BACKGROUND: Male factor infertility affect up to 50% of couples unable to conceive spontaneously. Several non-hormonal pharmacological treatments have been proposed to boost spermatogenesis and increase chances of conception in men with infertility. Still, no clear evidence exists on the most effective treatment strategy.
OBJECTIVE: We aimed to compare the effectiveness of non-hormonal pharmacological treatment options for men with infertility using a systematic review and network meta-analysis.
METHODS: We searched MEDLINE, EMBASE, and CENTRAL until October 2023 for randomised/quasi-randomised trials that evaluated any non-hormonal pharmacological treatment options for men with idiopathic semen abnormalities or those with hypogonadism. We performed pairwise and network meta-analyses using a random effect model. We assessed risk of bias, heterogeneity, and network inconsistency. We calculated the mean rank and the surface under the cumulative ranking curve (SUCRA) for each intervention the maximum likelihood to achieve each of reported outcomes. We reported primarily on sperm concentration and other important semen and biochemical outcomes using standardised mean difference (SMD) and 95% confidence-intervals(CI).
RESULTS: We included 14 randomised trials evaluating four treatments (Clomiphene citrate, Tamoxifen, Aromatase inhibitors, anti-oxidants) and their combinations in 1342 men. The overall quality of included trials was low. Sperm concentration improved with clomiphene compared to anti-oxidants (SMD 2.15, 95%CI 0.78-3.52), aromatase inhibitor (SMD 2.93, 95%CI 1.23-4.62), tamoxifen (SMD - 1.96, 95%CI -3.57; -0.36) but not compared to placebo (SMD - 1.53, 95%CI -3.52- 0.47). Clomiphene had the highest likelihood to achieve the maximum change in sperm concentration (SUCRA 97.4). All treatments showed similar effect for sperm motility, semen volume, and normal sperm morphology. FSH levels showed significant improvement with clomiphene vs.anti-oxidant (SMD 1.48, 95%CI 0.44-2.51) but not compared to placebo. The evidence networks for LH and testosterone suffered from significant inconsistency (p = 0.01) with similar trend of improvement with clomiphene compared to other treatments but not compared to placebo.
CONCLUSIONS: There is insufficient evidence to support the routine use of Clomiphene, tamoxifen, and aromatase inhibitors to optimise semen parameters in men with infertility. Future randomised trials are needed to confirm the efficacy of clomiphene in improving fertility outcomes in men.
UNASSIGNED: CRD42023430179.

Clomiphene citrate (CC) and letrozole are the predominant medical interventions for the management of infertility in patients with polycystic ovary syndrome (PCOS). To comprehensively summarize the evidence, a systematic review and meta-analysis of randomized clinical trials (RCTs) was carried out to assess the effect of letrozole and CC on pregnancy outcomes in PCOS patients. We searched PubMed/MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials from inception to January 2023. We included RCTs conducted on PCOS women comparing letrozole to CC and assessing endometrial thickness, the number and size of follicles, and ovulation and pregnancy rates. The endpoints were summarized as risk ratio (RR) or standardized mean difference (SMD) with 95% confidence interval (CI) using the random-effects model. Heterogeneity was examined using the I2 statistic. Fifty trials met our inclusion criteria. The mean endometrial thickness was significantly higher in the letrozole group compared to CC group (SMD: 0.89; 95% CI: 0.49, 1.28; I2=97.72%); however, the number of follicles was higher in the CC group (SMD: -0.56; 95% CI: -0.96, -0.17; I2=96.34%). Furthermore, letrozole intake induced higher ovulation rate (RR: 1.20; 95% CI: 1.13, 1.26; I2=54.49%) and pregnancy rate (RR: 1.44; 95% CI: 1.28, 1.62; I2=65.58%) compared to CC. Compared to CC, letrozole has a positive effect on endometrial thickness, monofollicular development, and ovulation and pregnancy rates suggesting that letrozole may be a strong alternative to CC as a first-line medical intervention for chronic anovulation in PCOS women. Larger studies are warranted to further clarify these findings.

To review the impact of testosterone and other androgenic-anabolic steroids (AASs) on male fertility, exploring potential drugs that can be used to preserve or restore male fertility upon AAS use or prior contact.
A review was performed to provide a unifying clinical link between drugs used to preserve or restore male fertility (ie, clomiphene citrate, human chorionic gonadotropin, selective estrogen receptor modulators, recombinant luteinizing and follicle-stimulating hormones, and human menopausal gonadotrophin) in the context of AAS-induced infertility and related aspects.
Human chorionic gonadotropin (125-500 IU every other day), clomiphene citrate (12.5-50 mg/d), recombinant luteinizing hormone (125-500 IU every other day), recombinant follicle-stimulating hormone (75-150 IU 1-3×/wk), and human menopausal gonadotrophin (75-150 IU 1-3×/wk) are promising early pharmacologic approaches to avert AAS-induced male infertility. Additionally, a full partner assessment is crucial to the success of a couple planning to have children. The partner\'s age and gynecopathies must be considered. Egg or sperm cryopreservation can also be alternatives for future fertility. Reinforcing AAS cessation is imperative to achieving better success in misusers.
The exponential increase in AAS misuse raises concerns about the impact on male fertility. This review suggests that gonadotropin analogs and selective androgen receptor modulators (clomiphene citrate) are viable approaches to early preserve or restore fertility in men on AAS use or with previous contact. However, proper standardization of doses and combinations is required and hence physicians should also be aware of patients\' and partners\' fertility.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is an endocrine, metabolic, and reproductive disorder which, according to the Rotterdam criteria, affects up to 24% of women of childbearing age. Although the prevalence of infertility in this subpopulation of women is high, the optimal treatment has not been fully established yet. Insulin resistance is considered to be an important mechanism involved in the development of PCOS; hence, the aim of this narrative review is to present an overview of the current pharmacological insulin-sensitizing treatment modalities for infertile women with PCOS.
METHODS: A MEDLINE and PubMed search for the years 1990-2023 was performed using a combination of keywords. Clinical trials with insulin sensitizers used for infertility treatment as well as analyses of systematic reviews and meta-analyses were evaluated. When deemed necessary, additional articles referenced in the retrieved papers were included in this narrative review.
RESULTS: Several insulin-sensitizing compounds and various therapeutical protocols are available for infertility treatment of women with PCOS. Metformin is the most common adjuvant medication to induce ovulation in infertile women with PCOS and is more frequently administered in combination with clomiphene citrate than on its own. Recently, inositol and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as possible options for infertility treatment in PCOS.
CONCLUSIONS: The future of medical treatment of PCOS women with infertility lies in a personalized pharmacological approach, which involves various compounds with different mechanisms of action that could modify ovarian function and endometrial receptivity, ultimately leading to better overall reproductive outcomes in these women.

To determine whether progestin-primed ovarian stimulation (PPOS) is more effective for women with diminished ovarian reserve (DOR) than clomiphene citrate (CC)/letrozole (LE) plus gonadotropin in IVF or ICSI treatment.
Nine databases were searched until May 24, 2023, to identify relevant studies. Forest plots were used to present the results of this meta-analysis. Begg\'s and Egger\'s tests were applied to estimate publication bias. Subgroup and sensitivity analysis were performed to check the potential sources of heterogeneity and verify the robustness of the pooled results, respectively.
A total of 14 studies with 4182 participants were included for meta-analysis. There was evidence of a statistically notable increase in clinical pregnancy rate (OR = 1.39, 95%CI [1.01, 1.91], p = 0.05), optimal embryos rate (OR = 1.50, 95%CI [1.20, 1.88], p = 0.0004), and cumulative pregnancy rate (OR = 1.73, 95%CI [1.14, 2.60], p = 0.009), the duration and the amount of gonadotropin required (MD = 1.56, 95%CI [0.47, 2.66], p = 0.005; SMD = 1.51, 95%CI [0.90, 2.12], p < 0.00001), along with decrease cycle cancellation rate (OR = 0.78, 95%CI [0.64, 0.95], p = 0.02), luteinizing hormone (LH) level on the day of hCG (SMD = -0.81, 95%CI [-1.10, -0.53], p < 0.00001), and premature LH surge rate (OR = 0.10, 95%CI [0.07, 0.15], p < 0.00001) when PPOS was used. No evidence for publication bias within results was revealed.
Based on evidence-based results, PPOS protocol seems to improve IVF/ICSI outcomes for women with DOR. More research with larger sample sizes and rigorous designs are required to further explore the value of PPOS among women diagnosed with DOR.
www.crd.york.ac.uk, identifier CRD42023430202.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is one of the most common causes of infertility in reproductive-age women. However, the efficacy and optimal therapeutic strategy for reproductive outcomes are still under debate. We conducted a systematic review and network meta-analysis to compare the efficacy of different first-line pharmacological therapies in terms of reproductive outcomes for women with PCOS and infertility.
METHODS: A systematic retrieval of databases was conducted, and randomized clinical trials (RCTs) of pharmacological interventions for infertile PCOS women were included. The primary outcomes were clinical pregnancy and live birth, and the secondary outcomes were miscarriage, ectopic pregnancy and multiple pregnancy. A network meta-analysis based on a Bayesian model was performed to compare the effects of the pharmacological strategies.
RESULTS: A total of 27 RCTs with 12 interventions were included, and all therapies tended to increase clinical pregnancy, especially pioglitazone (PIO) (log OR 3.14, 95% CI 1.56 ~ 4.70, moderate confidence), clomiphene citrate (CC) + exenatide (EXE) (2.96, 1.07 ~ 4.82, moderate confidence) and CC + metformin (MET) + PIO (2.82, 0.99 ~ 4.60, moderate confidence). Moreover, CC + MET + PIO (2.8, -0.25 ~ 6.06, very low confidence) could increase live birth most when compared to placebo, even without a significant difference. For secondary outcomes, PIO showed a tendency to increase miscarriage (1.44, -1.69 ~ 5.28, very low confidence). MET (-11.25, -33.7 ~ 0.57, low confidence) and LZ + MET (-10.44, -59.56 ~ 42.11, very low confidence) were beneficial for decreasing ectopic pregnancy. MET (0.07, -4.26 ~ 4.34, low confidence) showed a neutral effect in multiple pregnancy. Subgroup analysis demonstrated no significant difference between these medications and placebo in obese participants.
CONCLUSIONS: Most first-line pharmacological treatments were effective in improving clinical pregnancy. CC + MET + PIO should be recommended as the optimal therapeutic strategy to improve pregnancy outcomes. However, none of the above treatments had a beneficial effect on clinical pregnancy in obese PCOS.
BACKGROUND: CRD42020183541; 05 July 2020.

To estimate the effect of letrozole and clomiphene citrate in women with infertility and polycystic ovarian syndrome (PCOS).
MEDLINE through PubMed, Web of Science, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched for relevant studies from inception to February 1, 2022. Two reviewers retrieved, filtered, and extracted data independently using the bibliographic software EndNote X9 and Excel workbook. We included randomized controlled trials (RCTs) reporting ovulation induction outcomes in women with infertility and PCOS treated with either letrozole or clomiphene citrate followed by timed intercourse or intrauterine insemination. The data were merged into a mean difference or risk ratio (RR) with 95% CI, depending on variable types.
Data collection and organization were conducted in accordance with the 2020 PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) statement. Twenty-nine RCTs were eligible, which included 3,952 women and 7,633 ovulation induction cycles. We acquired evidence from 22 RCTs for the ovulation rate, 28 RCTs for the clinical pregnancy rate, and eight RCTs for live-birth rate. Pooled analysis indicated that letrozole treatment prevailed against clomiphene citrate in ovulation rate (RR 1.14, 95% CI 1.06-1.21, P <.001), clinical pregnancy rate (RR 1.48, 95% CI 1.34-1.63, P <.001), and live-birth rate (RR 1.49, 95% CI 1.27-1.74, P <.001).
Letrozole was associated with improved ovulation, pregnancy, and live-birth rates compared with clomiphene citrate. We recommend letrozole over clomiphene citrate as an ovulation induction drug in women with infertility and PCOS, although the quality of the evidence is mixed.
PROSPERO, CRD42022308777.

OBJECTIVE: To explore the association between ovulation induction drugs and ovarian cancer.
METHODS: Systematic review and meta-analysis.
METHODS: Not applicable.
METHODS: Women without ovarian cancer who ever or never underwent ovarian induction.
METHODS: An extensive electronic search of the following databases was performed: PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library and CNKI, from inception until January 2022. A total of 34 studies fulfilled our inclusion criteria and were included in the final meta-analysis. The odds ratio (OR) and random-effects model were used to estimate the pooled effects. The Newcastle-Ottawa Scale was used to assess the quality of included studies. Funnel plots and Egger tests were used to assess publication bias.
RESULTS: New diagnosed borderline ovarian tumor (BOT) and invasive ovarian cancer (IOC) between ovulation induction (OI) group and control (CT) group considering fertility outcome, OI cycles and specific OI drugs.
RESULTS: Primarily, there was no significant difference in the incidence of IOC and BOT between the OI and CT groups. Secondly, OI treatment did not increase the risk of IOC and BOT in the multiparous women, nor did it increase the risk of IOC in the nulliparous women. However, the risk of BOT appeared to be higher in nulliparous women treated with OI treatment. Thirdly, among women exposed to OI, the risk of IOC and BOT was higher in nulliparous women than in multiparous women. Fourthly, the risk of IOC did not increase with increasing OI cycles. Lastly, exposure to specific OI drugs also did not contribute to the risk of IOC and BOT.
CONCLUSIONS: Overall, OI treatment did not increase the risk of IOC and BOT in most women, regardless of OI drug type and OI cycle. However, nulliparous women treated with OI showed a higher risk of ovarian cancer, necessitating their rigorous monitoring and ongoing follow-up.

Male infertility is a prevalent and worldwide problem with various difficulties in treatment. Clomiphene citrate is a selective estrogen receptor modulator and may improve semen quality by stimulating hormone synthesis and spermatogenesis. There is lack of evidence on the efficacy of clomiphene citrate as therapy for male infertility.
Therefore, a systematic review and meta-analysis was performed to assess the efficacy of clomiphene citrate on sperm quality in infertile men.
A search was conducted in the PubMed, EMBASE and Cochrane databases for effectiveness in infertile males treated with clomiphene citrate. Both intervention and observational studies were included. Primary outcome measures were semen parameters (concentration, motility and morphology). Secondary outcomes included hormonal evaluation, pregnancy rate and side effects. Studies were included for meta-analysis if they provided absolute numbers for outcomes before and during treatment with appropriate SD or SE.
Total 1799 studies were identified during the search, 18 studies remained for qualitative analysis (n = 731) and 15 studies for meta-analysis (n = 566). Study populations ranged between 11 and 140 participants. Sperm concentration was higher during treatment, with a mean difference 8.38 × 106 /ml (95% confidence interval: 5.17-11.59; p < 0.00001; I2  = 87%). Total sperm motility was higher during treatment, with a mean difference of 8.14% (95% confidence interval: 3.83-12.45; p < 0.00001; I2  = 76%). There was no difference in sperm morphology before and during treatment. Total testosterone, follicle-stimulating hormone, luteinizing hormone and estradiol were higher during clomiphene citrate treatment. During follow-up, no serious adverse effects occurred. In 10 studies, pregnancy rate was reported and yielded a mean of 17% during clomiphene citrate treatment (range: 0%-40%).
Clomiphene citrate increased sperm concentration and motility and could be considered as a safe therapy for improving sperm parameters in infertile males.

Although selective estrogen receptor modulators have been proposed as a treatment for men with central functional hypogonadism, only a few data have been produced in men with obesity-related functional androgen deficiency.
To determine whether and to what extent selective estrogen receptor modulators are an effective and safe therapy in men with obesity-related functional androgen deficiency.
A thorough search of PubMed, Web of Science, Scopus, and Cochrane Library databases was performed to identify studies comparing testosterone levels before and after treatment. Mean differences with 95% coefficient intervals were combined using random effects models. Funnel plot, Egger\'s test, and trim-and-fill analysis were used to assess publication bias.
Seven studies met the inclusion criteria providing information on 292 men with obesity-related functional androgen deficiency treated with clomiphene citrate (12.5-50 mg daily) or enclomiphene citrate (12.5-25 mg daily) for 1.5-4 months. The pooled estimates indicated a significant increase in testosterone levels both with clomiphene (mean difference: 11.56 nmol/L; 95% coefficient interval: 9.68, 13.43; I2  = 69%, pfor heterogeneity  = 0.01) and enclomiphene citrate (mean difference: 7.50 nmol/L; 95% coefficient interval: 6.52, 8.48; I2  = 4%, pfor heterogeneity  = 0.37). After the exclusion of one study on severely obese men, who exhibited the highest response rate to clomiphene citrate, the heterogeneity disappeared (mean difference: 10.27 nmol/L; 95% coefficient interval: 9.39, 11.16; I2  = 0%, pfor heterogeneity  = 0.66). No publication bias was revealed by Egger\'s test and trim-and-fill analysis. No treatment-related unexpected findings regarding safety profile were registered.
Treatment with clomiphene citrate and enclomiphene citrate may be an effective and safe alternative to testosterone replacement therapy in men with obesity-related functional androgen deficiency. Further long-term studies are warranted to define clinical reflections of the selective estrogen receptor modulators-induced increase in testosterone levels and to better clarify the safety profile.