Two-cell, two-gonadotrophin interactions within the ovarian follicle involve stimulating theca cells with luteinizing hormone (LH) to produce androgens which enter granulosa cells where, under the influence of follicle stimulating hormone (FSH), they are aromatized to estradiol. In nonprimate species, autocrine and paracrine functions for estradiol within the follicle have been shown to mediate the trophic effects of FSH on granulosa cells resulting in proliferation, increased expression of FSH receptors, antrum formation, induction of LH receptors, and inhibition of apoptosis. The axiom that estradiol is particularly necessary for follicular growth and maturation has been routinely adopted and perpetuated for decades in discussions on the regulation of follicular function in primates. Focus on the level of estradiol in follicular fluid as an index of follicle, and hence oocyte, quality by many investigators yielded conflicting results. Nonetheless, development of ovarian stimulation protocols that employ exogenous administration of both FSH and LH for the treatment of infertility in women rely on the correlation between the growth of multiple follicles and increasing serum levels of estradiol to predict a successful outcome. Initial reports of rare conditions causing defects in follicular estradiol biosynthesis, such as with P450-17αhydroxylase/17,20 lyase deficiency, associated the disruption of follicular development with estradiol deprivation. However, the elevated levels of gonadotrophins also observed in these patients rather than the absence of intrafollicular estradiol may have led to the dysregulation of folliculogenesis. Evidence to counter the notion that follicles can only grow in an estradiol-replete environment was provided by studies of women with hypogonadal hypogonadism and of medically hypophysectomized macaques, wherein low levels of estradiol were accompanied by induction of multiple preovulatory follicles upon treatment with urinary preparations of FSH alone. Unfortunately, there are no data available from these studies on oocyte performance under conditions of low estradiol resulting from steroidogenic enzyme deficiencies or hypogonadal hypogonadism. Recent studies of steroid-depleted as well as hypogonadal women and macaques reinvestigated the hypothesis that estradiol plays a pivotal role in folliculo- and gametogenesis in primates and are discussed below.

Reproductive and developmental toxicology has existed, in some form, at least since the Middle Ages when women commonly used naturally derived abortifacients for birth control. Percival Pott was the first to observe that environmental exposures could detrimentally affect the male reproductive system. He noticed that chimney sweeps exposed to soot developed testicular cancer and infertility at unusually young ages. The formal investigation of male-mediated effects on offspring (germline mutagenesis) began with the pioneering studies of Muller, Hertwig, Snell, Brenneke, and others, who established X-rays as the first identified agent capable of inducing hereditary changes in mice. They showed that litters sired by irradiated males contained fewer pups than controls. Because sperm motility and density were not affected, but chromosome abnormalities were found in fertilized eggs, they concluded that irradiated sperm were the source of the abnormal chromosomes. Since that discovery, the mutagenic effects of radiation on the male germline have been studied extensively (see below). Later, Auerbach & Robson and Bock & Jackson were the first to demonstrate that exposing mice to chemicals decreases their fertility and induces chromosomal abnormalities and other mutations in the male germline. The subsequent five decades of work on chemical mutagens has resulted in a detailed biochemical and genetic characterization of chemical mutagenesis in the male germline and male-mediated developmental problems in laboratory animals (see below).

Female infertility results from a myriad of causes – genetic and nongenetic. Sometimes a genetic aetiology is clearly evident. In other disorders heritable tendencies exist, but the precise genetic aetiology remains obscure. In this communication we shall consider the genetics of selected common causes of female infertility: premature ovarian failure; leiomyomata; polycystic ovarian disease; endometriosis. Not discussed here are disorders of gonadal differentiation primarily causing gonadal failure and disorders of female internal ducts, both considered elsewhere by the author and colleagues. The current contribution inevitably mirrors these other publications.

The ejaculate is analyzed in the clinic primarily to obtain an estimation of sperm number, motion characteristics and cell morphology. Based on these data, conclusions are formulated as to the overall ‘fertility’ of the male. A major problem has been that the conclusions derived are often not (well) correlated with expected outcome, i.e., fertility. As a consequence, adjunct tests, e.g., sperm function tests, have been developed in an effort to uncover those defects/assets not revealed when measuring standard semen parameters. While some of these tests, e.g., hemizona assay, have helped to shed light on dysfunctional processes associated with fertilization, e.g., zona binding and penetration, individually they do not totally suffice for identifying fertile (defined as being capable of producing offspring) males.

Polycystic ovary syndrome (PCOS) is usually defined clinically by hyperandrogenism and anovulation. Hyperinsulinaemia and insulin resistance are prominent features both in obese and nonobese women with PCOS, the latter having been shown to be more insulin resistant and hyperinsulinaemic than age- and weight-matched normal women. There is now a substantial body of evidence implicating hyperinsulinaemia in the pathogenesis of this disorder.

Female-dependent methods of contraception have been the subject of considerable scientific advance since the introduction of the combined contraceptive pill, offering effective and male-independent contraception, but there is an emerging emphasis that men should be more involved in family planning. The supremacy of modern, female methods in the developed world obscures the fact that one-third of all couples worldwide rely on a male-dependent method of contraception, mostly the condom or withdrawal, methods that have been used since antiquity. Potential methods of male contraception include withdrawal of the gonadotrophic support to the testis, interference with spermatogenesis within the seminiferous tubules, or with post-testicular functions. Effects on maturation within the epididymis can be induced by chloro-6-deoxy sugars or plant-derived glycosides. Although advances in assisted conception, particularly associated with intracytoplasmic sperm injection (ICSI), have demonstrated the functional competence of the nucleus and centriole of testicular spermatozoa and other less mature forms, it has been suggested that normal passage through the male reproductive tract is necessary for conventional conception. Advances in both testicular and post-testicular methods of contraception have been hampered by toxicity and remain in preclinical testing, reflecting the limited extent of (and thus the need for) scientific knowledge in this area. While progress in these areas is fully acknowledged, the pretesticular hormonal approach is currently at a considerably more advanced stage of development with prospects for a real product becoming increasingly likely on a realistic time-scale. This review will therefore confine itself to this, the hormonal approach.

The menstrual cycle of the adult woman depends on the regulatory function of the hypothalamo–pituitary–gonadal axis. Hypothalamic luteinizing hormone releasing hormone (LHRH) plays the central regulatory role in this control. As early as 1932 the German scientists Hohlweg and Junkmann postulated an active sexuality centre, placed over the pituitary gland, as the organ with direct stimulatory effect on the ovaries. It was shown that the stimulatory activity of the pituitary gland depends on hypothalamic function, revealing a neural control mechanism. LHRH is a peptide composed of ten amino acids, first isolated and characterized in 1971. LHRH is secreted by neural cells of the nucleus arcuatus in the mediobasal portion of the hypothalamus. The axons of these neurones are in intimate contact with the vessels of the hypothalamo–pituitary portal system. The pulsatile release of LHRH by the hypothalamic neurones causes the gonadotrophic cells of the pituitary gland, which make up about 10% of the gland's cell mass, to release follicle stimulating hormone (FSH) and luteinizing hormone (LH), also in pulsatile fashion. FSH and LH in turn control follicular maturation and gonadal sex steroid biosynthesis. Circulating LHRH is extremely short-lived, with a plasma half-life of two to five minutes, due to rapid enzymatic degradation by peptidases which preferentially interact with the peptide bonds in position six of the molecule. This short half-life ensures that hypothalamic pulses of LHRH are recognized as single events by pituitary receptors. Conversely, continuous administration of LHRH causes a decrease of LHRH receptor density on the gonadotrophic cells of the pituitary gland, reduced LH and FSH levels, and arrest of follicular maturation and sex steroid biosynthesis. The elucidation of neuroendocrine control of the menstrual cycle in adult women based on these findings is one of the most important observations in reproductive medicine during the last three decades, and has had a major clinical impact on the treatment of hormonal disorders in gynaecology and paediatrics, infertility treatment and oncology.

The original title that I was given when asked to write this article was “Recent advances in endometrial resection”. Whilst there have been a number of recent important publications regarding the results and place of endometrial resection, there have been no advances in the technique itself. There have however been a number of recent advances in other methods of endometrial ablation. I therefore changed the title so as to encompass all the advances in this area and I use the term endometrial ablation to cover all methods of resecting or destroying the endometrium.

Over the past ten years mortality for breast cancer in the UK has been falling. The decrement has been more substantial in the 20 to 69 age group, which has seen a 22% decrease, while in the 70 to 79 age group the decrease has been milder at 12%. The incidence of the disease, however, is increasing and many women have a relative or friend with a disease that they perceive to be extremely mutilating. Fear of breast cancer is such among women that it is mistakenly viewed as the most common cause of death in females. Postmenopausal hormone replacement therapy (HRT) has many benefits and is particularly effective in the prevention of osteoporosis. But, to obtain this effect, HRT has to be continued for many years and long-term treatment has been shown to slightly increase the risk of breast cancer. This fact forcefully stimulated the imagination of both press and public alike.

Over the last fifty years the understanding of a number of symptomatic gynaecological conditions has crystallized to the point where a coherent framework of pathogenesis and a systematic approach to treatment can be discerned. Examples are endometriosis, menorrhagia, premenstrual syndrome and the symptoms associated with the climacteric. Chronic pelvic pain is only now reaching the stage of similar systematization, and it is interesting to speculate why this has taken so long. Two factors can perhaps be cited as relevant: in the conditions listed above, either reasonably plausible models for causation based on visible pathology have been available, as with endometriosis, or effective treatments have been readily available, for example hormone replacement therapy (HRT) for estrogen deficiency symptoms. In the case of pelvic pain, models of causation have often been speculative rather than based on research, and simple effective treatments have proved elusive. In this review current concepts of pain physiology and therapy are discussed with a view to placing in perspective the clinical problem of pelvic pain. The condition is best seen from a bio-psycho-social perspective but the main focus of the present review is the neurobiological aspect.

Diabetes mellitus is the most common chronic disease in the industrialized world. In North America and Europe the prevalence in adults is 7–8% and it is estimated that there are more than 100 million cases worldwide. With the increasing prevalence of non-insulin-dependent diabetes mellitus (NIDDM) this figure continues to rise. The World Health Organization predicts that the number of patients with diabetes will rise from 130 million to over 300 million over the next 25 years. Diabetes affects 1 in 30 people living in England and Wales and accounts for more than £2 billion of hospital costs annually. The number of diabetic patients in the UK is predicted to double to 3 million by the year 2010.

The endometrium undergoes cyclical changes under the influence of ovarian steroids, resulting in a tissue receptive to embryo implantation. These changes involve complex interactions between stromal cells, overlying epithelium, blood vessels and the embryo itself. For many women endometrial dysfunction is the source of considerable ill health, causing menstrual problems, pain and infertility. As the use of fertility control has become more widespread across the world, regular menstruation is the norm and abnormalities of menstruation have increased in consequence. Hormone treatments have had limited success in treating these longstanding problems, and new approaches to modulating endometrial functions such as menstruation and implantation (including contraceptives) are needed.

The transfer of a blastocyst established the first human clinical pregnancy following in vitro fertilization (IVF). Nine years later Cohen et al. reported pregnancies resulting from the transfer of cryopreserved human blastocysts. However, it was another six years before the first report of births resulting from the transfer of human blastocysts produced in vitro appeared in the medical literature. In the intervening period clinics have opted to transfer embryos at the early cleavage stage to the uterus, despite the fact that in vivo the embryo does not enter the uterus until two to three days later at the morula to blastocyst stage of development. The viability and potential for implantation of blastocysts is high, as indicated by the finding that more than 60% of in-vivo-derived blastocysts, recovered by uterine lavage following artificial insemination of fertile donors, implant and develop into viable fetuses when transferred to recipients. This is in stark contrast to the 10–20% of in-vitro-produced embryos transferred at the early cleavage stage of development that result in a live-birth. This reduction in viability following transfer of in-vitro-derived early cleavage stage embryos may have several possible explanations: (1) a failure of implantation due to poor synchronization between the embryo and the uterine endometrium; (2) a hostile environment in the uterus for early cleavage stage embryos; (3) sub-optimal in vitro culture conditions which result in a reduction in embryo viability; (4) the assumption that all oocytes retrieved in an IVF cycle have an equal ability to develop into viable embryos; and (5) the failure to identify the most viable embryo in a cohort. Certainly, improving culture conditions and laboratory techniques for developing high quality blastocysts routinely in vitro will not only address many of the above questions but will also improve the quality and viability of earlier stages of embryo development.

Since the introduction of more complex and invasive forms of assisted reproductive technologies (ART), there has been much speculation as to whether the genetic integrity of the offspring can be maintained. For example, Y microdeletions and cystic fibrosis mutations can be transmitted to the offspring following intracytoplasmic sperm injection (ICSI), as can karyotype disorders. Furthermore, speculation has arisen over the transmission of mitochondrial DNA (mtDNA) to offspring and whether maternal inheritance patterns are maintained.

The inter-relationship between the pituitary and the gonad has long appeared too complex to be regulated solely through the mediation of the two pituitary gonadotrophins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Within the last decade, discoveries of additional regulatory mechanisms involved in the neuroendocrine control of the testis and ovary have provided new insight into the control of this sophisticated biological phenomenon. The possible contribution of inhibins and activins to the hypothalamo–pituitary–gonadal axis, and their role as paracrine regulators in the testis and ovary have received increasing attention over the years following their isolation and sequencing. This review will assess current knowledge concerning the endocrine and paracrine actions of inhibins and activins in the reproductive biology of the male, with particular attention being paid to possible cross-species differences in function.