Aromatase Inhibitors in the Treatment of Oligozoospermic Or Azoospermic Men: a Systematic Review of Randomized Controlled Trials
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JBRA Assisted Reproduction 2016;20(2):82-88 doi: 10.5935/1518-0557.20160019 Review Article Aromatase inhibitors in the treatment of oligozoospermic or azoospermic men: a systematic review of randomized controlled trials Mariana A. Ribeiro1, Luís F. O. Gameiro2, Wellerson R. Scarano1, Christine Briton-Jones3, Anil Kapoor4,5, Mauro B. Rosa6, Regina El Dib5,7 1Department of Morphology, Institute of Biosciences, Sao Paulo State University, UNESP, Botucatu, SP, Brazil 2Physiotherapy Service School of Medicine, Sao Paulo State University, UNESP, Botucatu, SP, Brazil 3Reproductive Medicine Partners of New York, New York, NY, USA 4Genito-Urinary Oncology Program, Juravinski Cancer Centre, Hamilton, ON, Canada 5McMaster Institute of Urology, at St. Joseph’s Healthcare, Hamilton, ON, Canada 6Hospital do Coração (HCOR), Sao Paulo,SP, Brazil 7Department of Anesthesiology, Faculdade de Medicina de Botucatu (FMB), Sao Paulo State University, UNESP, Botucatu, SP, Brazil ABSTRACT endogenous testosterone production without the asso- The aim of this study as to analyze published evidence ciated increase in circulating estrogens seen with es- regarding the effectiveness of aromatase inhibitor therapy trogen receptor modulators (Pavlovich et al., 2001). on improving spermatogenesis in infertile men. We carried AIs are classified as either steroidal or nonsteroidal. Ste- out a systematic review of randomized controlled trials. roidal inhibitors (such as testolactone, formestane, and The date of the most recent search was October 4, 2015. exemestane) competitively inhibit aromatase by mimick- Two authors independently selected relevant clinical trials, ing androstenedione, causing irreversible enzyme inhibi- assessing their methodological quality and extracting data. tion. Letrozole and anastrozole are nonsteroidal inhibitors Three studies were included in this review with a total of that cause reversible enzyme inhibition. Although anastro- 100 participants; however, we were able to include data zole or letrozole suppression is close to 100% in wom- from only 54 participants in the analysis. In the repre- en, men do not show such a profound decrease, this is sentation of meta-analysis with a single study comparing probably related to their high plasma T levels (de Ronde testolactone versus placebo, related to the hormone con- & de Jong, 2011; Stephens & Polotsky, 2013). Nonethe- centrations, there was a statistically significance difference less, letrozole is a more potent AI than anastrozole (Schle- favoring the use of testolactone for Luteinizing Hormone gel, 2012) with both commonly used off-label for treat- (LH); Estrogen (E2); free Testosterone (free T); free Estro- ing oligospermia and azoospermia (Stephens & Polotsky, gen (free E2); 17-Hydroxyprogesterone (17OHP); prolactin 2013). (PRL). In another analysis from a single study comparing Recent studies have identified a potential specific -en letrozole versus anastrozole, there was also a statistically docrine defect in men with severe male factor infertility significance difference favoring the use of letrozole for the (Pavlovich et al., 2001). Some men with severely im- increase in both the sperm count and LH. There is only low paired sperm production have a relative excess of es- quality evidence regarding the effectiveness of aromatase trogen to testosterone, quantitatively measured as an inhibitor therapy in infertile men. Further trials are needed increased testosterone/estradiol (T/E) ratio. Pavlovich et with standardized interventions and outcomes. al. (2001) characterized men with severe male infertility as having a T/E ratio of 6.9, whereas men with normal Keywords: aromatase inhibitors, spermatogenesis, spermatogenesis had a mean T/E ratio of 14.5. Based infertile men, meta-analysis on these observations, they proposed a cutoff point of 10 as the lower limit of normal T/E ratios in men (cal- INTRODUCTION culated using T in ng/dL, and estradiol as pg/mL). Spermatogenesis is regulated by the interaction of en- Clinical studies of aromatase inhibitors have focused on docrine and paracrine signals, it is dependent on mainte- men with defective spermatogenesis associated with nance of high levels of intratesticular testosterone as well low serum testosterone levels and abnormal T/E ratios as Sertoli cell stimulation with FSH (Jarow & Zirkin, 2005). (Schlegel, 2012). Furthermore, LH released by the anterior pituitary binds to Since males have testosterone levels detected by the receptors on Leydig cells surface and stimulates T produc- pituitary primarily by estrogen levels rather than testos- tion, a steroid hormone which diffuses in the seminiferous terone alone, inhibition of estrogen production by an aro- tubules (Walker & Cheng, 2005). matase inhibitor can be a potent stimulant for increased For men with idiopathic infertility, there are no reliable LH production and hence intratesticular and circulating treatments to enhance fertility. However, increased sperm testosterone levels (Santen, 1981). For men with a low production or motility has been associated with empiric serum testosterone and low T/E ratio, treatment with an medical therapy using estrogen receptor modulators such aromatase inhibitor to increase sperm production would as clomiphene citrate or tamoxifen citrate. Such medical be more rational than treatment with a selective estrogen therapy to improve spermatogenesis has primarily focused receptor modulator. on enhancement of intratesticular testosterone levels and To the best of our knowledge, there is no systematic stimulation of FSH production. Unfortunately, use of es- review comparing the use of aromatase inhibitors on men trogen receptor modulators results in increased estro- with impaired spermatogenesis. Therefore, the objective gen levels as well as increased testosterone production of our study was to review the literature on the effective- (Schlegel, 2012). ness and safety of aromatase inhibitors in infertile men Aromatase inhibitors (AI) have the ability to increase spermatogenesis. Received November 11, 2015 82 Accepted January 26, 2016 Review Article 83 MATERIALS AND METHODS Summary measurements and synthesis of results This systematic review of the literature on interven- For dichotomous data, we used relative risk (RR) as the tion studies was carried out in accordance with the PRIS- effect measurement, with 95% confidence intervals (CI), MA (Preferred Reposting Items for Systematic Reviews and along with a fixed-effects model. The null hypothesis of ho- Meta-analysis) statement (Moher et al., 2009). mogeneity across individual studies was tested using the chi-square test and the I2 value. Eligibility criteria We took into consideration all randomized and qua- RESULTS si-randomized controlled clinical trials evaluating the ef- The electronic search yielded a total of 2,971 refer- fectiveness of aromatase inhibitors in the spermatogenesis ences through database searches. After screening by title of infertile men. and then by abstract, 2,921 papers were excluded due to The main outcomes measured were sperm count and failure of randomization or lack of appropriate controls, 50 hormone concentrations (e.g., total estradiol and testos- studies were identified as potentially eligible for inclusion terone levels). Studies were excluded from the review if in the review. Crosschecking of the references and manual they were duplicate publications on a study that had al- searches did not yield any additional studies for inclusion. ready been included, animal studies, case reports or re- Of these, three (Clark & Sherins, 1989; Gregoriou et al., view papers. 2012; Cavallini et al., 2013) studies met the inclusion cri- teria. Therefore, 42 further references were excluded from Search strategy this review, as they were either case series or cross-sec- There was no restriction on language, year of publi- tional studies (Figure 1). cation or publication status. The search was performed in the following electronic databases: the Cochrane database of clinical trials (CENTRAL, the Cochrane Library 2015, Figure 1. Flowchart of the systematic review issue 5), PubMed (1966-2015), Embase (1980-2015), Lilacs (1982-2015) and Scientific Electronic Library On- line (SciELO). The databases were searched for available published and unpublished studies up to October 4, 2015. The search was conducted using multiple combinations of the following key words “aromatase inhibitor”, “azoosper- mia” as well as oligozoospermia” (Table 1). Table 1. Search strategy (Azoospermia OR azoospermic OR azoospermic man OR azoospermic men OR Male Infertility OR Male Sterility OR Male Subfertility OR Male Sub-Fertility OR Male Sub fertility OR Oligozoospermia OR Low Sperm Count OR Low Sperm Counts OR Hypospermatogenesis OR Tera- tozoospermia) AND (aromatase inhibitor OR aromatase inhibitors OR letrozole OR 4,4’-(1H-1,2,4-triazol-1-yl- methylene)- bis(benzonitrile) OR Femara OR Novartis Brand of Letrozole OR Femara OR CGS20267 OR CGS- 20267 OR Clomiphene OR Clomiphene citrate OR Clo- mifene OR Clomifen OR Chloramiphene OR Clomid OR Clomide OR Clomiphene Citrate OR Clomiphene Hy- drochloride OR Gravosan OR Klostilbegit OR Clostilbe- git OR Serophene OR Androxal OR Repros Therapeutic Brand Enclomiphene Citrate OR Dyneric OR Indux OR Aromatase Inhibitors) Study selection and data extraction The titles and abstracts were reviewed by two re- searchers (MAR and RED) to identify potentially relevant papers. The papers were obtained and independently read in full by the two reviewers. Differences were resolved