Metabolic abnormalities in patients with PCO syndrome demand that we change our clinical approach to PCO syndrome. No longer should the approach be short-term and driven by symptoms, rather it must recognize that PCO syndrome is a chronic disorder. Associated metabolic abnormalities may have long-term sequelae and their recognition influences not only how we evaluate patients, but also how we implement prevention. Observational, interventional, epidemiological and now mechanistic studies need to focus on interactive issues. Outcome study results are awaited to determine the likelihood of sequelae and to optimize preventive strategies. The PCO paradigm is a complex biological experiment on nature that offers a superb opportunity to begin to understand the many ways in which hormones affect atherogenesis. It is important to understand the clinical syndromes encompassed in this paradigm. Atherogenic consequences are still responsible for the majority of deaths in the industrialized world!

It has been estimated that 500 million couples world-wide have no access to contraception and that approximately 20% of births between 1995 and 2000 will be unwanted. Such statistics have important implications for the rate of world population growth and the possibility of maintaining a sustainable population. Although political change and the empowerment of women across the world will help address these issues, it will also be important to increase the availability of contraceptives; not only the modalities that are in current use, but also novel methods that will satisfy needs that are presently unfulfilled. One such alternative could be a vaccine targeting the human spermatozoon.

The disciplines of reproduction and immunology, once quite discrete, are now closely associated, with compelling evidence to suggest that immune mechanisms play important roles in the cervix, uterus, fallopian tubes and ovary. Cells and mediators classically described as part of the immune system are found throughout the reproductive tract. Disorders of reproduction, including pre-eclampsia, unexplained infertility, endometriosis, recurrent miscarriage and disturbed fetal growth almost certainly have some of their origins in the dysfunction of immune regulation. There appears to be some evidence that immune disorders, such as rheumatoid arthritis and scleroderma, can manifest as infertility, before clinical disease becomes apparent.

Idiopathic male infertility has previously been diagnosed imprecisely, and has been treated using regimes that are not based on a clear understanding of the underlying pathophysiology; however, this is gradually changing, and a more rational approach is being adopted. Testosterone and its metabolite, DHT, is allimportant for the maintenance of sperm production and this has led us to examine the AR for causes of male infertility. Some, but not all, androgen-binding studies have indicated that in a certain proportion of cases of male infertility, defective androgen binding occurs. The cloning of the AR gene allowed for a more rigorous examination of the molecular pathogenesis which turned out to be both subtle and heterogeneous. Genetic screening of a large group of men with defective spermatogenesis has indicated that up to 30% of infertile males could have variations in the androgenicity of their AR caused by polymorphisms in the length of the polyglutamine tract. Substitutions of the AR in the LBD and the DBD can also lead to reduced AR function and male infertility. In this regard, it is interesting to note that depressed spermatogenesis and prostate cancer represent opposite ends of the spectrum of AR action (Figure 6). Although empirical treatment of AR mutants in some cases has been shown to restore normal AR function and to improve spermatogenesis, a fully rational basis of treatment has to be based on an understanding of the crystallographic structure of the AR LBD. A full understanding could lead to the construction and the administration of ‘designer’ androgen analogues to treat male infertility caused by mutations of the AR gene.