Oestrogen deficiency in men: where are we today?

The precise role of oestrogen in mammals is poorly understood. Actually, the importance of oestrogen for the normal postnatal female physiology is well known, but uncertainty regarding the mechanisms and sites of action in health and disease within a variety of target tissues both in males and females does exist. Oestrogens exert a wide range of biological effects on a large variety of cell types, for example they regulate cell growth and apoptosis, being major regulators of many physiological functions in the adult, especially those associated with reproduction. Furthermore, oestrogens are involved in the organization and differentiation of the developing organism, notably of the endocrine system, nervous system and peripheral reproductive structures. Remarkably, oestrogen receptors (ERs) were found at very early stages of embryonic development and it seemed obvious that oestrogen insensitivity would be a lethal condition as a consequence of the defective implantation of the blastocyst (1). Indeed, until recently no condition of oestrogen insensitivity had been reported, unlike well-documented inactivating mutations of other members of the steroid/ thyroid/retinoid receptor gene superfamily, such as androgen (2), thyroid hormone (3, 4) and glucocorticoid hormone receptors (5). Thus, the general acceptance that oestrogens are essential for life worked until the beginning of this decade, when sporadic cases of congenital oestrogen deficiency in humans were reported (6–11) and a viable line of mutant mice lacking functional ERs was created (12, 13). Since then, the idea of a pivotal role of oestrogen for survival has begun to look thin in the light of these new findings, which undoubtedly raise many questions in turn. Here we will discuss recent breakthroughs in our understanding of the consequences of congenital oestrogen deficiency, which vary widely within the target tissues, from the skeletal to the reproductive tract. In particular, this review addresses many aspects of congenital oestrogen deficiency in the male, including recent developments in molecular studies and treatment options. Until now, two different conditions have been identified as possible underlying causes of congenital oestrogen deficiency in humans: (a) oestrogen resistance caused by disruptive mutations of the ER gene (11); and (b) aromatase deficiency due to mutations of the gene encoding aromatase cytochrome P450 (P450arom) (6–10, 14–17), the enzyme responsible for aromatization of the A ring of androgens to form the A ring characteristic of oestrogens. Whatever the mechanism, all the tissueand organ-specific physiological responses triggered by oestrogens are lacking.