Preliminary study of letrozole use for improving spermatogenesis in non-obstructive azoospermia patients with normal serum FSH

Abstract

We investigated whether letrozole (2.5 mg day 21 ) improves sperm count in non-obstructive azoospermia (NOA) patients. Four men were included in this study, and they had folliculo-stimulating hormone and other hormone levels within the normal range and no varicoceles or chromosomal aberrations. These four patients were administered letrozole for 3 months. Sperm count, testicular volume, gonadotropin, testosterone (T) and estradiol (E2) blood levels were assessed before, during and 1 week after the suspension of treatment. All patients showed spermatozoa in their ejaculate, increased gonadotropin and T levels and lower E2 levels (P,0.05 in all cases), when letrozole was administered. This suggests that letrozole treatment might improve sperm count in an NOA sub-population; however, more studies, including the proper controls, are needed to confirm its efficacy. Asian Journal of Andrology (2011) 13, 895-897; doi:10.1038/aja.2011.44; published online 27 June 2011Keywords: letrozole; medical treatment; non-obstructive azoospermia; spermatogenesis INTRODUCTION Azoospermia indicates the absence of spermatozoa in the ejaculate after two assessments of centrifuged semen. Its prevalence is about 1% in the general population and 10%-15% in infertile couples. 1 Azoospermia is classified as obstructive (OA) or non-obstructive (NOA). NOA is defined by the clinical evidence of strongly affected spermatogenesis, and OA results from a seminal-tract obstruction. Men with OA typically have normal-sized testes, possible epididymal fullness and normal serum follicle-stimulating hormone (FSH) levels. Men with NOA present frequently with small testes and an elevated FSH level; however, a minority of these men have normal testicles and FSH levels within the normal range. 2 Only men with hypogonadotropic-hypogonadism NOA or varicocele-associated NOA may yield spermatozoa in their ejaculate after treatment; however, the majority of men with NOA and normal or elevated FSH levels are only able to father children after surgical retrieval of the spermatozoa from the testicles, which is performed by testicular sperm extraction (TESE) or with fine-needle aspiration (FNA). TESE and FNA yield spermatozoa in 30%-60% of cases depending on the technique used. 1 Patry et al. 3 recently reported one case of hypospermatogenesis (having FSH levels within the normal range), which was converted to active spermatogenesis after letrozole (Femara; Sanofi-Novartis, Paris, France) use. However, the patient remained azoospermic due to an obstruction in the epididymis that was not adequately assessed when surgery was performed. Saylam et al. 4 recently treated 17 NOA patients who had low (,10) testosterone (T)/estradiol (E2) ratios with letrozole. Four of these men showed spermatozoa in their ejaculate after 6 months of therapy.

Multivariate analysis to predict letrozole efficacy in improving sperm count of non-obstructive azoospermic and cryptozoospermic patients: a pilot study

“…Hormonal differences between pre-and postletrozole administration agree with previous literature, which indicated that letrozole increases sperm count by increasing gonadotrophin, T/E2 and testosterone levels. [2][3][4] Because the literature is in agreement with the data presented here, we can confirm that letrozole increased the sperm count in dispermic patients with T/E2 ,10.…”

“…Furthermore, the number of the patients studied is similar or even higher than that reported in previous studies. [2][3][4][5][6] Our data show that BMI and the T/E2 ratio were not strictly equivalent in predicting the results of active drug administration or spermatogenesis impairment, even though BMI is closely associated with the T/E2 ratio and spermatogenesis. 20,21 Interestingly, these data were in agreement with the previous results of Raman and Schlegel, where obese patients did not have a greater benefit of treatment than other patients, even though aromatase from adipose tissue could increase aromatase activity.…”

“…FSH and T strongly increased in all cases. 4 Although all investigators described a sperm count increase after letrozole/anastrozole treatment and similar increases of blood hormone levels, there are strong differences in the sperm count and in side effects between the different studies. These differences may indicate that individual differences in letrozole/anastrozole efficacy might occur, such as when this drug was used to treat breast cancers.…”

“…Blocking of oestrogen production has been shown to provoke increased gonadotropin and androgen levels in the blood and a parallel E2 decrease, resulting in spermatogenesis stimulation. [2][3][4][5] Our team has previously used letrozole; 4 however, a placebo-controlled study examining the efficacy and safety of letrozole is lacking, and it is unknown whether letrozole efficacy might be influenced by clinical spermatogenesis markers such as baseline follicle-stimulating hormone (FSH), testicular volume and body mass index (BMI). The current pilot prospective, double-blind, controlled study tested the hypothesis that letrozole administration to NOA or to cryptozoospermic patients with T/E2,10 could increase their sperm count more significantly than a placebo in relation to baseline FSH, testicular volume and BMI.…”

“…2,3 Non-obstructive azoospermic (NOA) patients with T/E2,10 also had their sperm count increased with letrozole and/or anastrozole treatment. [4][5][6] Letrozole and anastrozole are members of a novel class of non-steroidal, hormone-targeting agents used for breast cancer therapy. They reversibly inhibit the aromatase enzyme, which converts the androgen precursors in adipose tissue to E2.…”