A Systematic Review and Meta-analysis of Clinical Trials Implementing Aromatase Inhibitors to Treat Male Infertility

Overview

Journal Asian J Androl

Specialty Urology

Date 2019 Oct 18

PMID 31621654

Citations 17

Authors

Francesco Del Giudice

Gian Maria Busetto

Ettore De Berardinis

Isabella Sperduti

Matteo Ferro

Martina Maggi

Martin S Gross

Alessandro Sciarra

Michael L Eisenberg

Affiliations

Soon will be listed here.

Abstract

Aromatase activity has commonly been associated with male infertility characterized by testicular dysfunction with low serum testosterone and/or testosterone to estradiol ratio. In this subset of patients, and particularly in those with hypogonadism, elevated levels of circulating estradiol may establish a negative feedback on the hypothalamic-pituitary-testicular axis by suppressing follicle-stimulating hormone (FSH) and luteinizing hormone (LH) production and impaired spermatogenesis. Hormonal manipulation via different agents such as selective estrogen modulators or aromatase inhibitors to increase endogenous testosterone production and improve spermatogenesis in the setting of infertility is an off-label option for treatment. We carried out a systematic review and meta-analysis of the literature of the past 30 years in order to evaluate the benefits of the use of aromatase inhibitors in the medical management of infertile/hypoandrogenic males. Overall, eight original articles were included and critically evaluated. Either steroidal (Testolactone) or nonsteroidal (Anastrozole and Letrozole) aromatase inhibitors were found to statistically improve all the evaluated hormonal and seminal outcomes with a safe tolerability profile. While the evidence is promising, future prospective randomized placebo-controlled multicenter trials are necessary to better define the efficacy of these medications.

Citing Articles

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References

Santen R . Feedback control of luteinizing hormone and follicle-stimulating hormone secretion by testosterone and estradiol in men: physiological and clinical implications. Clin Biochem. 1981; 14(5):243-51. DOI: 10.1016/s0009-9120(81)90964-4. View

Gregoriou O, Bakas P, Grigoriadis C, Creatsa M, Hassiakos D, Creatsas G . Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril. 2012; 98(1):48-51. DOI: 10.1016/j.fertnstert.2012.04.005. View

Cavallini G, Biagiotti G, Bolzon E . Multivariate analysis to predict letrozole efficacy in improving sperm count of non-obstructive azoospermic and cryptozoospermic patients: a pilot study. Asian J Androl. 2013; 15(6):806-11. PMC: 3854065. DOI: 10.1038/aja.2013.99. View

Aus G, Chapple C, Hanus T, Irani J, Lobel B, Loch T . The European Association of Urology (EAU) guidelines methodology: a critical evaluation. Eur Urol. 2008; 56(5):859-64. DOI: 10.1016/j.eururo.2008.07.012. View

TSjoen G, Giagulli V, Delva H, Crabbe P, De Bacquer D, Kaufman J . Comparative assessment in young and elderly men of the gonadotropin response to aromatase inhibition. J Clin Endocrinol Metab. 2005; 90(10):5717-22. DOI: 10.1210/jc.2005-0982. View

Pavlovich C, King P, Goldstein M, Schlegel P . Evidence of a treatable endocrinopathy in infertile men. J Urol. 2001; 165(3):837-41. View

Clark R, Sherins R . Treatment of men with idiopathic oligozoospermic infertility using the aromatase inhibitor, testolactone. Results of a double-blinded, randomized, placebo-controlled trial with crossover. J Androl. 1989; 10(3):240-7. DOI: 10.1002/j.1939-4640.1989.tb00094.x. View

de Ronde W, Hofman A, Pols H, de Jong F . A direct approach to the estimation of the origin of oestrogens and androgens in elderly men by comparison with hormone levels in postmenopausal women. Eur J Endocrinol. 2005; 152(2):261-8. DOI: 10.1530/eje.1.01830. View

van Houwelingen H, Arends L, Stijnen T . Advanced methods in meta-analysis: multivariate approach and meta-regression. Stat Med. 2002; 21(4):589-624. DOI: 10.1002/sim.1040. View

10.

Boivin J, Bunting L, Collins J, Nygren K . International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod. 2007; 22(6):1506-12. DOI: 10.1093/humrep/dem046. View

11.

de Ronde W, de Jong F . Aromatase inhibitors in men: effects and therapeutic options. Reprod Biol Endocrinol. 2011; 9:93. PMC: 3143915. DOI: 10.1186/1477-7827-9-93. View

12.

Ko E, Siddiqi K, Brannigan R, Sabanegh Jr E . Empirical medical therapy for idiopathic male infertility: a survey of the American Urological Association. J Urol. 2012; 187(3):973-8. DOI: 10.1016/j.juro.2011.10.137. View

13.

Kim E, Crosnoe L, Bar-Chama N, Khera M, Lipshultz L . The treatment of hypogonadism in men of reproductive age. Fertil Steril. 2012; 99(3):718-24. DOI: 10.1016/j.fertnstert.2012.10.052. View

14.

Raman J, Schlegel P . Aromatase inhibitors for male infertility. J Urol. 2002; 167(2 Pt 1):624-9. DOI: 10.1016/S0022-5347(01)69099-2. View

15.

Ho C, Tan H . Treatment of the Hypogonadal Infertile Male-A Review. Sex Med Rev. 2013; 1(1):42-49. DOI: 10.1002/smrj.4. View

16.

Hussein A, Ozgok Y, Ross L, Rao P, Niederberger C . Optimization of spermatogenesis-regulating hormones in patients with non-obstructive azoospermia and its impact on sperm retrieval: a multicentre study. BJU Int. 2012; 111(3 Pt B):E110-4. DOI: 10.1111/j.1464-410X.2012.11485.x. View

17.

Geisler J, Haynes B, Anker G, Dowsett M, Lonning P . Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002; 20(3):751-7. DOI: 10.1200/JCO.2002.20.3.751. View

18.

Dias J, Melvin D, Simonsick E, Carlson O, Shardell M, Ferrucci L . Effects of aromatase inhibition vs. testosterone in older men with low testosterone: randomized-controlled trial. Andrology. 2015; 4(1):33-40. PMC: 5836312. DOI: 10.1111/andr.12126. View

19.

Whiting P, Rutjes A, Westwood M, Mallett S, Deeks J, Reitsma J . QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011; 155(8):529-36. DOI: 10.7326/0003-4819-155-8-201110180-00009. View

20.

Raven G, de Jong F, Kaufman J, de Ronde W . In men, peripheral estradiol levels directly reflect the action of estrogens at the hypothalamo-pituitary level to inhibit gonadotropin secretion. J Clin Endocrinol Metab. 2006; 91(9):3324-8. DOI: 10.1210/jc.2006-0462. View