CLINICAL STUDY The effects of the aromatase inhibitor anastrozole on bone metabolism and cardiovascular risk indices in ovariectomized, androgen-treated female-to-male transsexuals Mathijs C M Bunck 1 , Arno W F T Toorians 1,2 , Paul Lips 1 and Louis J G Gooren 1,2 1 Department of Endocrinology and 2 Section of Andrology, VU University Medical Center, PO Box 7057, 1007 MBAmsterdam, The Netherlands (Correspondence should be addressed to L J G Gooren; Email: ljg.gooren@vumc.nl) Abstract Objective: Cases of men with estrogen resistance and aromatase deficiency have highlighted the effects of estrogens on bone metabolism, the cardiovascular system and biochemical variables of the meta- bolic syndrome. In eugonadal men, administration of an aromatase inhibitor induces a substantial elevation of LH and testosterone due to the decreased negative-feedback signal of estrogen and may thwart the interpretation of results. As there is no gonad for LH to act on, no increase of serum testosterone concentration will be seen in female-to-male transssexuals. The aim of this study was to investigate the effects of estrogen deprivation on bone metabolism and vascular par- ameters without the interference of counter-regulatory effects as seen in eugonadal men. Design: Thirty ovariectomized female-to-male transsexuals participated in this double-blind, random- ized trial. During 3 months, subjects received the aromatase inhibitor anastrozole 1 mg/day (n ¼ 16) or a placebo (n ¼ 14) in addition to parenteral testosterone esters (Sustanon 250 every 2 weeks). Results: Serum 17b-estradiol (E 2 ) concentration fell significantly from 134.0^78.8 to 77.7^130.6 pmol/l compared with placebo (P , 0.01). LH and FSH levels rose without the rise of testosterone levels observed in eugonadal men. Within the placebo group, E 2 remained at baseline levels. Of the endpoint variables measured (bone metabolism and vascular parameters) no significant changes were observed compared with placebo, or within the anastrozole-treated group. Conclusions: These results may indicate that the negative effects of estrogen deprivation in men only become manifest when the concentration falls below the levels induced by our intervention with ana- strozole (77 pmol/l). This assumption is supported by the observation in the anastrozole group that, although effects of the reduction of serum E 2 on vascular parameters could not be demonstrated in subjects as a group, there was a correlation between individual serum E 2 and several vascular parameters. European Journal of Endocrinology 154 569–575 Introduction Traditionally conceptualized as ‘female hormones’, estro- gens appear to have significant biological effects in the male. Estrogens have an important effect on the final phases of skeletal maturation and bone mineralization in puberty (1). In addition, from some studies in elderly men it appears that estrogen levels show a higher corre- lation with bone mineral density (BMD) than androgen levels (for review see Riggs et al. (2)) (3–5). Impaired estrogen action in men leads to dyslipide- mia and to impaired flow-mediated vasodilatation (FMD) in peripheral arteries in response to an ischemic stimulus, probably resulting from endothelial dysfunc- tion (6). Evidence suggests that the effects of estrogen on the vascular system are not limited to the classic (slow) genomic pathway of steroid hormone action. Rapid, nitric oxide-mediated, vasodilatory effects occur after binding of circulating estradiol to a cal- cium-dependent cell surface estrogen receptor (7). Estrogen effects on the brain are also increasingly recognized (8). Observation in men with aromatase deficiency show that these men have a complex dysmetabolic syndrome characterized by insulin resistance, diabetes mellitus type 2, acanthosis nigricans, liver steatosis hepatitis, and signs of precocious atherogenesis (9). Men with aromatase deficiency are extremely rare. Only four cases have been reported so far (9). To further explore the role of estrogens in men, studies have been undertaken in eugonadal men in whom the endogenous estrogen production from European Journal of Endocrinology (2006) 154 569–575 ISSN 0804-4643 q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02126 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 05/06/2020 06:09:11AM via free access