Abstract
Male hypogonadism, which is characterized by low testosterone levels, has a significant impact on male sexual function, overall health, and fertility. Testosterone replacement therapy (TRT)is the conventional treatment for this condition, but it has potential adverse effects and is not suitable for men seeking to conceive. Testosterone plays an essential role in male sexual function, metabolism, mood, and overall well-being. Clomiphene citrate, a drug originally developed for female infertility, has recently gained attention as an off-label treatment for male hypogonadism. By blocking the negative feedback of estrogen on the hypothalamus and pituitary glands, clomiphene stimulates gonadotropin secretion, leading to increased endogenous testosterone production, which, in turn,improves sperm parameters and fertility and alleviates the symptoms of hypogonadism. Regarding the safety profile of clomiphene compared with TRT, clomiphene appears to confer a lower risk than TRT, which is associated with adverse effects such as polycythemia. Furthermore, combination therapy with clomiphene and anastrozole or human chorionic gonadotropin has been investigated as a potential approach to enhancing the effectiveness of treatments for improving hypogonadism symptoms. In conclusion, clomiphene citrate may offer a promising alternative to TRT for men with hypogonadism, particularly those desiring fertility preservations. However, its long-term efficacy and safety remain inadequately understood. Future research should focus on exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.
1. Introduction
2. HPG Axis in Men
3. Testosterone Synthesis
4. Biological Function of Testosterone
5. Male Hypogonadism
6. Male Infertility
7. Treatment Options for Male Hypogonadism
8. Clomiphene
In the 1960s, clomiphene citrate (2-[4-[(Z)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine) first brought about a revolutionary change in the treatment of female infertility and polycystic ovarian syndrome thanks to its ability to induce ovulation. Recently, clomiphene has been used for the off-label treatment of male hypogonadism despite not being approved by the FDA, being the most commonly prescribed medication by urologists for the empirical medical therapy of male infertility according to a cohort study of the American Urological Association [76]. Clomiphene is a racemic mixture composed of 38% zuclomiphene (cis-isomer) and 62% enclomiphene (trans-isomer), which is excreted through the intestines and has a half-life of 5 days [27]. Structurally, clomiphene is a derivative of triphenylethylene, substituted with a chloride anion and an amino alkoxy side chain, and is related to another nonsteroidal SERM, tamoxifen [77]. It is also classified as a catechol-estrogen, which is attributed to the presence of a diethylamino group [27].
9. Hormonal Measurement
10. Treatment of Hypogonadism Symptoms
11. Treatment of Infertility
12. Safety
Clomiphene is typically viewed as a relatively tolerable medication in clinical practice. However, due to its dual action as both an estrogen agonist and antagonist, it is associated with a range of adverse effects. The anti-estrogenic properties of clomiphene can lead to side effects such as hot flashes, headaches, and visual disturbances [111,112]. Additionally, other reported adverse events include mood alterations, dizziness, gynecomastia, breast and nipple tenderness, and testicular enlargement [113].
13. Population Variability in Treatment Response
14. Combination Therapy
15. Treatment Cost
16. Conclusions
In conclusion, clomiphene effectively increases serum testosterone levels in men with hypogonadism by inhibiting the negative feedback of estrogen and increasing LH and FSH levels, as well as intratesticular testosterone levels, thereby improving sperm parameters. Furthermore, clomiphene administration showed a positive effect on fertility and hypogonadism symptoms without major adverse effects, such as polycythemia and infertility, which are commonly associated with TRT. Therefore, clomiphene is a promising alternative, particularly for patients aiming to preserve fertility. However, the long-term efficacy and safety profiles of clomiphene are not fully understood. Future research should focus on elucidating these aspects and exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.
Male hypogonadism, which is characterized by low testosterone levels, has a significant impact on male sexual function, overall health, and fertility. Testosterone replacement therapy (TRT)is the conventional treatment for this condition, but it has potential adverse effects and is not suitable for men seeking to conceive. Testosterone plays an essential role in male sexual function, metabolism, mood, and overall well-being. Clomiphene citrate, a drug originally developed for female infertility, has recently gained attention as an off-label treatment for male hypogonadism. By blocking the negative feedback of estrogen on the hypothalamus and pituitary glands, clomiphene stimulates gonadotropin secretion, leading to increased endogenous testosterone production, which, in turn,improves sperm parameters and fertility and alleviates the symptoms of hypogonadism. Regarding the safety profile of clomiphene compared with TRT, clomiphene appears to confer a lower risk than TRT, which is associated with adverse effects such as polycythemia. Furthermore, combination therapy with clomiphene and anastrozole or human chorionic gonadotropin has been investigated as a potential approach to enhancing the effectiveness of treatments for improving hypogonadism symptoms. In conclusion, clomiphene citrate may offer a promising alternative to TRT for men with hypogonadism, particularly those desiring fertility preservations. However, its long-term efficacy and safety remain inadequately understood. Future research should focus on exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.
1. Introduction
2. HPG Axis in Men
3. Testosterone Synthesis
4. Biological Function of Testosterone
5. Male Hypogonadism
6. Male Infertility
7. Treatment Options for Male Hypogonadism
8. Clomiphene
In the 1960s, clomiphene citrate (2-[4-[(Z)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethylethanamine) first brought about a revolutionary change in the treatment of female infertility and polycystic ovarian syndrome thanks to its ability to induce ovulation. Recently, clomiphene has been used for the off-label treatment of male hypogonadism despite not being approved by the FDA, being the most commonly prescribed medication by urologists for the empirical medical therapy of male infertility according to a cohort study of the American Urological Association [76]. Clomiphene is a racemic mixture composed of 38% zuclomiphene (cis-isomer) and 62% enclomiphene (trans-isomer), which is excreted through the intestines and has a half-life of 5 days [27]. Structurally, clomiphene is a derivative of triphenylethylene, substituted with a chloride anion and an amino alkoxy side chain, and is related to another nonsteroidal SERM, tamoxifen [77]. It is also classified as a catechol-estrogen, which is attributed to the presence of a diethylamino group [27].
9. Hormonal Measurement
10. Treatment of Hypogonadism Symptoms
11. Treatment of Infertility
12. Safety
Clomiphene is typically viewed as a relatively tolerable medication in clinical practice. However, due to its dual action as both an estrogen agonist and antagonist, it is associated with a range of adverse effects. The anti-estrogenic properties of clomiphene can lead to side effects such as hot flashes, headaches, and visual disturbances [111,112]. Additionally, other reported adverse events include mood alterations, dizziness, gynecomastia, breast and nipple tenderness, and testicular enlargement [113].
13. Population Variability in Treatment Response
14. Combination Therapy
15. Treatment Cost
16. Conclusions
In conclusion, clomiphene effectively increases serum testosterone levels in men with hypogonadism by inhibiting the negative feedback of estrogen and increasing LH and FSH levels, as well as intratesticular testosterone levels, thereby improving sperm parameters. Furthermore, clomiphene administration showed a positive effect on fertility and hypogonadism symptoms without major adverse effects, such as polycythemia and infertility, which are commonly associated with TRT. Therefore, clomiphene is a promising alternative, particularly for patients aiming to preserve fertility. However, the long-term efficacy and safety profiles of clomiphene are not fully understood. Future research should focus on elucidating these aspects and exploring the benefits of combination therapies and personalized treatment strategies based on individual patient characteristics.
