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www.uconnfertility.com An academic affiliate of UCONN School of Medicine John Nulsen, MD Claudio Benadiva, MD, HCLD David Schmidt, MD Lawrence Engmann, MD, MRCOG Andrea DiLuigi, MD Can We Prevent or Reverse Male Infertility? By Stanton Honig, MD Male factor infertility accounts for approximately 50% of all infertility. For this reason, evaluation and treatment of the male is critical to a comprehensive program for the infertile couple. Because there are many treatable, reversible and preventable causes of male factor infertility, early evaluation and treatment is very important. In 1994, Drs. Honig, Jarow and Lipshultz reported the incidence of significant medical pathology associated with the evaluation and treatment of male factor infertility. In 1% of patients, a significant medical condition, sometimes life-threatening (such as a cancer of the testis, brain or spinal cord tumor) caused male infertility. Subsequent studies have shown a significantly higher incidence of testis cancer in infertile men despite variable semen quality. Early intervention was crucial to treat the life-threatening condition and improve the couple’s overall chance of conceiving. We believe that early evaluation of the male should include a semen analysis and, if abnormal, an early consultation with a urologist well-trained in male infertility disorders. This should occur before or in conjunction with assisted reproductive technologies. Interestingly, new data suggest that testis cancer can CAUSE infertility, CAN BE FOUND on a male infertility evaluation and patients with male factor infertility have an OVERALL HIGHER CANCER RISK than the general population! What can be done as “preventive medicine” for male factor infertility? Prevention starts with avoiding lifestyle issues that may be detrimental to sperm quality. Acquired causes of male infertility include exposure to toxins such as illicit drugs (marijuana, cocaine, anabolic steroids, etc.), heavy alcohol use, cigarette smoking, medications and excessive heat to the scrotal area. It is becoming increasingly clear that recreational drugs can have an adverse effect on the testes and sperm quality. Chronic marijuana use may lower testosterone levels and affect sperm quality. This has become more of a problem since laws requiring marijuana use have loosened. Cocaine has been shown to have direct effects on germ cell apoptosis, and may affect sperm concentration, motility and DNA integrity. Anabolic steroids used for bodybuilding clearly have direct effects on the testis through lowering the body’s ability to make its own testosterone. It also decreases spermatogenesis and azoospermia, which 06/2016 is sometimes irreversible. Education of high school and college students regarding the negative impact of anabolic steroids and other recreational drugs is critical to prevent male fertility problems down the road. Cigarette smoking and heavy alcohol use have been shown in clinical and research studies to affect hormone levels, as well as direct toxic effects on the testicle. Basic science data has shown increased testicular apoptosis when exposed to environmental toxins. Many medications used for treatment of unrelated medical conditions may have negative effects on sperm quality, as well. It is the job of the reproductive specialist to educate physicians and the public on these effects. Some medications that may affect sperm quality are testosterone, calcium channel blockers for high blood pressure, sulfasalazine (Crohn’s disease-bowel disease), cyclosporine (organ transplants) and chemotherapy for cancers or rheumatologic disease. Many of these medications can be interchanged with similar drugs that have less toxic side effects. For example, we have seen a MAJOR increase in the use of testosterone in men of reproductive age. This has been driven by the sense that testosterone will bring “the fountain of youth”. Unfortunately, this “overuse” in men has resulted in lowering of sperm counts, in some cases to zero. Luckily, most of the time, this is reversible. In addition, there are other medications that can increase testosterone via the hypothalamic pituitary axis that can be utilized instead to improve libido, sexual function, energy level, etc. With high blood pressure, it appears that calcium channel blocker medication may directly affect the sperm’s ability to bind to egg receptors. Switching to a different medication may remove this risk. In irritable bowel disease, mesalazone may be substituted for sulfasalazine having less reproductive side effects with similarly good disease control results. Chemotherapy for cancer and other chronic diseases (like rheumatoid arthritis, renal disease, autoimmune illnesses) can also affect sperm quality. Important considerations include freezing sperm prior to starting any toxic drug regimens and using the least toxic chemotherapy regime with equal survival results. Younger males with prostate cancer should be asked about future fertility interests prior to definitive therapy. Radical prostatectomy, radiation therapy and hormone deprivation therapy have specific deleterious effects on spermatogenesis and/or sperm transport. 2 Batterson Park Road • Farmington, CT 06032 • Tel. (844) HOPEIVF (844-467-3483) 50 Columbus Boulevard • Hartford, CT 06106 • Tel. (860) 525-8283 4 Shaws Cove • Suite 201 • New London, CT 06320 • Tel. (877) 860-8044 Occupational exposure to toxins may also affect sperm quality. Agents like pesticides, cadmium, lead and manganese may interfere with reproductivity, so checking and removing work exposures is important. Direct heat to the testis can be a major cause of diminished sperm quality and male infertility. Varicoceles are one of the most common, treatable and reversible causes of male factor infertility. Although the exact mechanism of how varicoceles affects sperm quality is not known, it is believed that this is usually through an increased heat effect. Multiple studies have shown that scrotal temperature is increased in patients with varicoceles. Varicocele repair has been shown to improve sperm concentration, motility, morphology and DNA integrity. Minimally invasive ligation of varicoceles can significantly improve the chances of pregnancy as compared to natural intercourse. In varicoceleassociated infertility, multiple studies have shown that it is more cost effective to perform varicocele repair as compared to going directly to IVF/ICSI in moderate male factor infertility cases. In addition, varicocele repair may upgrade semen quality to allow couples to proceed with less invasive/less costly hyperstimulation/IUI as opposed to going directly to IVF/ICSI. External heat effects on the testis may affect semen quality as well. We recommend abstinence of hot tub use or lowering the temperature to 97 degrees (same as scrotal temperature). Conventional lay information regarding types of underwear is vastly overplayed. Scientific studies have shown that there is no difference in sperm quality between boxer shorts and briefs. Coital factors are extremely important in achieving pregnancy. Although timing intercourse with ovulation may be tedious, it is critical with male factor patients. Timing with basal body temperature or ovulation predictor kits is extremely useful to determine approximate timing of intercourse. Intercourse every 24-48 hours around the time of ovulation is critical to achieving pregnancy naturally. Some patients maintain good semen parameters despite frequent ejaculation, and in these patients, intercourse every 24 hours or so may be beneficial. In addition, avoidance of spermatoxic lubricants such as K-Y jelly, surgilube and lubrifax, is important. A natural lubricant, such as “Replens” or “Pre-seed”, may be substituted and is not sperm toxic. Are vitamins and supplements helpful? Scientific data is quite mixed. Some supplements used for other reasons (depression, memory loss, “prostate health”) may affect semen quality, while others have been studied to determine if they’ll improve semen quality in patients with male infertility. Below are vitamins and supplements that are recommended: Vitamin C 500-1000 mg/daily Carnitine and/or L-acetyl carnitine Vitamin E 3gms/daily 400 -800 iu/daily There is a large amount of literature evaluating the effects of antioxidant vitamins (C and E) on sperm. These studies have been performed on patients taking these vitamins by mouth as well as mixing them with semen. It appears clear that some male factor patients have an increase in “reactive oxygen species” or oxidants in their semen. Reactive oxygen species may have affects both directly on the sperm and indirectly on the sperm environment. Vitamins C and E are antioxidants and may serve to lower the level of reactive oxygen species and, therefore, negate its deleterious effects. Many of these studies suffer from being non randomized, non placebo controlled studies, so definitive conclusions are difficult to ascertain. Carnitine appears to play an important role in both the function of the epididymis and possibly in sperm energy/motility. Some studies from Italy have suggested some benefit in using this supplement (mostly with improvement in sperm motility), with no significant side effects. We recommend 3gms of carnitine and L-acetyl carnitine. Be careful with supplements that claim they are “Male Fertility Supplements”, as they may contain only tiny amounts of the recommended supplements. Most other supplements (such as zinc, selenium, folate, coenzyme Q-10) are not necessary if a balanced diet is maintained, since most are present in healthy foods. Not all nutritional supplements are good for sperm. Saw palmetto may have a negative effect on sperm production and ejaculate volume. It is thought that saw palmetto lowers levels of dihydrotestosterone (DHT), which is thought to be important for sperm production and ejaculation. Studies on the effects of 1 mg of finasteride (Propecia-for male pattern baldness) showed no negative effects on sperm quality. Saw palmetto may work similar to a higher dose of this drug used for benign prostate enlargement. It would be my recommendation that any patient trying to achieve a pregnancy stop using saw palmetto until further studies show that there are no deleterious effects. Summary Preventive medicine has an important role in male factor infertility. A thorough evaluation and physical examination by a physician familiar with male infertility is important to identify treatable, reversible and potentially life-threatening medical conditions. In addition, modification of lifestyle behaviors, and avoiding toxic recreational drugs such as anabolic steroids may improve chances of pregnancy. Avoiding supplements that may negatively affect male infertility and using other vitamins and supplements that may positively impact male fertility related disorders are important to consider, as well. Patients should ask their physicians and seek out organizations like RESOLVE, the American Society for Reproductive Medicine (www.asrm.org), The Society for the Study of Male Reproduction (www.ssmr.org), American Urological Association (www.urologyhealth. org/urologic-conditions/male-infertility), and path2parenthood (www.path2parenthood.org/library/category/male-reproductive-health-1. Dr. Honig works closely with The Center for Advanced Reproductive Services and is a Clinical Professor of Surgery in the Department of Urology at UConn Health. He is also the Director of Men’s Health and a full time faculty member at Yale University Department of Urology. Dr. Honig sees patients in New Haven, the Shoreline and in Farmington. He can be reached at 203-789-2222 or 860-679-4100. Find the series–Urology Nerds Drinking Beer, a webseries about Men’s Health issues at http://www.path2parenthood.org/library/category/male-reproductive-health-1.