Reprod Biol Endocrinol. 2011; 9: 93.
Published online 2011 Jun 21. doi: 10.1186/1477-7827-9-93
PMCID: PMC3143915
Aromatase inhibitors in men: effects and therapeutic options
Willem de Ronde1 and Frank H de Jong 2
Aromatase inhibitors are classified as either steroidal or nonsteroidal, or as first, second or third generation. Steroidal inhibitors such as formestane and exemestane inhibit aromatase activity by mimicking the substrate androstenedione. Nonsteroidal enzyme inhibitors such as anastrozole and letrozole inhibit enzyme activity by binding with the heme iron of the enzyme. First-generation aromatase inhibitors such as aminoglutethimide are relatively weak and nonspecific; they can also block other steroidogenic enzymes necessitating adrenal steroid supplementation. Third-generation inhibitors such as letrozole and anastrozole are potent and do not inhibit related enzymes. They are well tolerated and apart from their effects on estrogen metabolism their use does not appear to be associated with important side effects in postmenopausal women [ 27]. Although aromatase inhibition by anastrozole and letrozole is reported to be close to 100%, administration of these inhibitors to men will not suppress plasma estradiol levels completely. In men third-generation aromatase inhibitors will decrease the mean plasma estradiol/testosterone ratio by 77% [ 28, 29]. This finding probably relates to the high plasma concentrations of testosterone, a major precursor for estradiol synthesis in adult men. As aromatase inhibition is dose dependent it has been suggested that aromatase is less suppressed in the testis compared to adipose and muscle tissue, explaining the incomplete efficacy of aromatase inhibition in men. Aromatase activity is high in the testes and the molar ratio of testosterone to letrozole is much higher in the testes compared with adipose and muscle tissue. When testicular testosterone and estradiol synthesis are suppressed and testosterone is administered exogenously in combination with letrozole, however, the estradiol/testosterone ratio is suppressed by 81% [ 30], which is only marginally different from the suppression of this ratio in intact men after treatment with letrozole. This incomplete suppression may be regarded as advantageous for it prevents excessive reduction of estrogen levels in men and the possible associated adverse effects. In postmenopausal women with breast carcinoma, long-term use of potent aromatase inhibitors reduces circulating estradiol levels by 88% [ 31] and is associated with adverse effects on bone [ 2, 3]. Due to the much higher estrogen levels in treated men it remains to be determined whether this also holds true for men.
Effects of aromatase inhibition on luteinizing hormone release and testosterone productionIt is well known from experimental evidence and from clinical observations that estradiol has powerful effects on gonadotropin release in men. Modulation of plasma estradiol levels within the male physiological range is associated with strong effects on plasma levels of LH through an effect at the level of the pituitary gland [ 32]. Lowering estradiol levels, by administering an aromatase inhibitor, is associated with an increase in levels of LH, follicle-stimulating hormone (FSH) and testosterone [ 28, 29]. Aromatase inhibitors, therefore, have been suggested as a tool to increase testosterone levels in men with low testosterone levels. Due to their mode of action the use of aromatase inhibitors is limited to men with at least some residual function of the hypothalamo-pituitary-gonadal axis. Therefore aromatase inhibitors have been tested in older men suffering from so-called late-onset hypogonadism or partial androgen deficiency. Aging in men is associated with a gradual decline of total and free testosterone levels [ 33] as a result of combined testicular and hypothalamic dysfunction. The decline of testosterone levels has been implicated in the pathogenesis of physical frailty in older men. Androgen treatment, therefore, has been advocated for older men with signs and symptoms of androgen deficiency and unequivocally low plasma testosterone levels [ 34, 35].
Aromatase inhibitors may be an attractive alternative for traditional testosterone substitution in elderly men because these compounds can be administered orally once daily and may result in physiological 24 h testosterone profiles. Additionally, misuse of aromatase inhibitors is unlikely since testosterone levels will not be stimulated to vastly supraphysiological levels. A small, controlled study demonstrated that anastrozole in a dose of 1 mg daily during 12 weeks will result in doubling of the mean bioavailable testosterone level in older men [ 36]. A more recent study also showed a moderate but significant effect of aromatase inhibition on estradiol and testosterone levels in older men [ 37]. Treatment with atamestane 100 mg once daily resulted in a 40% increase in total testosterone levels after 36 weeks. However, no beneficial effects were seen on muscle strength, body composition or quality-of-life scores. A similar increase of testosterone levels in the absence of effects on body composition and strength was reported in a study, in which elderly men with borderline low levels of serum testosterone were treated with anastrozole during 1 year [ 38]. There is a number of possible explanations for the lack of a clear treatment effect. First of all, the numbers of studied subjects were relatively small. Moreover, the mean baseline testosterone levels in the treated groups were in, or only slightly below, the normal range for young adult men and the relative increase in testosterone levels may have been too small. It has been suggested that men with the lowest baseline testosterone levels benefit most from testosterone substitution [ 39]. Finally, the decreased levels of estradiol may have affected the expected rise in lean body mass [ 38]. These observations outline a serious limitation of the use of aromatase inhibitors in older men; the stimulating effect on testosterone levels may be too weak, especially in the men with the lowest baseline testosterone levels who would potentially benefit most.
Effects of aromatase inhibition in obese menPeripheral androgen aromatization is enhanced in subjects with increased body mass index [ 40]. Massively obese men show markedly increased plasma estradiol concentrations and low testosterone concentrations [ 41]. In three small studies, letrozole or testolactone has been administered to morbidly obese men to improve their testosterone levels [ 42- 44]. Treatment resulted in normalization of testosterone levels in all subjects, with a concomitant suppression of the originally increased levels of estradiol. This normalization of the estradiol/testosterone ratio might be of advantage, because of the suppressive effects of testosterone on the expression of the estrogen receptor ß, which in itself, in the presence of high levels of estradiol, can suppress the expression of GLUT-4, leading to insulin insensitivity [ 45]. A case study describes a morbidly obese infertile man, who after a similar treatment with anastrozole showed a normalized pituitary-testis axis, spermatogenesis and fertility [ 46]. However, testosterone levels will also improve on weight loss [ 47], which is the intervention of choice for obese men with or without low testosterone levels. |
