madman
Super Moderator
Clomiphene citrate for male infertility: A systematic review and meta-analysis (2023)
M Huijben, R L N Huijsmans, M T W T Lock, V F de Kemp, L M O de Kort, H M K van Breda
ABSTRACT
BACKGROUND – Male infertility is a prevalent and worldwide problem with various difficulties in treatment. Clomiphene citrate (CC) is a selective estrogen receptor modulator and may improve semen quality by stimulating hormone synthesis and spermatogenesis. There is a lack of evidence on the efficacy of CC as therapy for male infertility.
OBJECTIVES - Therefore, a systematic review and meta-analysis were performed to assess the efficacy of CC on sperm quality in infertile men.
METHODS – A search was conducted in the PubMed, EMBASE, and Cochrane databases for effectiveness in infertile males treated with CC. 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.
RESULTS – 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 of 8.38 x10^6/mL (95% CI, 5.17, 11.59; P < 0.00001; I2 = 87%). Total sperm motility was higher during treatment with a mean difference of 8.14% (95% CI, 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 CC treatment. During follow-up, no serious adverse effects occurred. In ten studies pregnancy rate was reported and yielded a mean of 17% during CC treatment (range, 0 – 40%).
CONCLUSIONS – Clomiphene citrate increased sperm concentration and -motility and could be considered a safe therapy for improving sperm parameters in infertile males.
INTRODUCTION
According to The International Glossary on Infertility and Fertility Care (2017), infertility is a ‘disease characterized by the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person's capacity to reproduce either as an individual or with his/her partner’. 1 Infertility affects an estimated 48 to 186 million people worldwide. 2,3 Male factor is the sole cause of approximately one-third of all cases of infertility. 4,5 Congenital anomalies, urogenital infections, trauma, systemic disorders, and varicocele are some of the causes and associated factors with male infertility. 6 In about 30-40% of the cases, infertile men have normal findings on physical examination and hormonal laboratory tests. This so-called idiopathic infertility, which has no known etiology, is difficult to treat. 6
An unfulfilled child wish is a reason that infertile couples are frequently treated with assisted reproductive techniques such as intrauterine insemination, in vitro fertilization, testicular sperm extraction, and intracytoplasmic sperm injection. Empirical therapies such as selective estrogen receptor modulators (SERMs) and antioxidants are potential treatment options to improve spermatogenesis. Although there is a lack of supporting data on the efficacy of these medications, empirical therapies are necessary for the treatment of idiopathic infertility.5
Clomiphene citrate (CC) is a SERM, it occupies estrogen receptors in the hypothalamus and pituitary, and so stimulates the hypothalamic-pituitary-gonadal (HPG) axis, resulting in the release of gonadotropins and improves testosterone production and may theoretically improve spermatogenesis. 7 CC has been used in women for ovulatory dysfunction since the 1960s. 8 Although, the U.S.A. Food and Drug Administration (FDA) never approved CC therapy for male infertility and hypogonadism, it has been used as an off-label medication. The advantage of CC over testosterone therapy is that it maintains spermatogenesis in the case of hypogonadal males and may improve spermatogenesis in infertile males. CC results from previous studies demonstrated safety on long-term use with minor side effects and costs. 9
Even though it is an off-label medication, many urologists utilize CC to treat male infertility. According to the survey conducted by the American Urological Association in 2012 and revised in 2020, 78% and 93%, of male fertility fellowship-trained urologists used CC, as well as other empirical therapies and surgery to treat infertile males.10,11
Even though CC is commonly used as an empirical treatment, the efficacy of therapy with CC for male infertility is insufficiently established. According to the FDA, appropriate or well-controlled trials demonstrating the efficacy of CC in the treatment of male infertility are needed. 12 We conducted a systematic review and meta-analysis to provide an overview of the published studies on the efficacy of CC therapy on sperm parameters in the treatment of male infertility.
DISCUSSION
According to the results of this systematic review and meta-analysis, CC therapy enhances sperm concentration and motility without causing major side effects. As far as we know, this is the most recent and comprehensive systematic review and meta-analysis that includes both clinical trials and observational studies.
Finally, there are a few potential limitations for this study to consider. First, despite the extended search, studies could have been missed for inclusion. Second, this review demonstrates the biochemical efficacy of CC on semen parameters in infertile males, as a proxy for pregnancy rates. Third, with the inclusion of retrospective study designs, there is a risk of confounding and detection bias. Fourth, there is notable heterogeneity across the included studies, with varying; dosage, laboratory measurements, and in- and exclusion criteria. Last to mention, demographic- and predictive factors were not well investigated or documented so it is difficult to draw conclusions regarding potential predictive factors for success. In further research, there is a need for documentation on demographic, patient-specific factors, and potential predictors in order to be able to determine who will benefit from CC therapy.
Importantly, there is a difference in the methodological quality of the included studies. The most important reasons for rating ‘moderate’ or ‘weak’ quality were; retrospective study design, unclear described study population, and undescribed important differences between groups prior to intervention in case of controlled clinical trials. With only three ‘strong’ rated studies.21,26,36, the conclusion of our results should be interpreted with caution. A future study with a more homogenous population, such as idiopathic infertility, is needed to further investigate the effect of CC on male infertility.
CONCLUSIONS
This systematic review on the use of CC to treat male infertility indicated that CC therapy enhanced sperm motility and concentration, with the presence of minor side effects. Future studies should be conducted to help the FDA reevaluate its approval of CC as a therapy option for infertile men.
M Huijben, R L N Huijsmans, M T W T Lock, V F de Kemp, L M O de Kort, H M K van Breda
ABSTRACT
BACKGROUND – Male infertility is a prevalent and worldwide problem with various difficulties in treatment. Clomiphene citrate (CC) is a selective estrogen receptor modulator and may improve semen quality by stimulating hormone synthesis and spermatogenesis. There is a lack of evidence on the efficacy of CC as therapy for male infertility.
OBJECTIVES - Therefore, a systematic review and meta-analysis were performed to assess the efficacy of CC on sperm quality in infertile men.
METHODS – A search was conducted in the PubMed, EMBASE, and Cochrane databases for effectiveness in infertile males treated with CC. 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.
RESULTS – 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 of 8.38 x10^6/mL (95% CI, 5.17, 11.59; P < 0.00001; I2 = 87%). Total sperm motility was higher during treatment with a mean difference of 8.14% (95% CI, 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 CC treatment. During follow-up, no serious adverse effects occurred. In ten studies pregnancy rate was reported and yielded a mean of 17% during CC treatment (range, 0 – 40%).
CONCLUSIONS – Clomiphene citrate increased sperm concentration and -motility and could be considered a safe therapy for improving sperm parameters in infertile males.
INTRODUCTION
According to The International Glossary on Infertility and Fertility Care (2017), infertility is a ‘disease characterized by the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person's capacity to reproduce either as an individual or with his/her partner’. 1 Infertility affects an estimated 48 to 186 million people worldwide. 2,3 Male factor is the sole cause of approximately one-third of all cases of infertility. 4,5 Congenital anomalies, urogenital infections, trauma, systemic disorders, and varicocele are some of the causes and associated factors with male infertility. 6 In about 30-40% of the cases, infertile men have normal findings on physical examination and hormonal laboratory tests. This so-called idiopathic infertility, which has no known etiology, is difficult to treat. 6
An unfulfilled child wish is a reason that infertile couples are frequently treated with assisted reproductive techniques such as intrauterine insemination, in vitro fertilization, testicular sperm extraction, and intracytoplasmic sperm injection. Empirical therapies such as selective estrogen receptor modulators (SERMs) and antioxidants are potential treatment options to improve spermatogenesis. Although there is a lack of supporting data on the efficacy of these medications, empirical therapies are necessary for the treatment of idiopathic infertility.5
Clomiphene citrate (CC) is a SERM, it occupies estrogen receptors in the hypothalamus and pituitary, and so stimulates the hypothalamic-pituitary-gonadal (HPG) axis, resulting in the release of gonadotropins and improves testosterone production and may theoretically improve spermatogenesis. 7 CC has been used in women for ovulatory dysfunction since the 1960s. 8 Although, the U.S.A. Food and Drug Administration (FDA) never approved CC therapy for male infertility and hypogonadism, it has been used as an off-label medication. The advantage of CC over testosterone therapy is that it maintains spermatogenesis in the case of hypogonadal males and may improve spermatogenesis in infertile males. CC results from previous studies demonstrated safety on long-term use with minor side effects and costs. 9
Even though it is an off-label medication, many urologists utilize CC to treat male infertility. According to the survey conducted by the American Urological Association in 2012 and revised in 2020, 78% and 93%, of male fertility fellowship-trained urologists used CC, as well as other empirical therapies and surgery to treat infertile males.10,11
Even though CC is commonly used as an empirical treatment, the efficacy of therapy with CC for male infertility is insufficiently established. According to the FDA, appropriate or well-controlled trials demonstrating the efficacy of CC in the treatment of male infertility are needed. 12 We conducted a systematic review and meta-analysis to provide an overview of the published studies on the efficacy of CC therapy on sperm parameters in the treatment of male infertility.
DISCUSSION
According to the results of this systematic review and meta-analysis, CC therapy enhances sperm concentration and motility without causing major side effects. As far as we know, this is the most recent and comprehensive systematic review and meta-analysis that includes both clinical trials and observational studies.
Finally, there are a few potential limitations for this study to consider. First, despite the extended search, studies could have been missed for inclusion. Second, this review demonstrates the biochemical efficacy of CC on semen parameters in infertile males, as a proxy for pregnancy rates. Third, with the inclusion of retrospective study designs, there is a risk of confounding and detection bias. Fourth, there is notable heterogeneity across the included studies, with varying; dosage, laboratory measurements, and in- and exclusion criteria. Last to mention, demographic- and predictive factors were not well investigated or documented so it is difficult to draw conclusions regarding potential predictive factors for success. In further research, there is a need for documentation on demographic, patient-specific factors, and potential predictors in order to be able to determine who will benefit from CC therapy.
Importantly, there is a difference in the methodological quality of the included studies. The most important reasons for rating ‘moderate’ or ‘weak’ quality were; retrospective study design, unclear described study population, and undescribed important differences between groups prior to intervention in case of controlled clinical trials. With only three ‘strong’ rated studies.21,26,36, the conclusion of our results should be interpreted with caution. A future study with a more homogenous population, such as idiopathic infertility, is needed to further investigate the effect of CC on male infertility.
CONCLUSIONS
This systematic review on the use of CC to treat male infertility indicated that CC therapy enhanced sperm motility and concentration, with the presence of minor side effects. Future studies should be conducted to help the FDA reevaluate its approval of CC as a therapy option for infertile men.
