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Temporal Changes of Clomiphene on Testosterone Levels and Semen Parameters in Subfertile Men (2022)
Tommy Jiang, John T. Sigalos, Vadim Osadchiy, Alvaro Santamaria, Michael H. Zheng, Neilufar Modiri, Keith V. Regets, Jesse N. Mills, Sriram V. Eleswarapu
Purpose: Clomiphene citrate (CC) is prescribed off-label in men to improve testosterone and sperm parameters, but the duration of treatment needed to reach maximal benefit remains unclear. Our objective was to examine the temporal effects of CC on total testosterone (TT) and semen analysis (SA) using longitudinal follow-up data in treated men.
Materials and Methods: We analyzed an IRB-approved database of men treated with CC (25 mg q.d. or 50 mg q.o.d.) from January 2016 through May 2021. We identified patients with 3, 6, 9, and 12-month follow-up data for TT and 3, 6, and 9-month follow-up SA. Mean absolute changes in TT and sperm concentration compared to baseline were calculated, along with 95% confidence intervals. Men with prior genitourinary procedures or hormone therapy were excluded. Paired t-tests were used to compare TT and sperm concentration at each time point to baseline (alpha=0.05).
Results: One hundred thirty-four men received CC, mean age 37.7 years (SD 6.7, range 24–52). TT at all follow-ups (3, 6, 9, and 12 months) was available for 25 men, and SA at 3, 6, and 9 months for 26 men. Baseline TT was 358±145 ng/dL and sperm concentration was 13±17.2 M/mL. Significant improvement in TT was identified at 3 months (62.7 ng/dL, 95% CI: 0.49–125.0, p=0.048), additional benefit at 6 months (181.8 ng/dL, 95% CI: 114.1–249.5, p<0.01), and plateau at 9 and 12 months. Improvement in sperm concentration was first observed at 9 months (20.7 M/mL, 95% CI: 10.2–31.2, p<0.01). Semen volume and sperm motility did not change.
Conclusions: Duration of treatment with clomiphene may impact testosterone and sperm concentration, and the historical 3-month milestone may be insufficient for clinical and research evaluation. Men taking CC may experience a plateau in TT at 6 months and the first benefit in sperm concentration at 9 months.
INTRODUCTION
Approximately 15% of couples fail to achieve pregnancy within one year of attempted conception with over 50% having a male contribution [1]. For men contending with subfertility, reproductive urologists depend upon lifestyle counseling, empiric medical therapy, and targeted surgical management to improve fertility outcomes. Clomiphene citrate (CC), an oral selective estrogen receptor modulator, is commonly prescribed to hypogonadotropic men [2] in an attempt to improve serum total testosterone (TT; reference range: 200–1,000 ng/dL) and semen parameters through the modulation of luteinizing hormone (LH; reference range: 2–12 miU/mL) and follicle-stimulating hormone (FSH; reference range: 1.6–9 miU/mL). Despite widespread prescribing of CC by reproductive urologists, discussion of CC is sparse within both the American Urological Association [3] and European Association of Urology [4] guidelines on male hypogonadism and infertility. Data supporting the use of CC vary widely: the largest randomized clinical trial by the World Health Organization (WHO) showed no improvement in pregnancy rates or sperm concentration (reference range >15 M/mL) with CC use compared to placebo at 6 months [5], whereas other retrospective studies have shown variable improvements in semen parameters with stricter initial sperm concentration and gonadotropin inclusion criteria [6,7]. Of note, few studies have evaluated outcomes of CC use in men beyond 3 months [8,9], and no temporal pattern of hormonal or seminal response has been identified. We sought to determine the magnitude of improvement in TT and sperm concentration in men taking CC for fertility optimization with long-term interval follow-up to investigate if and when patients may experience a plateau with CC monotherapy.
DISCUSSION
1. Longitudinal effect of clomiphene citrate on testosterone
CC has been shown consistently to improve both TT [10] and symptoms of hypogonadism [10,11] with a limited side effect profile [9]. AUA guidelines currently recommend CC to improve low testosterone in infertile men with the common practice of using 3 months as the primary endpoint in evaluating efficacy. Our study suggests men may experience the full benefit of CC with a longer duration of use, as we observed maximal benefit in TT at 6 months of CC monotherapy before a plateau at the 9 and 12-month follow-up dates. There are some data in the literature to suggest the benefits of longer durations of CC in hypogonadism. Krzsatek et al [8] found that a majority of hypogonadal men became eugonadal with at least 3 years of CC use; however, interval data was not provided in this study. Additionally, some studies have reported longitudinal data showing sustained TT response with CC alone; however, these studies do not specifically explore the temporal pattern of response and allowed for up-titration of CC when TT was not maintained at a certain threshold [9,10,12]. Taken together with our results, the data from these studies suggest that 6 months may be a more suitable endpoint in studying CC efficacy than the typical 3-month milestone historically evaluated in the scientific literature. Such data may be helpful in counseling patients regarding expectations for CC treatment duration during shared decision-making conversations in the clinical context.
2. Longitudinal effect of clomiphene citrate on sperm parameters
The efficacy of CC for sperm parameters in subfertile men remains less clear. Gundewar et al [13] reported that up to 24% of men may experience a paradoxical decline in sperm concentration during 3-month follow-up, with 17% of patients never recovering to baseline upon discontinuation of CC. Studying CC in male fertility has been stymied by a lack of knowledge on predictors of efficacy; multiple studies have reported that even baseline LH and FSH poorly correlate with sperm parameter improvement at 3-month follow-up [14]. Our data suggest that 3 months may not be a sufficient duration of treatment to experience a fertility benefit from CC. Our cohort of patients first showed statistical improvement in sperm concentration at 9 months. These data may be useful in setting timing expectations for couples trying to conceive, since 9 months (or longer) may be too burdensome a timeline before opting for intrauterine insemination or in vitro fertilization. Indeed, one of the reasons we observe a diminishing sample size at longer durations of treatment with CC is that couples tend to move forward with advanced reproductive technologies after the frustrating experience of seeing no meaningful improvement in sperm parameters after 3 months of CC, which is typically the timing of first follow-up SA.
The relationship between serum testosterone and sperm parameters continues to be an important topic of study in the male fertility research community. For example, dual therapy of CC with anastrozole has been studied with the idea that improving TT and the testosterone-to-estradiol ratio provides a lateral effect on fertility optimization [15]. Other groups have shown that optimizing TT may improve sperm retrieval rates in microsurgical sperm extraction in men with azoospermia [16,17]. While it remains unclear if CC alone is definitively effective in optimizing fertility parameters in subfertile men, longer intervals of treatment will likely be needed to answer this question.
CONCLUSIONS
Overall, our study raises the question of what a suitable endpoint may be when studying CC monotherapy in the context of male subfertility and hypogonadism. We pose that 6 months of CC may be needed to achieve maximal benefit in TT while 9 months may be necessary to observe statistical benefit in sperm concentration. The findings from this work may serve as additional data for reproductive urologists to use to counsel men regarding the potential benefits of CC monotherapy for subfertility.
Tommy Jiang, John T. Sigalos, Vadim Osadchiy, Alvaro Santamaria, Michael H. Zheng, Neilufar Modiri, Keith V. Regets, Jesse N. Mills, Sriram V. Eleswarapu
Purpose: Clomiphene citrate (CC) is prescribed off-label in men to improve testosterone and sperm parameters, but the duration of treatment needed to reach maximal benefit remains unclear. Our objective was to examine the temporal effects of CC on total testosterone (TT) and semen analysis (SA) using longitudinal follow-up data in treated men.
Materials and Methods: We analyzed an IRB-approved database of men treated with CC (25 mg q.d. or 50 mg q.o.d.) from January 2016 through May 2021. We identified patients with 3, 6, 9, and 12-month follow-up data for TT and 3, 6, and 9-month follow-up SA. Mean absolute changes in TT and sperm concentration compared to baseline were calculated, along with 95% confidence intervals. Men with prior genitourinary procedures or hormone therapy were excluded. Paired t-tests were used to compare TT and sperm concentration at each time point to baseline (alpha=0.05).
Results: One hundred thirty-four men received CC, mean age 37.7 years (SD 6.7, range 24–52). TT at all follow-ups (3, 6, 9, and 12 months) was available for 25 men, and SA at 3, 6, and 9 months for 26 men. Baseline TT was 358±145 ng/dL and sperm concentration was 13±17.2 M/mL. Significant improvement in TT was identified at 3 months (62.7 ng/dL, 95% CI: 0.49–125.0, p=0.048), additional benefit at 6 months (181.8 ng/dL, 95% CI: 114.1–249.5, p<0.01), and plateau at 9 and 12 months. Improvement in sperm concentration was first observed at 9 months (20.7 M/mL, 95% CI: 10.2–31.2, p<0.01). Semen volume and sperm motility did not change.
Conclusions: Duration of treatment with clomiphene may impact testosterone and sperm concentration, and the historical 3-month milestone may be insufficient for clinical and research evaluation. Men taking CC may experience a plateau in TT at 6 months and the first benefit in sperm concentration at 9 months.
INTRODUCTION
Approximately 15% of couples fail to achieve pregnancy within one year of attempted conception with over 50% having a male contribution [1]. For men contending with subfertility, reproductive urologists depend upon lifestyle counseling, empiric medical therapy, and targeted surgical management to improve fertility outcomes. Clomiphene citrate (CC), an oral selective estrogen receptor modulator, is commonly prescribed to hypogonadotropic men [2] in an attempt to improve serum total testosterone (TT; reference range: 200–1,000 ng/dL) and semen parameters through the modulation of luteinizing hormone (LH; reference range: 2–12 miU/mL) and follicle-stimulating hormone (FSH; reference range: 1.6–9 miU/mL). Despite widespread prescribing of CC by reproductive urologists, discussion of CC is sparse within both the American Urological Association [3] and European Association of Urology [4] guidelines on male hypogonadism and infertility. Data supporting the use of CC vary widely: the largest randomized clinical trial by the World Health Organization (WHO) showed no improvement in pregnancy rates or sperm concentration (reference range >15 M/mL) with CC use compared to placebo at 6 months [5], whereas other retrospective studies have shown variable improvements in semen parameters with stricter initial sperm concentration and gonadotropin inclusion criteria [6,7]. Of note, few studies have evaluated outcomes of CC use in men beyond 3 months [8,9], and no temporal pattern of hormonal or seminal response has been identified. We sought to determine the magnitude of improvement in TT and sperm concentration in men taking CC for fertility optimization with long-term interval follow-up to investigate if and when patients may experience a plateau with CC monotherapy.
DISCUSSION
1. Longitudinal effect of clomiphene citrate on testosterone
CC has been shown consistently to improve both TT [10] and symptoms of hypogonadism [10,11] with a limited side effect profile [9]. AUA guidelines currently recommend CC to improve low testosterone in infertile men with the common practice of using 3 months as the primary endpoint in evaluating efficacy. Our study suggests men may experience the full benefit of CC with a longer duration of use, as we observed maximal benefit in TT at 6 months of CC monotherapy before a plateau at the 9 and 12-month follow-up dates. There are some data in the literature to suggest the benefits of longer durations of CC in hypogonadism. Krzsatek et al [8] found that a majority of hypogonadal men became eugonadal with at least 3 years of CC use; however, interval data was not provided in this study. Additionally, some studies have reported longitudinal data showing sustained TT response with CC alone; however, these studies do not specifically explore the temporal pattern of response and allowed for up-titration of CC when TT was not maintained at a certain threshold [9,10,12]. Taken together with our results, the data from these studies suggest that 6 months may be a more suitable endpoint in studying CC efficacy than the typical 3-month milestone historically evaluated in the scientific literature. Such data may be helpful in counseling patients regarding expectations for CC treatment duration during shared decision-making conversations in the clinical context.
2. Longitudinal effect of clomiphene citrate on sperm parameters
The efficacy of CC for sperm parameters in subfertile men remains less clear. Gundewar et al [13] reported that up to 24% of men may experience a paradoxical decline in sperm concentration during 3-month follow-up, with 17% of patients never recovering to baseline upon discontinuation of CC. Studying CC in male fertility has been stymied by a lack of knowledge on predictors of efficacy; multiple studies have reported that even baseline LH and FSH poorly correlate with sperm parameter improvement at 3-month follow-up [14]. Our data suggest that 3 months may not be a sufficient duration of treatment to experience a fertility benefit from CC. Our cohort of patients first showed statistical improvement in sperm concentration at 9 months. These data may be useful in setting timing expectations for couples trying to conceive, since 9 months (or longer) may be too burdensome a timeline before opting for intrauterine insemination or in vitro fertilization. Indeed, one of the reasons we observe a diminishing sample size at longer durations of treatment with CC is that couples tend to move forward with advanced reproductive technologies after the frustrating experience of seeing no meaningful improvement in sperm parameters after 3 months of CC, which is typically the timing of first follow-up SA.
The relationship between serum testosterone and sperm parameters continues to be an important topic of study in the male fertility research community. For example, dual therapy of CC with anastrozole has been studied with the idea that improving TT and the testosterone-to-estradiol ratio provides a lateral effect on fertility optimization [15]. Other groups have shown that optimizing TT may improve sperm retrieval rates in microsurgical sperm extraction in men with azoospermia [16,17]. While it remains unclear if CC alone is definitively effective in optimizing fertility parameters in subfertile men, longer intervals of treatment will likely be needed to answer this question.
CONCLUSIONS
Overall, our study raises the question of what a suitable endpoint may be when studying CC monotherapy in the context of male subfertility and hypogonadism. We pose that 6 months of CC may be needed to achieve maximal benefit in TT while 9 months may be necessary to observe statistical benefit in sperm concentration. The findings from this work may serve as additional data for reproductive urologists to use to counsel men regarding the potential benefits of CC monotherapy for subfertility.
