Aromatase inhibitors for male infertility

Aromatase inhibitors increase serum testosterone levels and can improve sperm production for infertile men with low serum testosterone and increased testosterone/estradiol ratios.

Peter Schlegel, M.D.

Volume 98, Issue 6, Pages 1359-1362, December 2012


Men with severely defective sperm production commonly have excess aromatase activity, reflected by low serum testosterone and relatively elevated estradiol levels. Aromatase inhibitors can increase endogenous testosterone production and serum testosterone levels. Treatment of infertile males with the aromatase inhibitors testolactone, anastrazole and letrozole has been associated with increased sperm production and return of sperm to the ejaculate in men with non-obstructive azoospermia. Randomized controlled trials are needed to define the magnitude of benefit of aromatase inhibitor treatment for infertile men.

  • Nachum Katlowitz MD

    The recent Article in Press
    The treatment of hypogonadism in men of reproductive age
    by Dr. Kim et al in F&S online yesterday

    states “At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data.”
    Given the above review article and the lack of alternative methods of treatment, as ‘just’ treating the testosterone can result in increased levels of Estradiol, I feel that a better statement might have been “should be used with caution and with a full explanation of the facts to the patient” pending the further accumulation of long term data. The use of the term not recommended can limit the use of such medication in cases where there are no other good alternatives. I would like to hear from others how they treat cases where the abnormality is not a lack of testicular function but hyper conversion.

    • Mark Sigman

      As is true in many areas of medicine, off-label use of medications is often commonly employed for what seem to be logical reasons. The use of aromatase inhibitors for low testosterone or low testosterone to estradiol ratios is not an uncommon approach. As was made clear in the article, while these medications do alter testosterone and estradiol levels -often moving them into the “normal” range – we lack good evidence of their effectiveness for improving spermatogenesis. As has been true with many treatment approaches, just because an approach seems logical does not mean it works. Only quality larger studies will determine effectiveness. While I use clomiphine citrate and aromatase inhibitors in infertile men, I make sure patients understand that these are being used for non-FDA approved indications and discuss the data that we currently have as well as any other alternative management options. My personal approach is to use clomiphene initially if the main problem is low testosterone without a high estradiol. I use an aromatase inhibitor if the initial estradiol level is high or becomes high
      after clomiphene use. That said, these approaches are not routinely used but
      reserved for couples who don’t want to pursue other management options. This
      is perfectly consistent with evidence based medicine which relies on the “best”
      evidence available – as limited as it is – and combines it with the unique
      characteristics of the patient.

      • Nachum Katlowitz MD

        Thank you for saying it more eloquently than I had posted. Again, I feel the term not recommended is a little strong but I would, and I think most would agree, would feel comfortable with the statement ‘not recommended as first line therapy when more evidenced based treatment options are available’.

      • Ajay Nangia

        In response to Dr Katlowitz and the question of aromatase inhibitors, I certainly appreciate the concern that he raises about the “boldness” of the statement in the article by Kim et al. Firstly, I would concur completely with Dr Sigman’s comments about the use of clomiphene and possible addition of an aromatase inhibitor depending on the estradiol level. I think we need to be careful not to mix discussions about the role of these agents in managing
        hypogonadism in the reproductive years as reviewed by Dr Kim et al with the role in managing a spermatogenic problem.

        The issue of hypogonadism in the reproductive years, as discussed by the Kim et al and in the “Reflections” section associated with this article, is becoming a problem and managing the symptoms of men with hypogonadism is “nebulous” with the testosterone levels difficult to correlate with symptoms. However, a recent article in the NEJM showed that testosterone levels did correlate with libido and erectile function (N Engl J Med. 2010 Jul 8;363(2):123-35. Identification of late-onset hypogonadism in middle-aged and elderly men.
        Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT; EMAS Group).

        The data on the testosterone:estradiol ratio in terms of treatment of hypogonadism is very poor to none and as such I support the statement as written by Kim et al. Also we have to be careful with the lack of long term data about bone health and the use of aromatase inhibitors and again another reason to not support the use of aromatase inhibitors for the treatment of hypogonadism.

        In terms of the role of aromatase inhibitors for the treatment of oligospermia etc, there is mixed data as you know with support of the use by Schelgel et al f(J Urol 2002:167; 624-629) or non obstructive azoospermia and oligospermia but also data that shows no benefit (Clark RV, Sherins RJ. J Androl 1989: 10; 240-247).

        There is an excellent review on this by Karen Boyle in the textbook “Infertility
        in the Male” 4th edition, Editors Liphultz, Howards and Niederberger p441, Cambridge Press 2009.

        Ajay Nangia

      • Great points, Mark. I too prescribe anastrozole based on the limited data available with a detailed explanation to the patient that includes off label use. I also prefer as short a course as possible, as it appears that estradiol is the primary player in the endocrine regulation of bone mineralization in men (Khosla S, Melton LJ 3rd, Atkinson EJ, O’Fallon WM. Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men. J Clin Endocrinol Metab. 2001 Aug;86(8):3555-61.) I also refer patients to my blog post on aromatase inhibition at as a supplement to our conversation.

        • Thanks for weighing in Craig. The issue I see from treating the spouses is a big need for couples to fully understand the potential magnitude of the expected benefits. I see at times urologists treating men with clomiphene or aromatase inhibitors when semen parameters are severely abnormal. Especially since its off-label it is vital for couples to understand the expected magnitude of benefit and time to reach it. Most would not want to spend 6+ months on uncertain treatments if sperm is not expected to move into a high enough range for treatment to change. In those cases most I see would chose rapid ART with more certain outcomes. My real issue is when these off-label treatments are offered as definitively beneficial without the physician clearly laying out the % chance of success, time frame, and full alternatives.

  • laurenwroth

    A comprehensive review of medical treatment for male factor infertility. There is obviously a great need for well designed clinical trials testing treatments for male factor infertility.

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