An Update on Treatments and Interventions for Male Infertility, and the Role of Nutriceutical Food Supplementation


 Male infertility, causes, treatment, antioxidants, food supplements.

How to Cite

Comhaire, F. H., & Mahmoud, A. (2012). An Update on Treatments and Interventions for Male Infertility, and the Role of Nutriceutical Food Supplementation . Journal of Pharmacy and Nutrition Sciences, 3(1), 1–16.


Congenital factors have been thoroughly explored in recent years revealing the role of genetic mutations and polymorphisms, and highlighting the contribution of epigenetics in the pathogenesis of certain forms of infertility. Acquired male infertility is commonly due to varicocele, male accessory gland infection, immunological infertility, and idiopathic oligozoospermia. The mechanisms by which these causes interfere with male reproduction are endocrine deregulation, inflammation through prostaglandins and cytokines, and oxidative overload damaging the cell membrane, inducing mutagenesis of the DNA, and impairing mitochondrial energy production. Causal treatment includes (non-surgical) interruption of spermatic venous reflux in varicocele, adequate antibiotic treatment with third generation Quinolones in accessory gland infection, assisted reproduction techniques in immunological infertility, and the anti-estrogen Tamoxifen for idiopathic oligozoospermia. In addition, a novel nutriceutical food supplement (NFS) has been formulated that aims at correcting the pathological mechanisms and at reducing the influence of detrimental environmental factors. Complementary NFS-treatment also may improve the fertilizing capacity of spermatozoa in some patients with a congenital cause of sperm deficiency. The efficiency of adding this NFS to causal therapy, or in assisted reproduction is expressed as numbers of couples needed to treat (NNT) to obtain one additional pregnancy.


Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992; 340: 17-8.

McDonald SD, Murphy K, Beyene J, Ohlsson A. Perinatel outcomes of singleton pregnancies achieved by in vitro fertilization: a systematic review and meta-analysis. J Obstet Gynaecol Can 2005; 27: 449-59.

Buckett WM, Chian RC, Holzer H, Dean N, Usher R, Tan SL. Obstetric outcomes and congenital abnormalities after in vitro maturation, in vitro fertilization, and intracytoplasmic sperm injection. Obstet Gynecol 2007; 110: 885-91.

Reefhuis J, Honein MA, Schieve LA, Correa A, Hobbs CA, Rasmussen SA. Assisted reproductive technology and major structural birth defects in the United States. Hum Reprod 2009; 24: 360-6.

Katari S, Turan N, Bibikova M, et al. DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet 2009; 18: 3769-78.

Comhaire F, Decleer W. Comparing the effectiveness of infertility treatments by numbers needed to treat (NNT). Andrologia 2012; 44: 401-4.

Laupacis A, Sackett DL, Roberts RS. An assessment of clinically useful measures of the consequences of treatment. N Engl J Med 1988; 318: 1728-33.

Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA. WHO manual for the standardized investigation, diagnosis and management of the infertile male. 1st ed. Cambridge: Cambridge University Press 2000.

Comhaire FH, de Kretser D, Farley TM, Rowe PJ. Towards more objectivity in diagnosis and management of male infertility. World Health Organization Task Force on the Diagnosis and Treatment of Infertility. Int J Androl 1987; (Suppl 7): 1-53.

Lombardo F, Sansone A, Romanelli F, Paoli D, Gandini L, Lenzi A. The role of antioxidant therapy in the treatment of male infertility: an overview. Asian J Androl 2011; 13: 690-7.

Weijer C, Grimshaw JM, Taljaard M, et al. Ethical issues posed by cluster randomized trials in health research. Trials 2011; 12: 100.

Anawalt BD, Bebb RA, Matsumoto AM, et al. Serum inhibin B levels reflect Sertoli cell function in normal men and men with testicular dysfunction. J Clin Endocrinol Metab 1996; 81: 3341-5.

Mahmoud AM, Comhaire FH, Depuydt CE. The clinical and biologic significance of serum inhibins in subfertile men. Reprod Toxicol 1998; 12: 591-9.

Andersson AM. Inhibin B in the assessment of seminiferous tubular function. Baillieres Clin Endocrinol Metab 2000; 14: 389-97.

Pierik FH, Vreeburg JT, Stijnen T, De Jong FH, Weber RF. Serum inhibin B as a marker of spermatogenesis. J Clin Endocrinol Metab 1998; 83: 3110-4.

Mahmoud AM, Goemaere S, El Garem Y, Van Pottelbergh I, Comhaire FH, Kaufman JM. Testicular volume in relation to hormonal indices of gonadal function in community-dwelling elderly men. J Clin Endocrinol Metab 2003; 88: 179-84.

Comhaire F, Mahmoud A. Rationale: Understanding normal anatomy and function: Endocrine regulation. In Schill WB, Comhaire F, Hargreave T, Eds. Andrology for the Clinician. 1st ed. Berlin, Heidelberg: Springer-Verlag 2006; pp. 288-91.

Hargreave T. Congenital disorders and male infertility. In Schill WB, Comhaire F, Hargreave T, Eds. Andrology for the Clinician. 1st ed. Berlin Heidelberg: Springer-Verlag 2006; pp. 63-6.

Bush A, Cole P, Hariri M, et al. Primary ciliary dyskinesia: diagnosis and standards of care. Eur Respir J 1998; 12: 982-8.

Jenkins TG, Carrell DT. The sperm epigenome and potential implications for the developing embryo. Reproduction 2012; 143: 727-34.

Dalgaard MD, Weinhold N, Edsgard D, et al. A genome-wide association study of men with symptoms of testicular dysgenesis syndrome and its network biology interpretation. J Med Genet 2012; 49: 58-65.

Rowe PJ, Comhaire FH, Hargreave TB, Mahmoud AMA. WHO manual for the standardized investigation, diagnosis and management of the infertile male. 1st ed. Cambridge: Cambridge University Press 2000.

Gat Y, Zukerman Z, Chakraborty J, Gornish M. Varicocele, hypoxia and male infertility. Fluid Mechanics analysis of the impaired testicular venous drainage system. Hum Reprod 2005; 20: 2614-9.

Comhaire F, Vermeulen A. Varicocele sterility: cortisol and catecholamines. Fertil Steril 1974; 25: 88-95.

Shiraishi K, Takihara H, Matsuyama H. Elevated scrotal temperature, but not varicocele grade, reflects testicular oxidative stress-mediated apoptosis. World J Urol 2010; 28: 359-64.

Comhaire F, Simons M, Kunnen M, Vermeulen L. Testicular arterial perfusion in varicocele: the role of rapid sequence scintigraphy with technetium in varicocele evaluation. J Urol 1983; 130: 923-6.

Comhaire F, Vermeulen A. Plasma testosterone in patients with varicocele and sexual inadequacy. J Clin Endocrinol Metab 1975; 40: 824-9.

Aitken RJ, De Iuliis GN. Origins and consequences of DNA damage in male germ cells. Reprod Biomed Online 2007; 14: 727-33.

Zalata A, Hafez T, Van Hoecke MJ, Comhaire F. Evaluation of beta-endorphin and interleukin-6 in seminal plasma of patients with certain andrological diseases. Hum Reprod 1995; 10: 3161-5.

Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M. Increased testicular 8-hydroxy-2'-deoxyguanosine in patients with varicocele. BJU Int 2007; 100: 863-6.

Terquem A, Dadoune JP. Morphological findings in varicocele: an ultrastructural study of 30 bilateral testicular biopsies. Int J Androl 1981; 4: 515-31.

Everaert K, Mahmoud A, Depuydt C, Maeyaert M, Comhaire F. Chronic prostatitis and male accessory gland infection--is there an impact on male infertility (diagnosis and therapy)? Andrologia 2003; 35: 325-30.

Comhaire F, Monteyne R, Kunnen M. The value of scrotal thermography as compared with selective retrograde venography of the internal spermatic vein for the diagnosis of "subclinical" varicocele. Fertil Steril 1976; 27: 694-8.

Depuydt C, Zalata A, Christophe A, Mahmoud A, Comhaire F. Mechanisms of sperm deficiency in male accessory gland infection. Andrologia 1998; 30(Suppl 1): 29-33.

Depuydt CE, Bosmans E, Zalata A, Schoonjans F, Comhaire FH. The relation between reactive oxygen species and cytokines in andrological patients with or without male accessory gland infection. J Androl 1996; 17: 699-707.

Meares EM, Stamey TA. Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 1968; 5: 492-518.

Comhaire FH, Vermeulen L, Pieters O. Study of the accuracy of physical and biochemical markers in semen to detect infectious dysfunction of the accessory sex glands. J Androl 1989; 10: 50-3.

Jager S, Kremer J, van Slochteren-Draaisma T. Presence of sperm agglutinating antibodies in infertile men and inhibition of in vitro sperm penetration into cervical mucus. Int J Androl 1979; 2: 117-30.

Zalata AA, Christophe AB, Depuydt CE, Schoonjans F, Comhaire FH. The fatty acid composition of phospholipids of spermatozoa from infertile patients. Mol Hum Reprod 1998; 4: 111-8.

Eertmans F, Dhooge W, Stuyvaert S, Comhaire F. Endocrine disruptors: effects on male fertility and screening tools for their assessment. Toxicol In vitro 2003; 17: 515-24.

Sharpe RM, Skakkebaek NE. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 1993; 341: 1392-5.

Dhooge W, Larebeke NV, Comhaire F, Kaufman JM. Reproductive parameters of community-dwelling men from two regions in Flanders are associated with the consumption of self-grown vegetables. J Androl 2007; 28: 836-46.

Dhooge W, Eertmans F, Comhaire F. Estrogen receptor based in vitro assays for the evaluation of endocrine disrupters. Folia Histochem Cytobiol 2001; 39(Suppl 2): 44-5.

Comhaire FH, Mahmoud AM, Schoonjans F. Sperm quality, birth rates and the environment in Flanders (Belgium). Reprod Toxicol 2007; 23: 133-7.

Zalata AA, Christophe AB, Depuydt CE, Schoonjans F, Comhaire FH. White blood cells cause oxidative damage to the fatty acid composition of phospholipids of human spermatozoa. Int J Androl 1998; 21: 154-62.

Zalata AA, Ahmed AH, Allamaneni SS, Comhaire FH, Agarwal A. Relationship between acrosin activity of human spermatozoa and oxidative stress. Asian J Androl 2004; 6: 313-8.

Saether T, Tran TN, Rootwelt H, Christophersen BO, Haugen TB. Expression and regulation of delta5-desaturase, delta6-desaturase, stearoyl-coenzyme A (CoA) desaturase 1, and stearoyl-CoA desaturase 2 in rat testis. Biol Reprod 2003; 69: 117-24.

Stoffel W, Holz B, Jenke B, et al. Delta6-desaturase (FADS2) deficiency unveils the role of omega3- and omega6-polyunsaturated fatty acids. EMBO J 2008; 27: 2281-92.

Retterstol K, Haugen TB, Tran TN, Christophersen BO. Studies on the metabolism of essential fatty acids in isolated human testicular cells. Reproduction 2001; 121: 881-7.

Venkatesh S, Deecaraman M, Kumar R, Shamsi MB, Dada R. Role of reactive oxygen species in the pathogenesis of mitochondrial DNA (mtDNA) mutations in male infertility. Indian J Med Res 2009; 129: 127-37.

DuPlessis SS, Makker K, Desai NR, Agarwal A. Impact of oxidative stress on IVF. Expert Review of Obstetrics and Gynecology 2008; 3: 539-54.

Comhaire FH, Christophe AB, Zalata AA, Dhooge WS, Mahmoud AM, Depuydt CE. The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men. Prostaglandins Leukot Essent Fatty Acids 2000; 63: 159-65.

Comhaire FH, Garem YE, Mahmoud A, Eertmans F, Schoonjans F. Combined conventional/antioxidant "Astaxanthin" treatment for male infertility: a double blind, randomized trial. Asian J Androl 2005; 7: 257-62.

Aitken RJ, Curry BJ. Redox regulation of human sperm function: from the physiological control of sperm capacitation to the etiology of infertility and DNA damage in the germ line. Antioxid Redox Signal 2011; 14: 367-81.

Hammarberg K, Baker HW, Fisher JR. Men's experiences of infertility and infertility treatment 5 years after diagnosis of male factor infertility: a retrospective cohort study. Hum Reprod 2010; 25: 2815-20.

Hara MR, Kovacs JJ, Whalen EJ, et al. A stress response pathway regulates DNA damage through b2-adrenoreceptors and b-arrestin-1. Nature 2011; [10368

Panossian A, Wikman G. Evidence-based efficacy of adaptogens in fatigue, and molecular mechanisms related to their stress-protective activity. Curr Clin Pharmacol 2009; 4: 198-219.

Ruiz-Luna AC, Salazar S, Aspajo NJ, Rubio J, Gasco M, Gonzales GF. Lepidium meyenii (Maca) increases litter size in normal adult female mice. Reprod Biol Endocrinol 2005; 3: 16.

Gonzales GF, Cordova A, Gonzales C, Chung A, Vega K, Villena A. Lepidium meyenii (Maca) improved semen parameters in adult men. Asian J Androl 2001; 3: 301-3.

Comhaire F, Kunnen M, Nahoum C. Radiological anatomy of the internal spermatic vein(s) in 200 retrograde venograms. Int J Androl 1981; 4: 379-87.

French DB, Sabanegh E. Advances in microsurgery and assisted reproduction for management of male infertility. Front Biosci (Elite Ed) 2009; 1: 381-9.

French DB, Desai NR, Agarwal A. Varicocele repair: does it still have a role in infertility treatment? Curr Opin Obstet Gynecol 2008; 20: 269-74.

Baazeem A, Belzile E, Ciampi A, et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol 2011; 60: 796-808.

Nilsson S, Edvinsson A, Nilsson B. Improvement of semen and pregnancy rate after ligation and division of the internal spermatic vein: fact or fiction? Br J Urol 1979; 51: 591-6.

Zaini A, Jennings MG, Baker HW. Are conventional sperm morphology and motility assessments of predictive value in subfertile men? Int J Androl 1985; 8: 427-35.

Morag B, Rubinstein ZJ, Madgar I, Lunenfeld B. The role of spermatic venography after surgical high ligation of the left spermatic veins: diagnosis and percutaneous occlusion. Urol Radiol 1985; 7: 32-4.

Nieschlag E, Hertle L, Fischedick A, Abshagen K, Behre HM. Update on treatment of varicocele: counselling as effective as occlusion of the vena spermatica. Hum Reprod 1998; 13: 2147-50.

Hargreave TB. Debate on the pros and cons of varicocele treatment--in favour of varicocele treatment. Hum Reprod 1995; 10(Suppl 1): 151-7.

Madgar I, Weissenberg R, Lunenfeld B, Karasik A, Goldwasser B. Controlled trial of high spermatic vein ligation for varicocele in infertile men. Fertil Steril 1995; 63: 120-4.

Krause W, Muller HH, Schafer H, Weidner W. Does treatment of varicocele improve male fertility? results of the 'Deutsche Varikozelenstudie', a multicentre study of 14 collaborating centres. Andrologia 2002; 34: 164-71.

Baazeem A, Belzile E, Ciampi A, et al. Varicocele and male factor infertility treatment: a new meta-analysis and review of the role of varicocele repair. Eur Urol 2011; 60: 796-808.

Comhaire FH. Concentration of pefloxacine in split ejaculates of patients with chronic male accessory gland infection. J Urol 1987; 138: 828-30.

Comhaire F, Decleer W. Quantifying the effectiveness and cost-efficiency of food supplementation with antioxidants for male infertility. Reprod Biomed Online 2011; 23: 361-2.

Baker HW, Brindle J, Irvine DS, Aitken RJ. Protective effect of antioxidants on the impairment of sperm motility by activated polymorphonuclear leukocytes. Fertil Steril 1996; 65: 411-9.

Mahmoud AM, Tuyttens CL, Comhaire FH. Clinical and biological aspects of male immune infertility: a case-controlled study of 86 cases. Andrologia 1996; 28: 191-6.

Comhaire F. Treatment of oligospermia with tamoxifen. Int J Fertil 1976; 21: 232-8.

Vermeulen A, Comhaire F. Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men. Fertil Steril 1978; 29: 320-7.

Bonde JP, Ernst E, Jensen TK, et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998; 352: 1172-7.

Adamopoulos DA, Pappa A, Billa E, Nicopoulou S, Koukkou E, Michopoulos J. Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril 2003; 80: 914-20.

WHO. A double-blind trial of clomiphene citrate for the treatment of idiopathic male infertility. World Health Organization. Int J Androl 1992; 15: 299-307.

Vandekerckhove P, Lilford R, Vail A, Hughes E. Clomiphene or tamoxifen for idiopathic oligo/asthenospermia. Cochrane Database Syst Rev 2000; CD000151.

Murthy K, Wadsworth P. Myosin-II-dependent localization and dynamics of F-actin during cytokinesis. Curr Biol 2005; 15: 724-31.

Duleba AJ, Dokras A. Is PCOS an inflammatory process? Fertil Steril 2012; 97: 7-12.

Gupta S, Goldberg JM, Aziz N, Goldberg E, Krajcir N, Agarwal A. Pathogenic mechanisms in endometriosis-associated infertility. Fertil Steril 2008; 90: 247-57.

Combelles CM, Gupta S, Agarwal A. Could oxidative stress influence the in-vitro maturation of oocytes? Reprod Biomed Online 2009; 18: 864-80.

Ko EY, Sabanegh ES, Jr. The role of over-the-counter supplements for the treatment of male infertility--fact or fiction? J Androl 2012; 33: 292-308.

Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database Syst Rev 2011; CD007411.

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: 2232-5.

Lipinski B. Is it oxidative or free radical stress and why does it matter? Oxid Antioxid Med Sci 2012; 1: 5-9.

Bernard D, Christophe A, Delanghe J, Langlois M, de Buyzere M, Comhaire F. The effect of supplementation with an antioxidant preparation on LDL-oxidation is determined by haptoglobin polymorphism. Redox Rep 2003; 8: 41-6.

Ragin C, Minor A, Agudo A, et al. Pooled analysis of studies on DNA adducts and dietary vitamins. Mutat Res 2010; 705: 77-82.

Chaumontet C, Bex V, Veran F, Martel P. The vitamin E analog tocopherol succinate strongly inhibits gap junctional intercellular communication in rat liver epithelial cells (IAR203). J Nutr Biochem 2008; 19: 263-8.

Rolf C, Cooper TG, Yeung CH, Nieschlag E. Antioxidant treatment of patients with asthenozoospermia or moderate oligoasthenozoospermia with high-dose vitamin C and vitamin E: a randomized, placebo-controlled, double-blind study. Hum Reprod 1999; 14: 1028-33.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright (c) 2012 Frank H. Comhaire , Ahmed Mahmoud