By: Caleb Bowen, DO
Editor’s Note: Our series continues with a summary of research from Iran published in 2019 by Peivandi et al. [1] Dr. Caleb Bowen reviewed the article and wrote this synopsis as a medical student while on the FACTS elective in fertility awareness. The study assessed the impact of letrozole, an aromatase inhibitor, on hormonal patterns as well as sperm quality. The findings offer hope for men with idiopathic infertility.
Introduction
The purpose of this trial was to evaluate a possible solution to male idiopathic infertility. Although this condition has been nearly impossible to treat, a correlation has been established between idiopathic male infertility and the ratio of testosterone to estrogen. This trial attempted to correct male infertility through the use of letrozole, a medication that prevents the conversion of testosterone to estradiol and androstenedione to estrogen. Letrozole is a well-studied inhibitor of aromatase, a key enzyme in these conversions; it is used commonly in women to treat breast cancer, infertility, and other estrogen-dependent conditions.
“A correlation has been established between idiopathic male infertility and the ratio of testosterone to estrogen.”
Methodology
Forty-one men diagnosed with idiopathic infertility were selected to participate in this trial. The men had a pretrial test of FSH, LH, testosterone, and estradiol levels including a calculated ratio of serum testosterone to estradiol. Their sperm was also collected and analyzed for concentration, motility, and morphology. They were then treated with 2.5mg of letrozole daily for 4 months. At the end of the trial, the men’s serum and semen were reanalyzed.
Results
The hormone levels showed an increase in LH, FSH, estradiol, and testosterone. Most important of these changes was the significantly increased testosterone-to-estradiol ratio [(5.89±2.84) to (7.09±2.35)]. On sperm analysis, the concentration and motility, specifically forward movement, were significantly increased, though morphology was only minimally altered.
“The hormone levels showed … a significantly increased testosterone-to-estradiol ratio … (and) on sperm analysis, the concentration and motility, specifically forward movement, were significantly increased.”
Discussion
In general, the research and established treatments for male infertility appear to be sparse compared to those for women, with many of the trials being of poor quality. Furthermore, the number of participants tends to be low, as in this trial. While this study did produce statistically significant results with the administration of letrozole, the low number of participants makes it difficult to adopt this agent as a standard treatment without further research.
This low participation rate aligns with one of the objectives that FACTS About Fertility strives to address: engaging men in the care of their fertility. Low reproductive knowledge and, consequently, low reproductive confidence coupled with social pressures cause many men to fear infertility assessments. Interestingly, in Iran, letrozole is already being used in routine practice. While most care focuses on female fertility, men may benefit from more education as well, even if only to gain the confidence to seek assessment and treatment for themselves. While the sample size of this trial was small, the results are significant enough to warrant discussion, and make a strong argument for future research and clinical experimentation of male fertility, overall health, and treatment.
Prior studies have provided evidence of an unidentified male endocrine disorder similar to the estrogen-dependent conditions seen in women. This would provide a good case for the use of aromatase inhibitors as a potential solution. The first- and second-generation aromatase inhibitors have been tested in clinical trials for male infertility but showed poor results. While hormone profiles did improve in the men in these trials, the seminal analyses showed no improvement. Unfortunately, sixteen months following these trials of first- and second-generation aromatase inhibitors, no participants had succeeded in conception.
With the advent of the third generation of aromatase inhibitors, many opportunities returned. The third-generation drugs, namely letrozole, are up to twenty times more potent. Given its selectivity, letrozole is a thousand times more effective than previous medications. Additionally, it does not affect glucocorticoids, mineralocorticoids, or thyroxine, while previous generations did. The increased sperm motility and forward movement in patients treated with letrozole is the most promising aspect of this trial, as this had not been seen previously.
“The increased sperm motility and forward movement in patients treated with letrozole is the most promising aspect of this trial.”
While this trial did show statistically significant numerical improvements despite the low sample size, the conclusion was unsatisfying. The purpose of this treatment was to improve the likelihood of conception for couples when the man has idiopathic infertility. The author’s conclusion is that letrozole should be an effective treatment for men with infertility due to a low testosterone-to-estradiol ratio. However, there are no follow-up results as to whether the treatments led to any of the men being able to conceive healthy children.
Due to the success of this treatment, at least according to lab results, the study deserves to be repeated with a larger sample. Furthermore, the follow-up period should be long enough to assess the effect on conception, healthy childbirth, as well as potential side effects or adverse events.
References
[1] Peivandi S, Jafarpour H, Abbaspour M, Ebadi A. Effect of letrozole on spermogram parameters and hormonal profile in infertile men: A clinical trial study. Endocr Regul. 2019 Oct 1;53(4):231-236. doi: 10.2478/enr-2019-0023. PMID: 31734656
ABOUT THE AUTHOR
Caleb Bowen, DO
Caleb Bowen, DO earned his medical degree at Kentucky College of Osteopathic Medicine in Pikeville, KY. He completed his undergraduate training at Mississippi State University. Dr. Bowen is a family medicine resident in Gulfport, MS. He enrolled in the FACTS elective to learn more about the various methods of natural family planning and ways to teach future patients how to use them.
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