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New Insights into the Medical Management of Idiopathic Male Infertility—What Works, What Does Not and Does it Matter?
New Insights into the Medical Management of Idiopathic Male Infertility—What Works, What Does Not and Does it Matter? WHEN seeing an infertile couple with male factor infertility, urologists are routinely confronted with questions about noninvasive treatment, optimizing semen parameters before assisted reproductive technique, and whether to bother with medical therapy or proceed directly to in vitro fertilization or intracytoplasmic sperm injection. Medical treatment of male factor infertility has been based on the classification of type of infertility and hormonal evaluation of the patient. Idiopathic male infertility is the most common and perplexing category. Semen parameters, male evaluation, and female partner age and health status determine the recommendations. To give sound advice, one has to understand the extent to which a particular therapy may improve fertilization potential, and whether a particular therapy will save time and money for the couple. For that we have to rely on evidence and the question is do we have it? Normalizing serum testosterone levels by stimulating endogenous production has been a common and accepted approach in optimizing male fertility potential. In this issue of The Journal Reifsnyder et al (page 532) evaluated the effect of normalization of serum testosterone level on sperm retrieval, clinical pregnancy and live birth rates in 1,054 consecutive patients with nonobstructive azoospermia undergoing microdissection testicular sperm retrieval. The therapeutic approach to the normalization of serum testosterone was based on hormonal evaluation. Medications used included testolactone, anastrozole, human chorionic gonadotropin and clomiphene citrate. The theoretical basis for the normalization of testosterone levels is derived from the necessity of adequate endogenous testosterone production for spermatogenesis. The authors arrived at the counterintuitive conclusion that sperm retrieval, clinical pregnancy and live birth rates were similar between the men who responded to hormonal therapy and those who did not. This information is clearly important for the proper counseling of patients with azoospermia undergoing microsurgical testicular sperm extraction. 0022-5347/12/1882-0355/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
AND
RESEARCH, INC.
The empirical treatment of male factor infertility has been a topic of substantial controversy and to my knowledge no practice guidelines exist. A recent survey of American Urological Association members showed wide variation among treatment approaches, with the most commonly used being anastrozole, clomiphene, human chorionic gonadotropin and tamoxifen.1 The literature is conflicting on the efficacy of empirical medical therapy. Treatment with gonadotropins showed a tendency to improve pregnancy rates but the number of patients was insufficient for definitive conclusions.2 Aromatase inhibitors prevent the conversion of testosterone to estrogen and theoretically decrease inhibitory effects on spermatogenesis. In practice, a limited trial in 25 men demonstrated no improvement in pregnancy rate or semen parameters.3 Antiestrogens also inhibit negative feedback on the hypothalamus, and increase the endogenous production of testosterone and follicle-stimulating hormone. Although improvement in testosterone was seen, no improvement in pregnancy rate was shown in a Cochrane database system review.4 Another common topic of discussion is the use of antioxidants, micro-elements and other food additives to improve semen quality. Despite the lack of evidence for the majority of supplements, a simple Google Shopping search for fertility supplements for men returned 1,020 different items. Most contain proprietary formulas that would include vitamins, plant extracts and other substances that alone or in combination were thought to be beneficial for male fertility. Let us not forget that scientific proof, and not wishful thinking, should be the cornerstone of our decision making. Oxidative stress continues to be a topic of intensive research interest and a target for medical therapy. Reactive oxygen species have been recognized as a substantial contributing factor in 40% to 88% of male infertility cases.5 Although the generation of reactive oxygen species by spermatozoa is physiological, excessive amounts may be responsible for pathological spermatozoa membrane lipid peroxidation6 and DNA fragmentation.7 http://dx.doi.org/10.1016/j.juro.2012.05.025 Vol. 188, 355-357, August 2012 Printed in U.S.A.
www.jurology.com
355
356
MEDICAL MANAGEMENT OF IDIOPATHIC MALE INFERTILITY
As such, multiple substances have been evaluated in controlled and uncontrolled trials. Vitamins E and C are common antioxidants but the theoretical advantage of supplementation did not pan out in a randomized controlled trial.8 The influence of vitamin A on male fertility has been evaluated in animal and cell culture studies, as well as in the experimental inhibition of testicular retinoic acid biosynthesis.9 However, there is a lack of randomized controlled trials to support the benefit of vitamin A administration in improving seminal parameters or fertility. Selenium is important in normal spermatogenesis, sperm motility and function. In theory, it may decrease oxidative stress via selenoenzymes and sperm capsular selenoprotein glutathione peroxidase. Although selenium deficiency may be associated with impaired fertility, supplementation with selenium has not been associated with improved pregnancy rates.10 The use of selenium with vitamin E was recently evaluated in a noncontrolled, prospective trial in 690 infertile men with idiopathic asthenoteratospermia who received supplemental selenium (200 mcg daily) and vitamin E (400 units).11 The authors noted modest improvement in sperm morphology and motility, but again, the practical utility of this regimen remains unaddressed. Lycopene is a part of a defense mechanism against free radicals, and it was evaluated in a preliminary study in 30 men by Gupta and Kumar.12 The authors used 200 mg lycopene twice daily for 3 months and found no improvement in patients with a baseline sperm concentration of less than 5 million per ml. No convincing randomized trials are currently available. Herb extracts have an aura of being all-powerful and safe for almost any purpose. One of the more common is Maca root (Lepidium meyenii), a Peruvian plant that has been used as an aphrodisiac and fertility enhancing supplement, and even appears among the concoctions available on the Internet and at local drug stores. Several rat experimental studies have suggested favorable properties, but in humans only 1 small study has been published.13 In a nonrandomized evaluation of 9 men benefit was claimed for 1,500 or 3,000 mg daily administration for 4 months on semen parameters without a change in gonadotropins or sex hormones.13 Although the annual export of Maca root from Peru exceeded $6 million in 2010, for now I would put it in the “not enough evidence” category. Carnitine is important in sperm energy metabolism and has been addressed in multiple studies, the latest of which was a randomized, controlled trial with administration of 2 gm daily.14 The improvement depended on initial sperm concentrations and no improvement in morphology was seen. Carnitine was also used with nonsteroidal anti-inflammatory
drugs, particularly in rectal suppository form.15 L-carnitine was evaluated in a comparative prospective trial with clomiphene citrate in 52 men with idiopathic infertility.16 Modest improvements in motility and normal morphology were seen in men taking 25 mg clomiphene daily for 3 months. Not all supplementation is an exercise in futility. A combination of clomiphene citrate (25 mg daily) and vitamin E (400 mg daily) was evaluated in a prospective, randomized, placebo controlled trial in 60 patients with idiopathic oligoasthenozoospermia.17 The authors found a strong influence of the regimen on seminal parameters and, most importantly, on pregnancy rates (with improvement from 13.3% to 36.7%). Also in this issue Safarinejad et al (page 526) examined the effects of ubiquinol (a reduced form of coenzyme Q10) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia. In a prospective, randomized, placebo controlled fashion the authors evaluated 228 men with unexplained infertility, and concluded that the administration of ubiquinol resulted in significant improvement in sperm density, sperm motility and strict morphology. The authors also monitored serum hormones, and found that follicle-stimulating hormone levels decreased and inhibin B increased during the active treatment phase. Seminal plasma antioxidant capacity was also measured and was increased in the active treatment group. The validity of their findings was confirmed by the return of semen and hormonal parameters to baseline after completion of the 26-week treatment period. The study did not track actual partner pregnancy status and we may only speculate about the true value of ubiquinol. Nevertheless, the degree of seminal parameter improvement was impressive. These findings clearly add to the body of evidence of the importance of oxidative stress in spermatogenesis. In conclusion, it is not enough to have a theoretical rationale for intervention as many plausible candidates for effective treatments did not bear fruit in human studies. The potential cost savings of noninvasive and benign medical therapy for infertility should be carefully weighed against the potential delays of more proven therapies. Sound evidence of benefits from controlled, well conducted studies should guide treatment recommendations. Lev Elterman* Department of Urology Rush University Chicago, Illinois
* Financial interest and/or other relationship with Watson, GSK and Warner Chilcott.
MEDICAL MANAGEMENT OF IDIOPATHIC MALE INFERTILITY
357
REFERENCES 1. Ko EY, Siddiqi K, Brannigan RE et al: Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol 2012; 187: 973.
7. Agarwal A, Makker K and Sharma R: Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol 2008; 59: 2.
2. Attia AM, Al-Inany HG, Farquhar C et al: Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev 2007; 4: CD005071.
8. Rolf C, Cooper TG, Yeung CH et al: Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with highdose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study. Hum Reprod 1999; 14: 1028.
3. Clark RV and Sherins RJ: Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover. J Androl 1989; 10: 240. 4. Vandekerckhove P, Lilford R, Vail A et al: Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev 2000; 2: CD000151. 5. Lewis SE, Boyle PM, McKinney KA et al: Total antioxidant capacity of seminal plasma is different in fertile and infertile men. Fertil Steril 1995; 64: 868. 6. Alkan I, Simsek F, Haklar G et al: Reactive oxygen species production by the spermatozoa of patients with idiopathic infertility: relationship to seminal plasma antioxidants. J Urol 1997; 157: 140.
9. Amory JK, Muller CH, Shimshoni JA et al: Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl 2011; 32: 111.
12. Gupta NP and Kumar R: Lycopene therapy in idiopathic male infertility–a preliminary report. Int Urol Nephrol 2002; 34: 369. 13. Gonzales GF, Cordova A, Gonzales C et al: Lepidium meyenii (Maca) improved semen parameters in adult men. Asian J Androl 2001; 3: 301. 14. Lenzi A, Sgrò P, Salacone P et al: A placebocontrolled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril 2004; 81: 1578. 15. Cavallini G, Ferraretti AP, Gianaroli L et al: Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J Androl 2004; 25: 761.
10. Vézina D, Mauffette F, Roberts KD et al: Seleniumvitamin E supplementation in infertile men. Effects on semen parameters and micronutrient levels and distribution. Biol Trace Elem Res 1996; 53: 65.
16. 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.
11. Moslemi MK and Tavanbakhsh S: Selenium-vitamin E supplementation in infertile men: effect on semen parameters and pregnancy rate. Int J Gen Med 2011; 4: 99.
17. Ghanem H, Shaeer O and El-Segini A: Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril 2010; 93: 2232.
AND
RESEARCH, INC.
The empirical treatment of male factor infertility has been a topic of substantial controversy and to my knowledge no practice guidelines exist. A recent survey of American Urological Association members showed wide variation among treatment approaches, with the most commonly used being anastrozole, clomiphene, human chorionic gonadotropin and tamoxifen.1 The literature is conflicting on the efficacy of empirical medical therapy. Treatment with gonadotropins showed a tendency to improve pregnancy rates but the number of patients was insufficient for definitive conclusions.2 Aromatase inhibitors prevent the conversion of testosterone to estrogen and theoretically decrease inhibitory effects on spermatogenesis. In practice, a limited trial in 25 men demonstrated no improvement in pregnancy rate or semen parameters.3 Antiestrogens also inhibit negative feedback on the hypothalamus, and increase the endogenous production of testosterone and follicle-stimulating hormone. Although improvement in testosterone was seen, no improvement in pregnancy rate was shown in a Cochrane database system review.4 Another common topic of discussion is the use of antioxidants, micro-elements and other food additives to improve semen quality. Despite the lack of evidence for the majority of supplements, a simple Google Shopping search for fertility supplements for men returned 1,020 different items. Most contain proprietary formulas that would include vitamins, plant extracts and other substances that alone or in combination were thought to be beneficial for male fertility. Let us not forget that scientific proof, and not wishful thinking, should be the cornerstone of our decision making. Oxidative stress continues to be a topic of intensive research interest and a target for medical therapy. Reactive oxygen species have been recognized as a substantial contributing factor in 40% to 88% of male infertility cases.5 Although the generation of reactive oxygen species by spermatozoa is physiological, excessive amounts may be responsible for pathological spermatozoa membrane lipid peroxidation6 and DNA fragmentation.7 http://dx.doi.org/10.1016/j.juro.2012.05.025 Vol. 188, 355-357, August 2012 Printed in U.S.A.
www.jurology.com
355
356
MEDICAL MANAGEMENT OF IDIOPATHIC MALE INFERTILITY
As such, multiple substances have been evaluated in controlled and uncontrolled trials. Vitamins E and C are common antioxidants but the theoretical advantage of supplementation did not pan out in a randomized controlled trial.8 The influence of vitamin A on male fertility has been evaluated in animal and cell culture studies, as well as in the experimental inhibition of testicular retinoic acid biosynthesis.9 However, there is a lack of randomized controlled trials to support the benefit of vitamin A administration in improving seminal parameters or fertility. Selenium is important in normal spermatogenesis, sperm motility and function. In theory, it may decrease oxidative stress via selenoenzymes and sperm capsular selenoprotein glutathione peroxidase. Although selenium deficiency may be associated with impaired fertility, supplementation with selenium has not been associated with improved pregnancy rates.10 The use of selenium with vitamin E was recently evaluated in a noncontrolled, prospective trial in 690 infertile men with idiopathic asthenoteratospermia who received supplemental selenium (200 mcg daily) and vitamin E (400 units).11 The authors noted modest improvement in sperm morphology and motility, but again, the practical utility of this regimen remains unaddressed. Lycopene is a part of a defense mechanism against free radicals, and it was evaluated in a preliminary study in 30 men by Gupta and Kumar.12 The authors used 200 mg lycopene twice daily for 3 months and found no improvement in patients with a baseline sperm concentration of less than 5 million per ml. No convincing randomized trials are currently available. Herb extracts have an aura of being all-powerful and safe for almost any purpose. One of the more common is Maca root (Lepidium meyenii), a Peruvian plant that has been used as an aphrodisiac and fertility enhancing supplement, and even appears among the concoctions available on the Internet and at local drug stores. Several rat experimental studies have suggested favorable properties, but in humans only 1 small study has been published.13 In a nonrandomized evaluation of 9 men benefit was claimed for 1,500 or 3,000 mg daily administration for 4 months on semen parameters without a change in gonadotropins or sex hormones.13 Although the annual export of Maca root from Peru exceeded $6 million in 2010, for now I would put it in the “not enough evidence” category. Carnitine is important in sperm energy metabolism and has been addressed in multiple studies, the latest of which was a randomized, controlled trial with administration of 2 gm daily.14 The improvement depended on initial sperm concentrations and no improvement in morphology was seen. Carnitine was also used with nonsteroidal anti-inflammatory
drugs, particularly in rectal suppository form.15 L-carnitine was evaluated in a comparative prospective trial with clomiphene citrate in 52 men with idiopathic infertility.16 Modest improvements in motility and normal morphology were seen in men taking 25 mg clomiphene daily for 3 months. Not all supplementation is an exercise in futility. A combination of clomiphene citrate (25 mg daily) and vitamin E (400 mg daily) was evaluated in a prospective, randomized, placebo controlled trial in 60 patients with idiopathic oligoasthenozoospermia.17 The authors found a strong influence of the regimen on seminal parameters and, most importantly, on pregnancy rates (with improvement from 13.3% to 36.7%). Also in this issue Safarinejad et al (page 526) examined the effects of ubiquinol (a reduced form of coenzyme Q10) on semen parameters and seminal plasma antioxidant capacity in infertile men with idiopathic oligoasthenoteratozoospermia. In a prospective, randomized, placebo controlled fashion the authors evaluated 228 men with unexplained infertility, and concluded that the administration of ubiquinol resulted in significant improvement in sperm density, sperm motility and strict morphology. The authors also monitored serum hormones, and found that follicle-stimulating hormone levels decreased and inhibin B increased during the active treatment phase. Seminal plasma antioxidant capacity was also measured and was increased in the active treatment group. The validity of their findings was confirmed by the return of semen and hormonal parameters to baseline after completion of the 26-week treatment period. The study did not track actual partner pregnancy status and we may only speculate about the true value of ubiquinol. Nevertheless, the degree of seminal parameter improvement was impressive. These findings clearly add to the body of evidence of the importance of oxidative stress in spermatogenesis. In conclusion, it is not enough to have a theoretical rationale for intervention as many plausible candidates for effective treatments did not bear fruit in human studies. The potential cost savings of noninvasive and benign medical therapy for infertility should be carefully weighed against the potential delays of more proven therapies. Sound evidence of benefits from controlled, well conducted studies should guide treatment recommendations. Lev Elterman* Department of Urology Rush University Chicago, Illinois
* Financial interest and/or other relationship with Watson, GSK and Warner Chilcott.
MEDICAL MANAGEMENT OF IDIOPATHIC MALE INFERTILITY
357
REFERENCES 1. Ko EY, Siddiqi K, Brannigan RE et al: Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol 2012; 187: 973.
7. Agarwal A, Makker K and Sharma R: Clinical relevance of oxidative stress in male factor infertility: an update. Am J Reprod Immunol 2008; 59: 2.
2. Attia AM, Al-Inany HG, Farquhar C et al: Gonadotrophins for idiopathic male factor subfertility. Cochrane Database Syst Rev 2007; 4: CD005071.
8. Rolf C, Cooper TG, Yeung CH et al: Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with highdose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study. Hum Reprod 1999; 14: 1028.
3. Clark RV and Sherins RJ: Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover. J Androl 1989; 10: 240. 4. Vandekerckhove P, Lilford R, Vail A et al: Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev 2000; 2: CD000151. 5. Lewis SE, Boyle PM, McKinney KA et al: Total antioxidant capacity of seminal plasma is different in fertile and infertile men. Fertil Steril 1995; 64: 868. 6. Alkan I, Simsek F, Haklar G et al: Reactive oxygen species production by the spermatozoa of patients with idiopathic infertility: relationship to seminal plasma antioxidants. J Urol 1997; 157: 140.
9. Amory JK, Muller CH, Shimshoni JA et al: Suppression of spermatogenesis by bisdichloroacetyldiamines is mediated by inhibition of testicular retinoic acid biosynthesis. J Androl 2011; 32: 111.
12. Gupta NP and Kumar R: Lycopene therapy in idiopathic male infertility–a preliminary report. Int Urol Nephrol 2002; 34: 369. 13. Gonzales GF, Cordova A, Gonzales C et al: Lepidium meyenii (Maca) improved semen parameters in adult men. Asian J Androl 2001; 3: 301. 14. Lenzi A, Sgrò P, Salacone P et al: A placebocontrolled double-blind randomized trial of the use of combined l-carnitine and l-acetyl-carnitine treatment in men with asthenozoospermia. Fertil Steril 2004; 81: 1578. 15. Cavallini G, Ferraretti AP, Gianaroli L et al: Cinnoxicam and L-carnitine/acetyl-L-carnitine treatment for idiopathic and varicocele-associated oligoasthenospermia. J Androl 2004; 25: 761.
10. Vézina D, Mauffette F, Roberts KD et al: Seleniumvitamin E supplementation in infertile men. Effects on semen parameters and micronutrient levels and distribution. Biol Trace Elem Res 1996; 53: 65.
16. 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.
11. Moslemi MK and Tavanbakhsh S: Selenium-vitamin E supplementation in infertile men: effect on semen parameters and pregnancy rate. Int J Gen Med 2011; 4: 99.
17. Ghanem H, Shaeer O and El-Segini A: Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril 2010; 93: 2232.