertility in the population of interest are limited. Larger randomised‐controlled trials with well‐defined inclusion criteria on the aetiology of secondary hypogonadism, cut‐off values for testosterone, gonadotrophin and semen parameters and fertility status are required to ascertain the effects of selective oestrogen receptor modulators/aromatase inhibitors on the fertility of these men. Outcomes such as semen parameters and fertility should be assessed with a longer follow‐up considering the time taken to normalise spermatogenesis before these agents can be recommended for clinical practice, even for off‐label use.AUTHOR CONTRIBUTIONSChanna N. Jayasena conceived and Nipun Lakshitha de Silva and Ranga Eshaka Wickramarachchi planned the review. Giovanni Corona and Suks Minhas supervised the methodological aspects of the review. Nipun Lakshitha de Silva and Harsha Dissanayake performed the search, screening and study selection. Nipun Lakshitha de Silva, Harsha Dissanayake and Camila Suarez performed data extraction and analysis. Channa N. Jayasena, Waljit S. Dhillo and Ranjith Ramasamy guided and supervised data extraction and analysis. Nipun Lakshitha de Silva drafted the initial manuscript. All authors revised and edited the manuscript.ACKNOWLEDGEMENTSThe Section of Endocrinology and Investigative Medicine is funded by grants from the MRC, NIHR and is supported by the NIHR Biomedical Research Centre Funding Scheme and the NIHR/Imperial Clinical Research Facility. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The following authors are also funded by: Channa N. Jayasena—NIHR Post‐Doctoral Fellowship; WSD—NIHR Senior Investigator Award.CONFLICT OF INTEREST STATEMENTThe authors declare they have no conflicts of interest.FUNDING INFORMATIONThe authors received no specific funding for this work.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available in the Supporting Information.REFERENCESBhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715‐1744.Minhas S, Bettocchi C, Boeri L, et al. European Association of Urology Guidelines on male sexual and reproductive health: 2021 update on male infertility. Eur Urol. 2021;80(5):603‐620.Isidori AM, Aversa A, Calogero A, et al. Adult‐ and late‐onset male hypogonadism: the clinical practice guidelines of the Italian Society of Andrology and Sexual Medicine (SIAMS) and the Italian Society of Endocrinology (SIE). 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Journal

Andrology – Wiley

Published: Jun 12, 2023

Keywords: aromatase inhibitors; fertility; hypogonadotropic hypogonadism; secondary hypogonadism; selective oestrogen receptor modulators; spermatogenesis

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