Extensive experience with third-generation aromatase inhibitors in postmenopausal women did not reveal major side effects related to their use. Long-term use in postmenopausal women is associated with a moderate increase in bone resorption and a modest decrease in BMD compared with placebo [
2,
3]. As outlined above, low BMD is a characteristic sign of aromatase deficiency but also in normal men most cross-sectional studies showed that bioavailable or total estradiol levels are associated with BMD [
73‐
77]. The primary concern, therefore, associated with aromatase inhibition in men is the negative effect it may have on bone metabolism. In most studies utilizing aromatase inhibitors in men estradiol levels decreased only moderately. Additionally, the suppression of plasma estradiol levels in men is associated with an increase in gonadotropin levels, which stimulate the production of testosterone, the main precursor for estradiol synthesis. Khosla et al. [
76,
78] proposed a threshold for bioavailable estradiol of 30 pM, below which BMD appeared to be strongly and negatively associated with the plasma bioavailable estradiol concentration in men. Thresholds should be interpreted with great caution because they rely heavily on the methods used to measure total or bioavailable estradiol levels. These authors used ammonium sulfate precipitation to measure bioavailable estradiol levels whereas if they had calculated bioavailable estradiol levels using the popular Sodergard equation [
79,
80] their proposed threshold may have been as high as 75 pM. In experimental settings, selective withdrawal of estradiol in men was associated with an increase in markers of bone resorption [
30,
81]. In the studies published so far aromatase inhibition in men did not appear to be associated with adverse effects on bone in a number of studies [
37,
59,
82,
83], but in a more recent study a decrease of spine BMD was observed after one year of treatment of elderly men with anastrozole [
84]. Additionally, one short-term study did not show adverse effects of aromatase inhibition in older men on cardiovascular markers. However, it is not clear that this conclusion also holds for boys: vertebral deformities were observed in boys treated for delayed onset of puberty [
85]. Furthermore, hyperandrogenism induced by treatment with aromatase inhibitors may result in decreased HDL-cholesterol and increased hemoglobin levels [
86], indicating the need for follow-up during treatment. The same group of investigators concluded that there were no effects of letrozole on cognitive performance could be detected in a group of prepubertal boys [
87]. In a group of elderly men who obtained exogenous testosterone enenthate, the addition of anastrozole to the injected androgen prevented the androgen induced improvement of verbal memory, but did not affect special memory [
88].