madman
Super Moderator
ABSTRACT
Background – Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is the first choice therapy, with several side effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism clomiphene citrate (CC) is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of CC therapy for men with hypogonadism.
Methods – The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effective studies of men with hypogonadism treated with CC. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic- and lipid profile, side-effects, safety aspects.
Results – We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone (TT) increased by 2.60 (95% CI 1.82 – 3.38) during CC treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Malesquestionnaire, which score improved during treatment. Reported side-effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.
Conclusion – CC is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. CC has few reported side effects and good safety aspects.
BACKGROUND
Hypogonadism is a common medical condition among men.1,2 Hypogonadism is a clinical and biochemical testosterone insufficiency syndrome, affecting various organ functions and quality of life, according to the European Association of Urology. 3,4 Common symptoms of hypogonadism are erectile dysfunction, reduced sexual activity and -desire, mood changes, and loss of muscle strength. 5,6 The prevalence for symptomatic hypogonadism at age 40-79 years, varies between 2.1%- 5.7% 2,6 and increases with age and presence of obesity, cardiovascular disease, chronic obstructive pulmonary disease (COPD), Diabetes Mellitus (DM) type 2, human immunodeficiency virus (HIV), chronic kidney disease, malignancies, and metabolic syndrome. 7
Causes of hypogonadism can be classified based on disruptions in various levels of the hypothalamic-pituitary-gonadal (HPG) axis. Primary hypogonadism is the most frequent cause of hypogonadism, resulting in low serum testosterone concentration and high serum gonadotropin concentration. 3 Primary hypogonadism results from direct testicular failure; the most common reasons are Klinefelter syndrome and testicular tumors.8,9 On the opposite, in secondary hypogonadism the testis are inadequately stimulated by gonadotropins, resulting in hypogonadism, usually with reduced or inappropriately normal serum concentration of gonadotropins. 3 Reasons for secondary hypogonadism are, e.g. hyperprolactinemia, Kallmann’s syndrome, and obesity.3,10,11 Adult-onset hypogonadism or late-onset hypogonadism, is a symptomatic testosterone deficiency in middle-aged and older men, with normal HPG-axis function. 6,12
Testosterone therapy (TTh) is the first-choice treatment for men with hypogonadism.13 The goal of this treatment aims to increase serum testosterone and restore androgen-dependent functions, e.g. muscle mass and strength, sexual functions, bone density, and general well-being. 4,14 However, TTh has some notable side effects. Subfertility is one of the most crucial side-effects of TTh, especially for men with an active or possible future child wish, because endogenous testosterone is reduced by negative feedback.15 Other side-effects are, e.g. increase in prostate volume, increase in prostate-specific antigen (PSA), elevated hematocrit (Ht) and serum estrogen concentration, and serum lipid alterations.15–17
Several studies and reviews are published about the effects of CC on subfertility. Few of these studies specifically examined the effect of CC in men with hypogonadism. 24–26 The purpose of this study was to determine if CC is an effective and safe therapy for men with hypogonadism. For this purpose, we conducted a systematic review and meta-analysis to provide oversight of the current literature on the effectiveness and safety of CC therapy for men with hypogonadism.
*To our knowledge, this is the first systematic review with meta-analysis of this subject, with various strengths and a large study population. With a limited number of studies on this subject with different study designs, it was difficult to find a reliable quality assessment tool. However, one of the strengths is that we found a validated instrument, suitable for all types of study designs. Furthermore, with the inclusion of both RCTs and observational studies, the study population in our study may cause a better representation of the patient population in daily clinical practice. Another strength is that with the sensitivity analysis for study design and study quality the results were still consistent.
CONCLUSION
CC for men with hypogonadism improves both clinical symptoms and biochemical testosterone insufficiency. CC therapy has few reported side effects and good safety aspects. It is probably necessary to stay on CC therapy to keep the biochemical and clinical effects. In our opinion, CC is a potentially effective and safe treatment and should be considered as a therapy in men with symptomatic hypogonadism, especially for those with an active or future child wish.
Background – Male hypogonadism is a clinical and biochemical androgen insufficiency syndrome, becoming more prevalent with age. Exogenous testosterone is the first choice therapy, with several side effects, including negative feedback of the hypothalamic-pituitary-gonadal axis, resulting in suppression of intratesticular testosterone production and spermatogenesis. To preserve these testicular functions while treating male hypogonadism clomiphene citrate (CC) is used as off-label therapy. This systematic review and meta-analysis aimed to evaluate the effectiveness and safety of CC therapy for men with hypogonadism.
Methods – The EMBASE, PubMed, Cochrane databases were searched in May 2021, for effective studies of men with hypogonadism treated with CC. Both intervention and observational studies were included. The Effective Public Health Practice Project Quality Assessment Tool, a validated instrument was used to assess methodological study quality. The primary outcome measure was the evaluation of serum hormone concentration. Secondary outcomes were symptoms of hypogonadism, metabolic- and lipid profile, side-effects, safety aspects.
Results – We included 19 studies, comprising four randomized controlled trials and 15 observational studies, resulting in 1642 patients. Seventeen studies were included in the meta-analysis, with a total of 1279 patients. Therapy and follow-up duration varied between one and a half and 52 months. Total testosterone (TT) increased by 2.60 (95% CI 1.82 – 3.38) during CC treatment. An increase was also seen in free testosterone, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, and estradiol. Different symptom scoring methods were used in the included studies. The most frequently used instrument was the Androgen Deficiency in Aging Malesquestionnaire, which score improved during treatment. Reported side-effects were only prevalent in less than 10% of the study populations and no serious adverse events were reported.
Conclusion – CC is an effective therapy for improving both biochemical as well as clinical symptoms of males suffering from hypogonadism. CC has few reported side effects and good safety aspects.
BACKGROUND
Hypogonadism is a common medical condition among men.1,2 Hypogonadism is a clinical and biochemical testosterone insufficiency syndrome, affecting various organ functions and quality of life, according to the European Association of Urology. 3,4 Common symptoms of hypogonadism are erectile dysfunction, reduced sexual activity and -desire, mood changes, and loss of muscle strength. 5,6 The prevalence for symptomatic hypogonadism at age 40-79 years, varies between 2.1%- 5.7% 2,6 and increases with age and presence of obesity, cardiovascular disease, chronic obstructive pulmonary disease (COPD), Diabetes Mellitus (DM) type 2, human immunodeficiency virus (HIV), chronic kidney disease, malignancies, and metabolic syndrome. 7
Causes of hypogonadism can be classified based on disruptions in various levels of the hypothalamic-pituitary-gonadal (HPG) axis. Primary hypogonadism is the most frequent cause of hypogonadism, resulting in low serum testosterone concentration and high serum gonadotropin concentration. 3 Primary hypogonadism results from direct testicular failure; the most common reasons are Klinefelter syndrome and testicular tumors.8,9 On the opposite, in secondary hypogonadism the testis are inadequately stimulated by gonadotropins, resulting in hypogonadism, usually with reduced or inappropriately normal serum concentration of gonadotropins. 3 Reasons for secondary hypogonadism are, e.g. hyperprolactinemia, Kallmann’s syndrome, and obesity.3,10,11 Adult-onset hypogonadism or late-onset hypogonadism, is a symptomatic testosterone deficiency in middle-aged and older men, with normal HPG-axis function. 6,12
Testosterone therapy (TTh) is the first-choice treatment for men with hypogonadism.13 The goal of this treatment aims to increase serum testosterone and restore androgen-dependent functions, e.g. muscle mass and strength, sexual functions, bone density, and general well-being. 4,14 However, TTh has some notable side effects. Subfertility is one of the most crucial side-effects of TTh, especially for men with an active or possible future child wish, because endogenous testosterone is reduced by negative feedback.15 Other side-effects are, e.g. increase in prostate volume, increase in prostate-specific antigen (PSA), elevated hematocrit (Ht) and serum estrogen concentration, and serum lipid alterations.15–17
Several studies and reviews are published about the effects of CC on subfertility. Few of these studies specifically examined the effect of CC in men with hypogonadism. 24–26 The purpose of this study was to determine if CC is an effective and safe therapy for men with hypogonadism. For this purpose, we conducted a systematic review and meta-analysis to provide oversight of the current literature on the effectiveness and safety of CC therapy for men with hypogonadism.
*To our knowledge, this is the first systematic review with meta-analysis of this subject, with various strengths and a large study population. With a limited number of studies on this subject with different study designs, it was difficult to find a reliable quality assessment tool. However, one of the strengths is that we found a validated instrument, suitable for all types of study designs. Furthermore, with the inclusion of both RCTs and observational studies, the study population in our study may cause a better representation of the patient population in daily clinical practice. Another strength is that with the sensitivity analysis for study design and study quality the results were still consistent.
CONCLUSION
CC for men with hypogonadism improves both clinical symptoms and biochemical testosterone insufficiency. CC therapy has few reported side effects and good safety aspects. It is probably necessary to stay on CC therapy to keep the biochemical and clinical effects. In our opinion, CC is a potentially effective and safe treatment and should be considered as a therapy in men with symptomatic hypogonadism, especially for those with an active or future child wish.
