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!

The relationship between antiphospholipid antibodies and the clinical features of placental insufficiency, pre-eclampsia, and fetal loss has emerged as one of the most exciting new observations in obstetrics in the last 15 years. Antiphospholipid syndrome is the only convincing ‘immunologic’ disturbance of pregnancy affecting the fetus other than anti-erythrocyte or antiplatelet alloimmunization disorders, and it is now routine to test patients with fetal loss for the two best characterized antiphospholipid antibodies, lupus anticoagulant and anticardiolipin. Although there is no proven mechanism for fetal loss, treatment of antiphospholipid antibody-positive mothers during pregnancy with heparin improves pregnancy outcome.

A growing body of information now supports the theory that oestrogen replacement therapy can substantially eliminate or attenuate the complications incurred as a result of the menopause. In particular, data support the claim that oestrogen replacement therapy for postmenopausal women is associated with the relief of vasomotor symptoms, the prevention of osteoporosis and urogenital atrophy, a lowering of cardiovascular morbidity and mortality, improved cognitive functioning, and a lower incidence of Alzheimer's disease.

Despite intense clinical interest, increasing numbers of infertile couples with endometriosis-associated infertility and ever more sophisticated diagnostic technology, optimal treatment of the infertility remains frustrating. In the absence of mechanical compromise of the pelvic viscera, there is no treatment directed towards the endometriosis itself, medical or surgical, which alleviates the infertility experienced by these couples. The reason for this lack of therapeutic progress is most likely related to the lack of consensus regarding the mechanism(s) by which the endometriosis or its pathophysiology may cause infertility. The possibility that infertility from another, as yet unidentifiable, cause(s) results in repetitive, nonconceptive, ovulatory menstrual cycles and leads to the development of endometriosis remains just as viable a hypothesis. The most useful current therapeutic approach is to consider these couples as having ‘unexplained’ infertility and utilize nonspecific cycle fecundity enhancement such as controlled ovarian hyperstimulation with intrauterine insemination or IVF. Since the fecundity of women with endometriosis in the later reproductive years continues to rapidly decline, this represents their most cost-effective option. While these nonspecific treatments may normalize the cycle fecundity, they are expensive and fraught with the hazards of multiple gestation and ovarian hyperstimulation. While efforts to reduce the risks of this approach are being made, improved therapeutic success with less hazard and cost will continue to remain elusive until the mechanism(s) of the infertility associated with endometriosis is conclusively defined.

In summary, apoptosis is an important concept in understanding many facets of human reproduction. Recent advances in the understanding of molecular mechanisms of apoptosis will allow us to understand this physiologically important process. How can the modulation of this process be applied to human reproduction? Studies to further understand the abnormalities of apoptosis, either too much or too little, may lead to a better understanding of the clinical problems in human reproduction.

We summarize future directions towards further understanding the roles of apoptotic processes in human reproduction in Table 3. The diseases listed in Table 3 are problems which could be approached from the apoptosis point of view. With further study using this concept as the lens, new diagnostic tools or therapies may be developed for these problems.

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.

Approximately one in ten couples experience infertility, and in about 40% of these infertile unions there are abnormalities in the fertility of the male partner. The clinical management of these infertile men is less than satisfactory because in 40% of such patients the cause of the abnormalities of sperm production and quality is unknown. The possibility that genetic disorders may account for a proportion of these disturbances of sperm production has been raised. It is well recognized that chromosomal abnormalities such as Klinefelter's syndrome cause azoospermia and that gene defects are the basis of testicular feminization, Kallman's syndrome and Reifenstein's syndrome. With the explosion in our knowledge of the human genome, the possibility exists that other genetic disorders may form the basis of other sperma-togenic abnormalities. The past decade has witnessed the accumulation of evidence linking abnormalities of the Y chromosome with disturbances in sperm production and these observations form the basis of this review.

Ovarian tissue freezing has been used successfully in animals and it has recently begun to be offered clinically to young women who have medical conditions with a high risk of sterility. Although no frozen human ovarian grafts have yet been returned to the donor and resulted in a pregnancy, there are many indications that this procedure should be feasible. Although live young have been derived from frozen grafts in several species, research should aim to make further improvements to the cryopreservation and grafting procedures to optimize follicle survival, and hence minimize the amount of tissue that needs to be collected, stored and returned. Ovarian tissue freezing, particular if used in combination with egg and embryo freezing, should allow a patient to safeguard their chance of becoming a parent later (Table 1). In cases where the patient has a systemic cancer or infection and malignant cells or viruses may be present in the systemic circulation and the gonadal tissue, ovarian tissue could be collected and frozen, but grafting is not currently recommended (Table 3).

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.

The short-term risks of fertility drug treatment, such as ovarian hyperstimulation syndrome, are well recognised by clinicians providing infertility treatment. There is uncertainty, however, about whether there are any longterm risks such as an increased risk of breast or gynaecological cancer. The possibility of such long-term risks is sometimes a concern for couples who are considering or receiving infertility treatment and their concerns need to be discussed using the best available evidence. The need for appropriate evaluation of long-term health effects of treatment with fertility drugs, including cancer, has been highlighted in major reviews of infertility treatments in Australia and Canada.

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.

Spermatogenesis in mammalian species begins after birth. The gonocytes, arrested at G2 of the cell cycle in the foetus, resume mitotic proliferation after birth. As identified in the mouse, the gonocytes migrate towards the periphery of the seminiferous cords at day 4 to day 6 after birth and are located in close contact with the basal lamina. From this stage the gonocytes are referred to as primitive type A spermatogonia. These cells continue mitotic proliferation and differentiate to form type B spermatogonia. By day 10 after birth, many of the type B spermatogonia have formed preleptotene primary spermatocytes which undergo a final phase of DNA synthesis (leptotene) prior to entering meiotic prophase (zygotene).