Clinical Endocrinology (2003) 58, 529–542 © 2003 Blackwell Publishing Ltd 529 Blackwell Science, Ltd Review The importance of oestrogens in males Willem de Ronde, Huibert A.P. Pols, Johannes P.T.M. van Leeuwen and Frank H. de Jong Department of Internal Medicine, University Hospital Dijkzigt, Rotterdam, the Netherlands (Received 22 November 2001; returned for revision 28 January 2002; finally revised 9 July 2002; accepted 8 August 2002) Introduction For a long time oestrogens in the human male have been regarded as a mere by-product of testosterone synthesis. Only since the descrip- tion of an oestrogen-resistant man (Smith et al., 1994) has it been fully realized that oestrogens play an import role in bone homeostasis, cardiovascular health and pituitary–gonadal interactions in men. Due to a disruptive homozygous oestrogen receptor alpha (ER α ) mutation, this man was virtually insensitive to oestrogens which lead to osteoporosis, unfused epiphyses resulting in linear growth into adulthood, increased gonadotrophin levels and evidence of premature atherosclerosis (Sudhir et al ., 1997a) and endothelial dysfunction (Sudhir et al ., 1997b). Additionally, there was low viability of sperm and glucose intolerance with acanthosis nigrans. Two adult aromatase-deficient men showed, besides undetectable oestrogen levels, low bone mass, unfused epiphyses, increased gonadotrophins and a unfavourable lipid profile (Morishima et al ., 1995; Carani et al ., 1997). Earlier, Korach (1994) described similar observations in ER α knockout mice. Heterozygous mice exhibited no obvious phenotypic abnormal- ities. Homozygous male mice proved to be infertile, showing smaller testes with dysmorphic seminiferous tubules and a sperm count of less than 10% compared to normal mice. Finally, bone mineral density was 20–25% lower in male and female mutants compared to wild-type animals. These reports indicate that oestrogens also play a central role in several metabolic processes in men. The interrelation between testosterone and oestrogen biosynthesis makes it difficult to separate their respective biolog- ical effects. Therefore, it is not unlikely that biological effects formerly attributed to testosterone actually represent effects of oestrogens. In light of the observations in oestrogen-resistant or -deficient males, and because of the wealth of evidence for the role of oestrogens in the (patho)physiology of bone and lipid meta- bolism, cardiovascular disease and the hypothalamo–pituitary– gonadal axis in women, this review will discuss these areas, focusing on the clinical importance of oestrogens in males. Oestrogen synthesis, plasma concentrations and binding proteins Oestradiol is the most potent oestrogen produced in the body. It is synthesized from testosterone or oestrone via the aromatase- or 17 β -hydroxysteroid dehydrogenase (17 β -HSD) enzymes, respectively (Fig. 1). The total oestradiol production rate in the human male has been estimated to be 35 – 45 µ g (0·130 – 0·165 µ mol) per day, of which approximately 15–20% is directly produced by the testes (Baird et al ., 1969a; MacDonald et al ., 1979). Roughly 60% of circulating oestradiol is derived from peri- pheral aromatization of circulating testosterone and 20% is the product of peripheral conversion of oestrone (Baird et al ., 1969a). Oestrone is the product of peripheral aromatization of andros- tenedione which is partly produced by the adrenal glands and partly derived from peripheral conversion of testosterone. Oestrone can also be directly secreted by the adrenals (Baird et al ., 1969b). The testes contribute more to the total amount of circulat- ing oestradiol than the adrenal glands. Therefore suppression of adrenal steroid synthesis using dexamethasone leads to moderately decreased oestradiol levels (Veldhuis et al ., 1992), whereas orchiectomy leads to a more dramatic suppression of plasma oestradiol concentrations (Bartsch et al ., 1977; Moorjani et al ., 1988). Of the circulating oestradiol only 2 – 3% is free, most hormone is bound to albumin or sex hormone binding globulin (SHBG) (Dunn et al ., 1981). Only the nonSHBG-bound fraction is con- sidered to be bioactive. One of the largest studies on peripheral levels of oestradiol in 1640 men aged 38–70 showed a mean total serum oestradiol concentration of 110 ± 54 pmol/l (mean ± SD; Longcope et al ., 1990). These concentrations are comparable to those in women in the early follicular phase of the menstrual cycle. Oestrogen concen- trations in postmenopausal women decrease to levels significantly lower than in men of the same age. The plasma concentrations of testosterone and androstenedione tend to decrease with advancing age in men (Vermeulen, 1991; Simon et al ., 1992; Field et al ., 1994; Ferrini & Barret-Connor, 1998). Oestradiol levels in men decrease mildly after the age of 30 (Simon et al ., 1992), remain constant until the age of 75 (Drafta et al ., 1982; Zumoff et al ., 1982) and decrease significantly after that age (Zumoff et al ., 1982; Ferrini & Barret-Connor, 1998). Circadian variation of oestradiol levels has hardly been investigated but is theoretically likely as levels of both testosterone and androstenedione show a circadian rhythm, being highest early in the morning. Jejuna et al . (1991) found a nadir of serum oestradiol concentrations between 24·00 and 02·00 h, and a zenith between 15·00 and 17·00 h in six Correspondence: W. de Ronde, Department of Internal Medicine, University Hospital Dijkzigt, Dr Molenwaterplein 40, 3015 GD Rotterdam, the Netherlands. E-mail: deronde@inw3.azr.nl