madman
Super Moderator
A paradoxical decline in semen parameters in men treated with clomiphene citrate
Tejas Gundewar | Manish Kuchakulla | Ranjith Ramasamy
Abstract
Clomiphene, a selective estrogen receptor modulator, has been utilized in managing male sub-fertility since 1967. Numerous controlled and uncontrolled studies have been published regarding the efficacy of clomiphene citrate in male sub-fertility cohorts. Although the primary intention of treating men with clomiphene citrate is to improve sperm parameters and testosterone levels, some studies have reported a paradoxical decline in semen parameters. The information available on the decline in sperm parameters following treatment with clomiphene is sparse. We conducted a systemic review using PubMed, Embase, Cochrane Library, and Scopus databases for original studies reporting adverse effects of clomiphene citrate therapy on sperm parameters. This systematic review includes 384 men from 11 different studies that reported adverse effects of clomiphene citrate therapy. Of the men included in these studies, 19%, 21%, 17%, and 24% of clomiphene-treated men demonstrated a decrease in sperm count, concentration, motility, and total motile sperm count respectively. In up to 17% of patients, deterioration of semen parameters did not recover following discontinuation of therapy. In the future, more studies should report on this aspect so the magnitude of this effect can be more clearly understood.
1 | INTRODUCTION
Clomiphene citrate is a selective estrogen receptor modulator initially developed for the treatment of female infertility in the 1960s (Wheeler et al., 2019). Due to its mechanism of action, many have also advocated for its use to treat hypogonadal men who wish to preserve fertility. Selective estrogen receptor modulators function by inhibiting the negative feedback of estrogen on the hypothalamus and pituitary to promote spermatogenesis and testosterone production (Krzastek et al., 2019; Wheeler et al., 2019). While its use for male hypogonadism is off label due to a lack of long-term data, its usage has been supported by the American Urological Association guidelines (Krzastek et al., 2019). Treatment with clomiphene citrate has consistently demonstrated increases in testosterone levels as well as improvement in hypogonadal symptoms (Bendre et al., 2015; Katz et al., 2012; Moskovic et al., 2012; Ramasamy et al., 2014; Taylor & Levine, 2010). Many studies have also reported improvements in fertility, but still, a paucity of data exists with regard to the true fertility outcomes in hypogonadal men treated with clomiphene citrate (ElSheikh et al., 2015; Hussein et al., 2013; Mićić & Dotlić, 1985; Moradi et al., 2010; Wheeler et al., 2019). While clomiphene citrate has generally been regarded as a safe drug, minimal evidence concerning adverse side effects is available (Wheeler et al., 2019).
Clomiphene citrate is associated with an increase in estrogen levels. According to a study by Keihani et al., 25.47% of patients treated with clomiphene citrate 50 mg/day or every other day experienced hyperoestrogenaemia (defined as oestradiol > 50 pg/ ml) 4 weeks after treatment initiation (Keihani et al., 2020). Supraphysiological estrogen levels have a deleterious effect on spermatogenesis (Morrish et al., 1990; O’Marcaigh et al., 1995; Sharpe & Skakkebaek, 1993; Young et al., 1996). There are different postulated mechanisms by which raised estrogens to affect sperm production. Elevated estradiol levels result in vacuolization and increased glycoprotein production impairing Sertoli cell function. It also disturbs communication with germ cells, increases collagen synthesis and fatty degeneration in the testicular connective tissue. All these actions collectively result in the induction of germ cell death (Leavy et al., 2017). Oestradiol also plays a critical role in round spermatid chromatin reorganization during spermiogenesis through its action on Estrogen Receptor Alpha (ERα) present on Sertoli cells (Cacciola et al., 2013). Overexposure to estrogens reduces the expression of ERα on Sertoli cells, impacting this critical action. Moreover, it has been recognized that supraphysiological concentrations of estrogen act as powerful apoptotic triggers that induce germ cell apoptosis (Correia et al., 2015). Consequently, increased estrogen levels due to clomiphene citrate therapy may result in impaired spermatogenesis and worsening of sperm parameters.
5 | CONCLUSION
Treatment with clomiphene citrate can be associated with a decrease in semen count, concentration, motility, morphology, and total motile sperm count in up to 20% of patients. Among men who had a decline in semen parameters, 17% of them may not recover following discontinuation of therapy. The benefits of therapy should be weighed against potential negative impacts on fertility, and close follow-up should be maintained. More studies should report on the decline in semen parameters so the magnitude of this effect can be more easily measured by reproductive specialists in the future.
Tejas Gundewar | Manish Kuchakulla | Ranjith Ramasamy
Abstract
Clomiphene, a selective estrogen receptor modulator, has been utilized in managing male sub-fertility since 1967. Numerous controlled and uncontrolled studies have been published regarding the efficacy of clomiphene citrate in male sub-fertility cohorts. Although the primary intention of treating men with clomiphene citrate is to improve sperm parameters and testosterone levels, some studies have reported a paradoxical decline in semen parameters. The information available on the decline in sperm parameters following treatment with clomiphene is sparse. We conducted a systemic review using PubMed, Embase, Cochrane Library, and Scopus databases for original studies reporting adverse effects of clomiphene citrate therapy on sperm parameters. This systematic review includes 384 men from 11 different studies that reported adverse effects of clomiphene citrate therapy. Of the men included in these studies, 19%, 21%, 17%, and 24% of clomiphene-treated men demonstrated a decrease in sperm count, concentration, motility, and total motile sperm count respectively. In up to 17% of patients, deterioration of semen parameters did not recover following discontinuation of therapy. In the future, more studies should report on this aspect so the magnitude of this effect can be more clearly understood.
1 | INTRODUCTION
Clomiphene citrate is a selective estrogen receptor modulator initially developed for the treatment of female infertility in the 1960s (Wheeler et al., 2019). Due to its mechanism of action, many have also advocated for its use to treat hypogonadal men who wish to preserve fertility. Selective estrogen receptor modulators function by inhibiting the negative feedback of estrogen on the hypothalamus and pituitary to promote spermatogenesis and testosterone production (Krzastek et al., 2019; Wheeler et al., 2019). While its use for male hypogonadism is off label due to a lack of long-term data, its usage has been supported by the American Urological Association guidelines (Krzastek et al., 2019). Treatment with clomiphene citrate has consistently demonstrated increases in testosterone levels as well as improvement in hypogonadal symptoms (Bendre et al., 2015; Katz et al., 2012; Moskovic et al., 2012; Ramasamy et al., 2014; Taylor & Levine, 2010). Many studies have also reported improvements in fertility, but still, a paucity of data exists with regard to the true fertility outcomes in hypogonadal men treated with clomiphene citrate (ElSheikh et al., 2015; Hussein et al., 2013; Mićić & Dotlić, 1985; Moradi et al., 2010; Wheeler et al., 2019). While clomiphene citrate has generally been regarded as a safe drug, minimal evidence concerning adverse side effects is available (Wheeler et al., 2019).
Clomiphene citrate is associated with an increase in estrogen levels. According to a study by Keihani et al., 25.47% of patients treated with clomiphene citrate 50 mg/day or every other day experienced hyperoestrogenaemia (defined as oestradiol > 50 pg/ ml) 4 weeks after treatment initiation (Keihani et al., 2020). Supraphysiological estrogen levels have a deleterious effect on spermatogenesis (Morrish et al., 1990; O’Marcaigh et al., 1995; Sharpe & Skakkebaek, 1993; Young et al., 1996). There are different postulated mechanisms by which raised estrogens to affect sperm production. Elevated estradiol levels result in vacuolization and increased glycoprotein production impairing Sertoli cell function. It also disturbs communication with germ cells, increases collagen synthesis and fatty degeneration in the testicular connective tissue. All these actions collectively result in the induction of germ cell death (Leavy et al., 2017). Oestradiol also plays a critical role in round spermatid chromatin reorganization during spermiogenesis through its action on Estrogen Receptor Alpha (ERα) present on Sertoli cells (Cacciola et al., 2013). Overexposure to estrogens reduces the expression of ERα on Sertoli cells, impacting this critical action. Moreover, it has been recognized that supraphysiological concentrations of estrogen act as powerful apoptotic triggers that induce germ cell apoptosis (Correia et al., 2015). Consequently, increased estrogen levels due to clomiphene citrate therapy may result in impaired spermatogenesis and worsening of sperm parameters.
5 | CONCLUSION
Treatment with clomiphene citrate can be associated with a decrease in semen count, concentration, motility, morphology, and total motile sperm count in up to 20% of patients. Among men who had a decline in semen parameters, 17% of them may not recover following discontinuation of therapy. The benefits of therapy should be weighed against potential negative impacts on fertility, and close follow-up should be maintained. More studies should report on the decline in semen parameters so the magnitude of this effect can be more easily measured by reproductive specialists in the future.
