Review Article Aromatase inhibitors in the treatment of oligozoospermic or azoospermic men: a systematic review of randomized controlled trials Mariana A. Ribeiro 1 , Luís F. O. Gameiro 2 , Wellerson R. Scarano 1 , Christine Briton-Jones 3 , Anil Kapoor 4,5 , Mauro B. Rosa 6 , Regina El Dib 5,7 1 Department of Morphology, Institute of Biosciences, Sao Paulo State University, UNESP, Botucatu, SP, Brazil 2 Physiotherapy Service School of Medicine, Sao Paulo State University, UNESP, Botucatu, SP, Brazil 3 Reproductive Medicine Partners of New York, New York, NY, USA 4 Genito-Urinary Oncology Program, Juravinski Cancer Centre, Hamilton, ON, Canada 5 McMaster Institute of Urology, at St. Joseph’s Healthcare, Hamilton, ON, Canada 6 Hospital do Coração (HCOR), Sao Paulo,SP, Brazil 7 Department of Anesthesiology, Faculdade de Medicina de Botucatu (FMB), Sao Paulo State University, UNESP, Botucatu, SP, Brazil ABSTRACT The aim of this study as to analyze published evidence regarding the effectiveness of aromatase inhibitor therapy on improving spermatogenesis in infertile men. We carried out a systematic review of randomized controlled trials. The date of the most recent search was October 4, 2015. Two authors independently selected relevant clinical trials, assessing their methodological quality and extracting data. Three studies were included in this review with a total of 100 participants; however, we were able to include data from only 54 participants in the analysis. In the repre- sentation of meta-analysis with a single study comparing testolactone versus placebo, related to the hormone con- centrations, there was a statistically signifcance difference favoring the use of testolactone for Luteinizing Hormone (LH); Estrogen (E2); free Testosterone (free T); free Estro- gen (free E2); 17-Hydroxyprogesterone (17OHP); prolactin (PRL). In another analysis from a single study comparing letrozole versus anastrozole, there was also a statistically signifcance difference favoring the use of letrozole for the increase in both the sperm count and LH. There is only low quality evidence regarding the effectiveness of aromatase inhibitor therapy in infertile men. Further trials are needed with standardized interventions and outcomes. Keywords: aromatase inhibitors, spermatogenesis, infertile men, meta-analysis INTRODUCTION Spermatogenesis is regulated by the interaction of en- docrine and paracrine signals, it is dependent on mainte- nance of high levels of intratesticular testosterone as well as Sertoli cell stimulation with FSH (Jarow & Zirkin, 2005). Furthermore, LH released by the anterior pituitary binds to receptors on Leydig cells surface and stimulates T produc- tion, a steroid hormone which diffuses in the seminiferous tubules (Walker & Cheng, 2005). For men with idiopathic infertility, there are no reliable treatments to enhance fertility. However, increased sperm production or motility has been associated with empiric medical therapy using estrogen receptor modulators such as clomiphene citrate or tamoxifen citrate. Such medical therapy to improve spermatogenesis has primarily focused on enhancement of intratesticular testosterone levels and stimulation of FSH production. Unfortunately, use of es- trogen receptor modulators results in increased estro- gen levels as well as increased testosterone production (Schlegel, 2012). Aromatase inhibitors (AI) have the ability to increase endogenous testosterone production without the asso- ciated increase in circulating estrogens seen with es- trogen receptor modulators (Pavlovich et al., 2001). AIs are classifed as either steroidal or nonsteroidal. Ste- roidal inhibitors (such as testolactone, formestane, and exemestane) competitively inhibit aromatase by mimick- ing androstenedione, causing irreversible enzyme inhibi- tion. Letrozole and anastrozole are nonsteroidal inhibitors that cause reversible enzyme inhibition. Although anastro- zole or letrozole suppression is close to 100% in wom- en, men do not show such a profound decrease, this is probably related to their high plasma T levels (de Ronde & de Jong, 2011; Stephens & Polotsky, 2013). Nonethe- less, letrozole is a more potent AI than anastrozole (Schle- gel, 2012) with both commonly used off-label for treat- ing oligospermia and azoospermia (Stephens & Polotsky, 2013). Recent studies have identifed a potential specifc en- docrine defect in men with severe male factor infertility (Pavlovich et al., 2001). Some men with severely im- paired sperm production have a relative excess of es- trogen to testosterone, quantitatively measured as an increased testosterone/estradiol (T/E) ratio. Pavlovich et al. (2001) characterized men with severe male infertility as having a T/E ratio of 6.9, whereas men with normal spermatogenesis had a mean T/E ratio of 14.5. Based on these observations, they proposed a cutoff point of 10 as the lower limit of normal T/E ratios in men (cal- culated using T in ng/dL, and estradiol as pg/mL). Clinical studies of aromatase inhibitors have focused on men with defective spermatogenesis associated with low serum testosterone levels and abnormal T/E ratios (Schlegel, 2012). Since males have testosterone levels detected by the pituitary primarily by estrogen levels rather than testos- terone alone, inhibition of estrogen production by an aro- matase inhibitor can be a potent stimulant for increased LH production and hence intratesticular and circulating testosterone levels (Santen, 1981). For men with a low serum testosterone and low T/E ratio, treatment with an aromatase inhibitor to increase sperm production would be more rational than treatment with a selective estrogen receptor modulator. To the best of our knowledge, there is no systematic review comparing the use of aromatase inhibitors on men with impaired spermatogenesis. Therefore, the objective of our study was to review the literature on the effective- ness and safety of aromatase inhibitors in infertile men spermatogenesis. JBRA Assisted Reproduction 2016;20(2):82-88 doi: 10.5935/1518-0557.20160019 Received November 11, 2015 Accepted January 26, 2016 82