12th March 2019, Dr Chee L Khoo
When couples present for investigations of infertility, semen analysis is one of the earliest investigations we order. Every so often, the results come back with reduced sperm numbers, motility or normal forms. It is frustrating as a GP when we are unable to advise them what they can take to improve their sperm parameters. The use of medical and nutritional supplements to improve semen parameters and pregnancy rates in couples with idiopathic infertility is big business. But the evidence base for their use in this setting is pretty controversial. What would you advise if your patient ask?
One in eight couples do not achieve pregnancy after one year. Infertility is due the male factor in about 50% of the cases and may include oligozoospermia, asthenozoospermia, terato- zoospermia or a combination of all three also known as oligoasthenoteratozoospermia. In up to 25% of the cases, the cause is unknown and we call that idiopathic.
Medical therapies use hormones to target the hypothalamic-pituitary-testicular axis:
FSH directly acts on Sertoli cells to stimulate spermatogenesis, while aromatase inhibitors (e.g. letrazole (Femara), Anastrozole (Arimidex)) act by inhibiting the peripheral conversion of testosterone to oestrogens, thereby reducing the negative feedback inhibition of oestrogens on the hypothalamic- pituitary-gonadal axis and promoting spermatogenesis. Clomiphene and tamoxifen are selective oestrogen receptor modulators that block negative feedback at the level of the hypothalamus and the pituitary, thus increasing LH and FSH excretion from the anterior pituitary, which raises testosterone levels and stimulates spermatogenesis. Gonadotropins (gonadotropin-releasing hormone [GnRH], luteinising hormone [LH], follicle-stimulating hormone [FSH], and human chorionic gonadotropin [hCG]) have all been used to treat idiopathic male infertility.
Nutritional and herbal supplements take a totally different approach. They work primarily by increasing seminal anti-oxidant capacity. Normal sperm function requires reactive oxygen species (ROS) but excessive ROS may be harmful. Elevated ROS levels are associated with abnormal sperm development, function, and fertilising capacity, and sperm DNA damage. Sperm DNA damage has been associated with recurrent fertilisation failure and recurrent pregnancy loss from both natural conception and assisted reproductive technologies.
Carnitines, N-acetyl cysteine, and selenium have antioxidant properties that protect sperm from the negative effects of ROS. Zinc and selenium both play a role in testicular function, spermatozoa oxygen consumption, sperm chromatin stabilisation, and sperm capacitation, and may mediate intratesticular testosterone levels. Several vitamins act as potent antioxidants, inhibiting free radical-induced damage to cell membranes and decreasing seminal ROS. Coenzyme Q10 (CoQ10) is implicated in mitochondrial bioenergetics, which is important in sperm maturation [8.
That’s the theory. What we want to know is does medical treatment or nutritional supplements improve sperm parameters. More importantly, do they improve pregnancy rates? A systematic review under the auspices of the European Association of Urology looked at evidence comparing the benefits of nutritional and medical therapy on pregnancy rates and semen parameters in men with idiopathic infertility. They searched electronic databases including MEDLINE, MEDLINE In-Process, Embase, the Cochrane Controlled Trials Register, and LILACS from January 1990 to September 2017. A total of 61 studies (59 RCTs and 2 non-RCTs) met the inclusion criteria and were included in the SR.
FSH and tamoxifen treatment resulted in improvements in sperm concentration, while sperm motility improved with tamoxifen and sperm morphology improved with FSH.
Antioxidants such as L-carnitine and CoQ10 appear to have a beneficial effect on sperm concentration, motility, and morphology. CoQ10 plays an integral role in cellular respiration, and high seminal CoQ10 levels are associated with sperm motility and antioxidant capacity. Selenium and N-acetyl cysteine also had a beneficial effect on all semen parameters.
The most objective outcome measure to indicate the effectiveness of intervention for male fertility is the pregnancy rate or live birth rate, which is superior to assessment of sperm parameters, although most studies only reported on semen parameters. However, it must be noted that “fertility” potential also depends on the fertility status of the female partner, which clearly influences the outcome of any medical or nutritional intervention in the male partner.
However, data on pregnancy rates with FSH and tamoxifen were limited by a low number of positive events. Anti-oestrogens in the treatment of male infertility concluded that there was a 2.4 times higher chance of pregnancy if men were treated with anti-oestrogens, but this was based on historical data predominantly generated before 1990.
Similarly, data on pregnancy rates in nutritional supplements are limited by low numbers of positive events.
Many of the studies had methodological flaws and provided conflicting results when evaluating the same treatment. As a result, the majority of outcomes were either rated as “low” or “very low” when assessing the certainty using the GRADE approach. Well-designed and -conducted prospective studies are needed to identify optimum dosage regimens and treatment durations while using pregnancy and live birth rates as primary outcome measures following therapeutic interventions.
Omar MI, et al. Benefits of Empiric Nutritional and Medical Therapy for Semen Parameters and Pregnancy and Live Birth Rates in Couples with Idiopathic Infertility: A Systematic Review and Meta-analysis. Eur Urol (2019), https://doi.org/10.1016/j.eururo.2018.12.022