- Email: [email protected]
Clomiphene Citrate for the Treatment of Hypogonadism
REVIEW
Clomiphene Citrate for the Treatment of Hypogonadism Karen M. Wheeler, MD, PHD,1 Devang Sharma, MD,1 Parviz K. Kavoussi, MD,2 Ryan P. Smith, MD,1 and Raymond Costabile, MD1
ABSTRACT
Introduction: Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle-stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamicepituitaryegonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility. Aim: To review the literature regarding the use of CC in the setting of hypogonadism. Methods: A review of the relevant literature through September 2018 was performed via PubMed. Main Outcome Measure: The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized. Results: Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated. Conclusion: CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility. Wheeler KM, Sharma D, Kavoussi PK, et al. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev 2018;XX:XXXeXXX. Copyright 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Hypogonadism; Clomiphene Citrate; Testosterone Replacement; Male Infertility
INTRODUCTION Clomiphene citrate (CC) is a selective estrogen receptor modulator initially developed for treatment of female infertility in the 1960s. It inhibits the negative feedback of estrogen at the level of the hypothalamus and pituitary. This results in increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. In women, CC is used for ovulation induction, whereas in men it stimulates the production of testosterone in Leydig cells. It has been used since the 1970s as an off-label treatment for hypogonadism, especially for men wanting to maintain fertility, because CC avoids the pathway of impaired Received May 14, 2018. Accepted October 4, 2018. 1
Department of Urology, University of Virginia, Charlottesville, VA, USA;
2
Austin Fertility and Reproductive Medicine, Department of Reproductive Urology, Austin, TX, USA
Copyright ª 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.sxmr.2018.10.001
Sex Med Rev 2018;-:1e5
spermatogenesis caused by testosterone replacement therapy (TRT).1,2 We aim to review the literature on the use of CC in the treatment of hypogonadism.
SCOPE The incidence of hypogonadism ranges widely between 2% and 13%3 with an estimated 0.8e1.6% yearly decline in total testosterone in middle-aged men.4 It is estimated that 40% of men aged 45 years old are hypogonadal.5 Presenting symptoms of hypogonadism commonly include decreased energy, decreased libido, depressed mood, decreased muscle mass, and increased body fat.6 The most common treatment for men with hypogonadism is TRT. Exogenous TRT may result in side effects such as gynecomastia, mastodynia, acne, secondary polycythemia, and testicular atrophy. Exogenous TRT also has an inhibitory effect on the hypothalamicepituitaryegonadal (HPG) axis, thereby decreasing production of LH and FSH, which play significant 1
2
roles in local testicular steroidogenesis and spermatogenesis, respectively. Treatment of men with hypogonadism with TRT typically impairs spermatogenesis, may adversely impact subsequent fertility, and may induce testicular atrophy. Testosterone replacement is not recommended for hypogonadal men who wish to maintain fertility potential or who are actively attempting to impregnate a partner.7,8 CC is an alternative treatment in hypogonadal men who wish to maintain fertility because it does not suppress the HPG axis. More nuanced patient selection remains a topic of ongoing research. Men with normal testicular volume and low/normal pretreatment LH levels may be better candidates for CC therapy. A retrospective study by Mazzola et al9 showed that a testicular volume <14 mL and LH level >6 IU/mL were significant predictors of improvement in serum testosterone in hypogonadal men treated with CC.
HORMONAL MODULATION CC exerts its effects centrally with a result of increased LH and FSH secretion and increased testicular testosterone production. Many studies have described significant increases in serum testosterone, LH, and FSH with CC treatment.10e13 Studies have revealed comparable increases in serum testosterone levels in hypogonadal men treated with CC compared with TRT.12,14,15 CC has also been compared with aromatase inhibitors, such as anastrozole, and CC has proven to be more effective in increasing testosterone levels.16 CC may result in an increase in estrogen production, altering the testosterone to estrogen (T:E) ratio and increasing estrogenic side effects, although there is limited data to support this. In a small retrospective study, Shabsigh et al17 showed a rise in the T:E ratio after low-dose CC treatment. Ramasamy et al14 showed no significant rise in serum estradiol in CC-treated men when compared with testosterone replacement gels or placebo. In a small randomized trial, Helo el al16 showed CC increased T:E ratio in hypogonadal infertile men, although to a lesser degree than anastrazole. The significance of T:E ratio in hypogonadal men is unclear. Gupta et al18 showed that T:E ratio was more predictive of low libido than total testosterone levels, but this was in cardiac patients, only 55% of whom were biochemically hypogonadal. CC is a combination of trans and cis isomers, enclomiphene and zuclomiphene, that have estrogen receptor antagonistic and agonistic properties, respectively. This fact led to the development of enclomiphene citrate, a preparation of the transisomer only. Phase 2 studies have shown a significant increase in serum testosterone levels with enclomiphene while preserving or improving spermatogenesis.19 Similar findings were reported with enclomiphene in a population of obese men.20 Enclomiphene citrate has yet to receive FDA approval owing to concerns that Phase 3 studies were not adequately designed to show clinical benefit in the target population of men with secondary hypogonadism and oligospermia. Specific concerns
Wheeler et al
were cited about study entry criteria, titration, and method validation. CC has been shown to increase bone mineral density10 and decrease body mass index in young obese men;13 both changes have been suggested to be related to hormonal changes.
TREATMENT OF SYMPTOMS In addition to biochemical outcomes, there is a large body of literature investigating the symptomatic satisfaction of hypogonadal men treated with CC. Multiple studies have used the androgen deficiency in aging men (ADAM) questionnaire and found an increase in satisfaction with CC treatment. Katz and Ramasamy et al11,14 found comparable improvements in ADAM scores in men treated with CC when compared with men treated with TRT. In a study specifically examining transdermal TRT in comparison to CC, Taylor and Levine12 describe a significant improvement in ADAM scoring, including the sexual function domain in men treated with CC. However, Patel et al21 reported fatigue and worsening mood symptoms in men treated with CC. There is limited data on the effects of CC on erectile function. Guay et al22 evaluated the effects of CC in men with secondary hypogonadism and erectile dysfunction over 4 months. The authors found that free testosterone improved in all patients and 75% reported improved sexual function. Few other authors have specifically studied the effects of CC on erectile function. Guay et al23 previously studied sexual function in impotent men with secondary hypogonadism by questionnaires and nocturnal penile tumescence and rigidity testing. This double-blind placebocontrolled trial only included 17 patients and showed no improvement in sexual function. Chandrapal et al24 assessed baseline and posttreatment Sexual Health Inventory for Men scores as part of a retrospective analysis of 77 men treated with CC for infertility and symptomatic hypogonadism. The mean baseline score was 21, and posttreatment mean was 19 (P ¼ .35). Further studies specifically examining the effects of CC on erectile function are needed.
FERTILITY OUTCOMES CC is often prescribed for hypogonadal men who wish to maintain fertility. However, there is a paucity of data regarding true fertility outcomes in hypogonadal men treated with CC.25 Studies looking at rates of fertility following CC treatment are outlined Table 1. In the largest randomized control trial on the topic, the World Health Organization found no change in pregnancy rates or sperm density among nearly 200 infertile men treated with 25 mg of clomiphene citrate compared with placebo controls over 6 months of treatment.26 Although a small number of studies were available to be included, a metaanalysis revealed a significant increase in fertility potential with CC treatment at 50 mg daily but not 25 mg daily.27 Sex Med Rev 2018;-:1e5
3
Clomiphene Citrate in Hyopgonadism
Table 1. Fertility rates in hypogonadal men treated with clomiphene citrate Duration of Treatment Comments
Treatments
Ghanem et al36
37% (vs 13% placebo; 6 months Unclear role of CC 25 mg/day þ vitamin Infertile men with oligoasthenospermia P ¼ .04) vitamin E E (N ¼ 30) vs placebo (N ¼ e30) CC 25 mg/day vs placebo Infertile couples (N ¼ 190) 8% (vs 12% placebo*) 6 months No clear male (normal female) evaluation CC 25 mg/day vs placebo Infertile couples (N ¼ 23) 9% (vs 44% placebo†) 12 months No clear male (presumed normal female) evaluation; unknown female evaluation Subfertile men (N ¼ 46) 22e37%* 6 months Both the 25 and CC 25 or 50 mg/day vs with idiopathic 50 mg dosing placebo vs mesterolone oligospermia raised T levels and vs pentoxifylline vs sperm density testosterone CC (50 mg) vs placebo Eugonadal infertile men 10% (vs 3% during 3 months Eugonadal; crossover crossover placebo*) after 3-month wash-out
World Health Organization26 Sokol et al37
Wang et al38
Rönnberg39
Population
Pregnancy Rate in CC arm
Authors
CC ¼ clomiphene citrate. *No P value reported. † P value non-significant.
In addition to studies looking at fertility rates, several studies have examined improvements in semen parameters in men treated with CC. Micic et al28 reported an increase in semen volume, sperm density, and sperm motility in oligospermic men treated with CC. El Shiek et al29 evaluated semen parameters in men with idiopathic oligoasthenospermia in a moderately sized, randomized prospective trial. They found CC treatment significantly improved sperm motility and the addition of Vitamin E had a synergistic effect. In a small prospective study, Moradi et al30 found significantly increased sperm counts and motility following CC treatment. In men with non-obstructive azoospermia, Hussein et al31 found that CC may result in the return of sperm to the semen as well as increase the rates of sperm retrieval during microdissection testicular sperm extraction.
SIDE EFFECTS CC has generally been accepted as a safe drug, but there is little data evaluating adverse effects, especially compared with treatment with TRT.32 Reported side effects on CC include headache, dizziness, visual changes, gynecomastia, and testicular enlargement.10 In contrast to studies showing no impact and improvement in male fertility, there are also case reports of men who developed azoospermia while on CC.33 Taylor and Levine12 did secondarily look at hemoglobin, cholesterol, and prostate-specific antigen levels after CC and TRT treatment and found no significant increase in either treatment group. Wheeler et al15 showed that the prevalence of secondary polycythemia among hypogonadal men treated with CC is markedly lower than in men on TRT (2% vs 11%, respectively); none of the nearly 200 men in the CC arm of the study developed a hematocrit high enough to require phlebotomy. Da Ros et al34 Sex Med Rev 2018;-:1e5
found no adverse events or statistically significant changes in pre- and posttreatment HDL-cholesterol, triglycerides, fasting glucose, or prolactin levels in 125 men receiving CC for hypogonadism. In women, there have been reports of exacerbation of psychiatric illness associated with CC treatment. In men, there are 2 isolated case reports of psychotic episodes and 1 of a suicide attempt associated with onset of CC treatment.35 No causation has ever been shown, however further work needs to be conducted. This concern has not been corroborated in men.
CONCLUSION CC is used off-label for the treatment of hypogonadism, especially in men who wish to maintain fertility potential. CC treatment increases serum testosterone levels as demonstrated in multiple studies and does not appear to adversely alter the T:E ratio. Results from studies on symptom relief from CC are conflicting, but there does appear to be an overwhelming suggestion that it improves the symptoms of hypogonadism. Many studies have found it to be a largely safe and cost-effective drug with health benefits, such as improving bone density, in hypogonadal men. We believe that CC is a safe and effective drug that should remain in the armament of urologists treating hypogonadal men. Corresponding Author: Ryan P. Smith, MD, Department of Urology, University of Virginia, PO Box 800422, Charlottesville, VA 22908, USA. Tel: 434-982-1081; Fax: 434-982-3652; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
4
Wheeler et al
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Karen M. Wheeler; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile (b) Acquisition of Data Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi (c) Analysis and Interpretation of Data Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile Category 2 (a) Drafting the Article Karen M. Wheeler; Devang Sharma (b) Revising It for Intellectual Content Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile Category 3 (a) Final Approval of the Completed Article Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile
REFERENCES 1. Paulson DF, Wacksman J. Clomiphene citrate in the management of male infertility. J Urol 1976;115:73-76. 2. Lo E, Rodriguez K, Pastuszak A, et al. Alternatives to testosterone therapy: A review. Sex Med Rev 2018;6:106-113. 3. Zarotsky V, Huang M, Carman W, et al. Systematic literature review of the risk factors, comorbidities, and consequences of hypogonadism in men. Andrology 2014;2:819-834. 4. Mohr BA, Guay AT, O’Donnell AB, et al. Normal, bound and nonbound testosterone levels in normally ageing men: Results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 2005;62:64-73. 5. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: The HIM study. Int J Clin Pract 2006;60:762-769. 6. Borst SE, Yarrow JF. Injection of testosterone may be safer and more effective than transdermal administration for combating loss of muscle and bone in older men. Am J Physiol Encocrinol Metab 2015;308:E1035-1042. 7. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med 2004;350:482-492. 8. Wang C, Swerdloff RS. Male contraception. Best Pract Res Clin Ob 2002;16:193-203. 9. Mazzola CR, Katz DJ, Loghamanieh N, et al. Predicting biochemical response to clomiphene citrate in men with hypogonadism. J Sex Med 2014;11:2302-2307. 10. Moskovic DJ, Katz DJ, Akhavan A, et al. Clomiphene citrate is safe and effective for long-term management of hypogonadism. BJU Int 2012;110:1524-1528.
11. Katz DJ, Nabulsi O, Tal R, et al. Outcomes of clomiphene citrate treatment in young hypogonadal men. BJU Int 2012; 110:573-578. 12. Taylor F, Levine L. Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism: Efficacy and treatment cost. J Sex Med 2010;7:269-276. 13. Bendre SV, Murray PJ, Basaria S. Clomiphene citrate effectively increases testosterone in obese, young, hypogonadal men. Reprod Syst Sex Disord 2015;4:155. 14. Ramasamy R, Scovell JM, Kovac JR, et al. Testosterone supplementation versus clomiphene citrate for hypogonadism: An age matched comparison of satisfaction and efficacy. J Urol 2014;192:875-879. 15. Wheeler KM, Smith RP, Kumar RA, et al. A comparison of secondary polycythemia in hypogonadal men treated with clomiphene citrate versus testosterone replacement: A multiinstitutional study. J Urol 2017;197:1127-1131. 16. Helo S, Ellen J, Mechlin C, et al. A randomized prospective double-blind comparison trial of clomiphene citrate and anastrozole in raising testosterone in hypogonadal infertile men. J Sex Med 2015;12:1761-1769. 17. Shabsigh A, Kang Y, Shabsign R, et al. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716-721. 18. Gupta N, Holland B, Mueller G, et al. MP84-11 calculated free T and T:E ratio but not total testosterone and estradiol predict low libido. J Urol 2017;197(4S):e1143-1144. 19. Kaminetsky J, Werner M, Fontenot G, et al. Oral enclomiphene citrate stimulates the endogenous production of testosterone and sperm counts in men with low testosterone: comparison with testosterone gel. J Sex Med 2013;10:1628-1635. 20. Kim ED, McCullough A, Kaminetsky J. Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: Restoration instead of replacement. BJU Int 2016;117:677-685. 21. Patel DP, Brant WO, Myers JB, et al. The safety and efficacy of clomiphene citrate in hypoandrogenic and subfertile men. Int J Impot Res 2015;27:221-224. 22. Guay AT, Jacobson J, Perez JB, et al. Clomiphene increases free testosterone levels in men with both secondary hypogonadism and erectile dysfunction: Who does and does not benefit? Int J Impot Res 2003;15:156-165. 23. Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: Double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995; 80(12):3546-3552. 24. Chandrapal JC, Nielson S, Patel DP, et al. Characterizing the safety of clomiphene citrate in male patients through prostatespecific antigen, haematocrit, and testosterone levels. BJU Int 2016;118(6):994-1000. 25. Helo S, Wynia B, McCullough A. “Cherchez la femme”: Modulation of estrogen receptor function with selective modulators: Clinical implications in the field of urology. Sex Med Rev 2017;5:365-386. Sex Med Rev 2018;-:1e5
Clomiphene Citrate in Hyopgonadism 26. World Health Organization. A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. Int J Androl 1992;15:299-307. 27. Chua ME, Escusa KG, Luna S, et al. Revisiting oestrogen antagonists (clomiphene or tamoxifen) as medical empiric therapy for idiopathic male infertility: A meta-analysis. Andrology 2013;1:749-757. 28. Micic S, Dotlic R. Evaluation of sperm parameters in clinical trial with clomiphene citrate of oligospermic men. J Urol 1985; 133:221-222. 29. El Sheikh MG, Hosny MB, Elshenoufy A, et al. Combination of vitamin E and clomiphene citrate in treating patients with idiopathic oligoasthenozoospermia: A prospective, randomized trial. Andrology 2015;3:864-867. 30. Moradi M, Moradi A, Alemi M, et al. Safety and efficacy of clomiphene citrate and L-carnitine in idiopathic male infertility: A comparative study. Urol J 2010;7:188-193. 31. Hussein A, Ozgok Y, Ross L, et al. Optimization of spermatogenesis-regulating hormones in patients with nonobstructive azoospermia and its impact on sperm retrieval: a multicentre study. BJU Int 2013;111:E110-114. 32. Willets AE, Corbo JM, Brown JN. Clomiphene for the treatment of male infertility. Reprod Sci 2013;20:739-744. 33. Pasqualotto FF, Fonseca GP, Pasqualotto EB. Azoospermia after treatment with clomiphene citrate in patients with oligospermia. Fertil Steril 2008;90:2014. e11e12.
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5 34. Da Ros CT, Averbeck MA. Twenty-five milligrams of clomiphene citrate presents positive effect on testosterone deficiency: A prospective study. Int Braz J Urol 2012; 38(4):512-518. 35. Knight JC, Pandit AS, Rich AM, et al. Clomiphene-associated suicide behavior in a man treated for hypogonadism: Case report and review of the literature. Psychosomatics 2015; 56:598-602. 36. Ghanem H, Shaeer O, El-Segini A. Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: A randomized controlled trial. Fertil Steril 2010;93:2232-2235. 37. Sokol RZ, Steiner BS, Bustillo M, et al. A controlled comparison of the efficacy of clomiphene citrate in male infertility. Fertil Steril 1988;49:865-870. 38. Wang C, Chan C, Wong K, et al. Comparison of the effectiveness of placebo, clomiphene citrate, mesterolone, pentoxifylline, and testosterone rebound therapy for the treatment of idiopathic oligospermia. Fertil Steril 1983; 40:358-365. 39. Rönnberg L. The effect of clomiphene citrate on different sperm parameters and serum hormone levels in preselected infertile men: A controlled double-blind cross-over study. Int J Androl 1980;3:479-486.
Clomiphene Citrate for the Treatment of Hypogonadism Karen M. Wheeler, MD, PHD,1 Devang Sharma, MD,1 Parviz K. Kavoussi, MD,2 Ryan P. Smith, MD,1 and Raymond Costabile, MD1
ABSTRACT
Introduction: Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle-stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamicepituitaryegonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility. Aim: To review the literature regarding the use of CC in the setting of hypogonadism. Methods: A review of the relevant literature through September 2018 was performed via PubMed. Main Outcome Measure: The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized. Results: Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated. Conclusion: CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility. Wheeler KM, Sharma D, Kavoussi PK, et al. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev 2018;XX:XXXeXXX. Copyright 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.
Key Words: Hypogonadism; Clomiphene Citrate; Testosterone Replacement; Male Infertility
INTRODUCTION Clomiphene citrate (CC) is a selective estrogen receptor modulator initially developed for treatment of female infertility in the 1960s. It inhibits the negative feedback of estrogen at the level of the hypothalamus and pituitary. This results in increased luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. In women, CC is used for ovulation induction, whereas in men it stimulates the production of testosterone in Leydig cells. It has been used since the 1970s as an off-label treatment for hypogonadism, especially for men wanting to maintain fertility, because CC avoids the pathway of impaired Received May 14, 2018. Accepted October 4, 2018. 1
Department of Urology, University of Virginia, Charlottesville, VA, USA;
2
Austin Fertility and Reproductive Medicine, Department of Reproductive Urology, Austin, TX, USA
Copyright ª 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.sxmr.2018.10.001
Sex Med Rev 2018;-:1e5
spermatogenesis caused by testosterone replacement therapy (TRT).1,2 We aim to review the literature on the use of CC in the treatment of hypogonadism.
SCOPE The incidence of hypogonadism ranges widely between 2% and 13%3 with an estimated 0.8e1.6% yearly decline in total testosterone in middle-aged men.4 It is estimated that 40% of men aged 45 years old are hypogonadal.5 Presenting symptoms of hypogonadism commonly include decreased energy, decreased libido, depressed mood, decreased muscle mass, and increased body fat.6 The most common treatment for men with hypogonadism is TRT. Exogenous TRT may result in side effects such as gynecomastia, mastodynia, acne, secondary polycythemia, and testicular atrophy. Exogenous TRT also has an inhibitory effect on the hypothalamicepituitaryegonadal (HPG) axis, thereby decreasing production of LH and FSH, which play significant 1
2
roles in local testicular steroidogenesis and spermatogenesis, respectively. Treatment of men with hypogonadism with TRT typically impairs spermatogenesis, may adversely impact subsequent fertility, and may induce testicular atrophy. Testosterone replacement is not recommended for hypogonadal men who wish to maintain fertility potential or who are actively attempting to impregnate a partner.7,8 CC is an alternative treatment in hypogonadal men who wish to maintain fertility because it does not suppress the HPG axis. More nuanced patient selection remains a topic of ongoing research. Men with normal testicular volume and low/normal pretreatment LH levels may be better candidates for CC therapy. A retrospective study by Mazzola et al9 showed that a testicular volume <14 mL and LH level >6 IU/mL were significant predictors of improvement in serum testosterone in hypogonadal men treated with CC.
HORMONAL MODULATION CC exerts its effects centrally with a result of increased LH and FSH secretion and increased testicular testosterone production. Many studies have described significant increases in serum testosterone, LH, and FSH with CC treatment.10e13 Studies have revealed comparable increases in serum testosterone levels in hypogonadal men treated with CC compared with TRT.12,14,15 CC has also been compared with aromatase inhibitors, such as anastrozole, and CC has proven to be more effective in increasing testosterone levels.16 CC may result in an increase in estrogen production, altering the testosterone to estrogen (T:E) ratio and increasing estrogenic side effects, although there is limited data to support this. In a small retrospective study, Shabsigh et al17 showed a rise in the T:E ratio after low-dose CC treatment. Ramasamy et al14 showed no significant rise in serum estradiol in CC-treated men when compared with testosterone replacement gels or placebo. In a small randomized trial, Helo el al16 showed CC increased T:E ratio in hypogonadal infertile men, although to a lesser degree than anastrazole. The significance of T:E ratio in hypogonadal men is unclear. Gupta et al18 showed that T:E ratio was more predictive of low libido than total testosterone levels, but this was in cardiac patients, only 55% of whom were biochemically hypogonadal. CC is a combination of trans and cis isomers, enclomiphene and zuclomiphene, that have estrogen receptor antagonistic and agonistic properties, respectively. This fact led to the development of enclomiphene citrate, a preparation of the transisomer only. Phase 2 studies have shown a significant increase in serum testosterone levels with enclomiphene while preserving or improving spermatogenesis.19 Similar findings were reported with enclomiphene in a population of obese men.20 Enclomiphene citrate has yet to receive FDA approval owing to concerns that Phase 3 studies were not adequately designed to show clinical benefit in the target population of men with secondary hypogonadism and oligospermia. Specific concerns
Wheeler et al
were cited about study entry criteria, titration, and method validation. CC has been shown to increase bone mineral density10 and decrease body mass index in young obese men;13 both changes have been suggested to be related to hormonal changes.
TREATMENT OF SYMPTOMS In addition to biochemical outcomes, there is a large body of literature investigating the symptomatic satisfaction of hypogonadal men treated with CC. Multiple studies have used the androgen deficiency in aging men (ADAM) questionnaire and found an increase in satisfaction with CC treatment. Katz and Ramasamy et al11,14 found comparable improvements in ADAM scores in men treated with CC when compared with men treated with TRT. In a study specifically examining transdermal TRT in comparison to CC, Taylor and Levine12 describe a significant improvement in ADAM scoring, including the sexual function domain in men treated with CC. However, Patel et al21 reported fatigue and worsening mood symptoms in men treated with CC. There is limited data on the effects of CC on erectile function. Guay et al22 evaluated the effects of CC in men with secondary hypogonadism and erectile dysfunction over 4 months. The authors found that free testosterone improved in all patients and 75% reported improved sexual function. Few other authors have specifically studied the effects of CC on erectile function. Guay et al23 previously studied sexual function in impotent men with secondary hypogonadism by questionnaires and nocturnal penile tumescence and rigidity testing. This double-blind placebocontrolled trial only included 17 patients and showed no improvement in sexual function. Chandrapal et al24 assessed baseline and posttreatment Sexual Health Inventory for Men scores as part of a retrospective analysis of 77 men treated with CC for infertility and symptomatic hypogonadism. The mean baseline score was 21, and posttreatment mean was 19 (P ¼ .35). Further studies specifically examining the effects of CC on erectile function are needed.
FERTILITY OUTCOMES CC is often prescribed for hypogonadal men who wish to maintain fertility. However, there is a paucity of data regarding true fertility outcomes in hypogonadal men treated with CC.25 Studies looking at rates of fertility following CC treatment are outlined Table 1. In the largest randomized control trial on the topic, the World Health Organization found no change in pregnancy rates or sperm density among nearly 200 infertile men treated with 25 mg of clomiphene citrate compared with placebo controls over 6 months of treatment.26 Although a small number of studies were available to be included, a metaanalysis revealed a significant increase in fertility potential with CC treatment at 50 mg daily but not 25 mg daily.27 Sex Med Rev 2018;-:1e5
3
Clomiphene Citrate in Hyopgonadism
Table 1. Fertility rates in hypogonadal men treated with clomiphene citrate Duration of Treatment Comments
Treatments
Ghanem et al36
37% (vs 13% placebo; 6 months Unclear role of CC 25 mg/day þ vitamin Infertile men with oligoasthenospermia P ¼ .04) vitamin E E (N ¼ 30) vs placebo (N ¼ e30) CC 25 mg/day vs placebo Infertile couples (N ¼ 190) 8% (vs 12% placebo*) 6 months No clear male (normal female) evaluation CC 25 mg/day vs placebo Infertile couples (N ¼ 23) 9% (vs 44% placebo†) 12 months No clear male (presumed normal female) evaluation; unknown female evaluation Subfertile men (N ¼ 46) 22e37%* 6 months Both the 25 and CC 25 or 50 mg/day vs with idiopathic 50 mg dosing placebo vs mesterolone oligospermia raised T levels and vs pentoxifylline vs sperm density testosterone CC (50 mg) vs placebo Eugonadal infertile men 10% (vs 3% during 3 months Eugonadal; crossover crossover placebo*) after 3-month wash-out
World Health Organization26 Sokol et al37
Wang et al38
Rönnberg39
Population
Pregnancy Rate in CC arm
Authors
CC ¼ clomiphene citrate. *No P value reported. † P value non-significant.
In addition to studies looking at fertility rates, several studies have examined improvements in semen parameters in men treated with CC. Micic et al28 reported an increase in semen volume, sperm density, and sperm motility in oligospermic men treated with CC. El Shiek et al29 evaluated semen parameters in men with idiopathic oligoasthenospermia in a moderately sized, randomized prospective trial. They found CC treatment significantly improved sperm motility and the addition of Vitamin E had a synergistic effect. In a small prospective study, Moradi et al30 found significantly increased sperm counts and motility following CC treatment. In men with non-obstructive azoospermia, Hussein et al31 found that CC may result in the return of sperm to the semen as well as increase the rates of sperm retrieval during microdissection testicular sperm extraction.
SIDE EFFECTS CC has generally been accepted as a safe drug, but there is little data evaluating adverse effects, especially compared with treatment with TRT.32 Reported side effects on CC include headache, dizziness, visual changes, gynecomastia, and testicular enlargement.10 In contrast to studies showing no impact and improvement in male fertility, there are also case reports of men who developed azoospermia while on CC.33 Taylor and Levine12 did secondarily look at hemoglobin, cholesterol, and prostate-specific antigen levels after CC and TRT treatment and found no significant increase in either treatment group. Wheeler et al15 showed that the prevalence of secondary polycythemia among hypogonadal men treated with CC is markedly lower than in men on TRT (2% vs 11%, respectively); none of the nearly 200 men in the CC arm of the study developed a hematocrit high enough to require phlebotomy. Da Ros et al34 Sex Med Rev 2018;-:1e5
found no adverse events or statistically significant changes in pre- and posttreatment HDL-cholesterol, triglycerides, fasting glucose, or prolactin levels in 125 men receiving CC for hypogonadism. In women, there have been reports of exacerbation of psychiatric illness associated with CC treatment. In men, there are 2 isolated case reports of psychotic episodes and 1 of a suicide attempt associated with onset of CC treatment.35 No causation has ever been shown, however further work needs to be conducted. This concern has not been corroborated in men.
CONCLUSION CC is used off-label for the treatment of hypogonadism, especially in men who wish to maintain fertility potential. CC treatment increases serum testosterone levels as demonstrated in multiple studies and does not appear to adversely alter the T:E ratio. Results from studies on symptom relief from CC are conflicting, but there does appear to be an overwhelming suggestion that it improves the symptoms of hypogonadism. Many studies have found it to be a largely safe and cost-effective drug with health benefits, such as improving bone density, in hypogonadal men. We believe that CC is a safe and effective drug that should remain in the armament of urologists treating hypogonadal men. Corresponding Author: Ryan P. Smith, MD, Department of Urology, University of Virginia, PO Box 800422, Charlottesville, VA 22908, USA. Tel: 434-982-1081; Fax: 434-982-3652; E-mail: [email protected] Conflict of Interest: The authors report no conflicts of interest. Funding: None.
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Wheeler et al
STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Karen M. Wheeler; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile (b) Acquisition of Data Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi (c) Analysis and Interpretation of Data Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile Category 2 (a) Drafting the Article Karen M. Wheeler; Devang Sharma (b) Revising It for Intellectual Content Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile Category 3 (a) Final Approval of the Completed Article Karen M. Wheeler; Devang Sharma; Ryan P. Smith; Parviz Kavoussi; Raymond Costabile
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