Prolactin is a pleiotrophic hormone that is associated with over 300 biological functions. These functions can be broadly classified into growth and development, immune regulation, metabolism, behaviour and reproduction. The human prolactin gene is located on chromosome 6 and is composed of 6 exons. The gene is approximately 10 kilobases (kb) long whereas the mature prolactin mRNA is about 1 kb in length. Prolactin is encoded by 199 amino acids and the protein is approximately 23 kDa in size. Sequence analysis revealed that prolactin is 40% homologous to growth hormone and placental lactogen. These three proteins are thought to have arisen by duplication of an ancestral gene 400 million years ago. The high sequence homology of these proteins enables prolactin, human growth hormone and placental lactogens to bind the prolactin receptor and activate prolactin intracellular signalling pathways.

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.

Late-onset or nonclassic hyperandrogenic congenital adrenal hyperplasia (CAH) is an attenuated deficiency of 21-hydroxylase, 3β-ol-hydroxysteroid dehydrogenase or 11β-hydroxylase which presents during childhood or adolescence and leads to an increased secretion of adrenal androgens. Many reviews of the genetic or hormonal characteristics of these syndromes have been published, but relatively little attention has been paid to the pathogenesis and treatment of hirsutism which, in most young women, is the main complaint. In fact, it is generally assumed that the hirsutism is strictly related to the increased secretion of adrenal androgens and that glucocorticoids are the treatment of choice. However, some recent studies have shown that the ovary contributes to the hyperandrogenism of these patients and some alternative therapies have been proposed. This forms the matter of the present review.

Whereas the direct action of sex steroids, namely of androgens, on prostate cell division was questioned as early as in the 1970s, and remains so, the interest in prostatic growth factors (GFs) is rather recent but has expanded tremendously in the last five years. This lag period can be partly explained by the fact that, at the time, androgen receptors had just been discovered, and newly developed hormonal regimens or strategies to treat patients with prostate carcinoma (PCa) or epithelioma had generated great enthusiasm and hopes in the medical and scientific community. Another point to consider was the difficulty in maintaining prostate tissues in organ cultures and the relative novelty of culturing prostate epithelial cells in monolayers. Failures of sex steroids to elicit a direct positive response on prostate cell division in vitro, as seen in vivo, were interpreted as resulting from inappropriate models or culture conditions. However, the increasing number of reports confirming the lack of mitogenic activity of sex steroids in vitro, coupled with the powerful mitogenic activity of GFs displayed in other systems, the discovery of GF receptors (GF-Rs), and the elucidation of their signalling pathways showing sex steroid receptors as potential substrates of GF-activated protein kinases gradually led to an increased interest in the putative role of GFs in prostate physiopathology. Of utmost importance was the recognition that hormone refractiveness was responsible for PCa progression, and for the poor outcome of patients with advanced disease under endocrine therapies. This problem remains a major issue and it raises several key questions that need to be solved at the fundamental and clinical levels.

Micromanipulation technology entered the forum of human conception in vitro in the late 1980s. It was erroneously perceived as a new technology – a purely mechanical approach to bypass failures of conception in vitro, the aetiology of which were unknown. In fact, it is the modification of technology developed since the beginning of this century, and its logical utilization for conception in vitro, preconception (polar body) biopsy and preimplantation (blastomere and trophectoderm) biopsy in the realm of human infertility and genetic disorders.

There is now considerable evidence that leucocytes and their products have significant effects on the functional capacity of spermatozoa both in the male and female reproductive tract. Recent advances in the accurate detection of these leucocytes and their products using monoclonal antibodies and a parallel increase in the application of sophisticated sperm function tests has now made it possible to further determine the influence of the leucocytes on sperm function. It is therefore likely that this field of reproductive biology will be an area of considerable activity in the near future.

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.

Advanced female reproductive age is an important factor when evaluating couples for infertility. Infertility is defined as a lack of pregnancy after 12 months of unprotected intercourse, a condition present in about 15% of couples of reproductive age. The proportion of couples considered infertile has not changed recently in spite of an increase in the number of couples seeking infertility evaluation and treatment. Reasons for this phenomenon include the aging of the baby-boom generation, deferment of childbearing to later years of reproductive life (because of changes in lifestyles), and increased exposure of patients to infertility services. More women are delaying childbearing until their late 30's and into their 40's for various reasons, one of them being to develop their professional careers. This voluntary delay in childbearing not only poses a problem in terms of the 30–50% reduced pregnancy potential of older women, but other risks also have to be taken into account: the effect of pregnancy on other maternal illnesses, an increased risk of pre-eclampsia, hypertension and diabetes, and an increased risk of chromosomal abnormalities, abortions, and stillbirth. The decrease of female fecundity beginning in the 30's, becoming more pronounced after 40, is well documented. There is an approximately 50% decrease in the fertility rate of women attempting pregnancy at the age of 40 or older compared with younger women, and a twofold to threefold increase in the rate of spontaneous abortions. Reports of artificial insemination and chromosomal analysis of unfertilized human oocytes and spare embryos in in vitro fertilization (IVF) suggest that the quality of the oocyte and the resulting embryo are affected seriously by age; again, an age of 40 years being the critical cutoff point. On the other hand, age (up to 64 years) does not seem to affect sperm characteristics or its ability to fertilize human eggs, and the resulting embryo development in vitro as well as implantation in recipient uteri are not affected by the age of the male providing the semen sample.

Preimplantation diagnosis of inherited and chromosomal diseases allows couples at risk of conceiving a genetically abnormal fetus to avoid the birth of an affected child without the need for a prenatal diagnosis and selective abortion of an affected fetus. For some couples this may be the only option, because they cannot accept termination of pregnancy as a measure of avoiding the birth of an affected child. Even for those who accept prenatal diagnosis, repeated termination of pregnancy forces them to look for other options to control the outcome of their pregnancies from the very outset. This may be achieved by genetic analysis of oocytes or cleaving embryos, which opens a new prospect for ‘prepregnancy’ genetic diagnosis. As will be shown, such an approach will also be a useful addition to assisted reproduction technologies, at least for in vitro fertilization (IVF) patients of advanced maternal age.

Gonadotropin-releasing hormone (GnRH) is also known as luteinizing hormone-releasing hormone (LHRH), formerly luteinizing hormone releasing factor (LRF). Since this hormone regulates the secretion of both FSH and LH, we prefer to call it GnRH. GnRH antagonists, as the name implies, are a class of compounds that actively compete with GnRH for the GnRH receptor, thereby neutralizing the effects of GnRH by competitive receptor occupancy. In order to fully appreciate their potential clinical utility, it is first important to comprehend the critical role of GnRH in the regulation of the pituitary-gonadal axis and secondly to familiarize ourselves with the mechanisms of action of GnRH, GnRH agonists and GnRH antagonists.

The human endometrium produces a number of proteins which are at least partly specific to that tissue. Two of these proteins have been the subject of much recent work. They were originally called ‘placental protein 12’ and ‘placental protein 14’ (PP12 and PP14) because they were isolated by Hans Bohn from extracts of whole placentae. However, it is now clear that they arise from the maternal endometrium (decidua) rather than the fetal trophoblast. Placental protein 12 has been shown to be identical to the insulin-like growth factor binding protein-1 (IGFBP-1). It is produced in many normal tissues and its measurement probably does not provide a specific index of endometrial function. By contrast, PP14 is detectable only in ‘reproductive’ tissues and, in theory, might be an excellent clinical test of endometrial function.

Embryo cryopreservation is a well established technique and is used widely for embryo banking of genetically valuable strains of mice, the transport and proliferation of farm animals and as a valuable adjunct to human in vitro fertilization (IVF). The range of methods presently used to cryopreserve human embryos has been recently reviewed. This article examines the results obtained by the established freezing techniques and developments in the new rapid cooling methods. There is a dramatic contrast in the simplicity, ease and cost between these new rapid techniques and the conventional slow cooling or equilibrium freezing methods and it is likely that the rapid freezing will replace conventional freezing by slow cooling which is presently in widespread use in IVF clinics.

Experimental animal models have shown that the in vitro embryo culture involved in many treatments for infertility results in a dramatic reduction in embryo viability. Recent advances in methodology such as RT-PCR for localization and quantitation of cytokines and their receptors, are revealing the role that this group of growth factors plays in the basic physiology of embryo development and the process of implantation itself. These studies offer the likelihood of dramatically improving in vitro embryo culture in humans and other species by supplementation of culture medium with growth factors or antagonists to improve embryo viability and hence implantation rates.

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.

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.

A brief look at the history of cytokine research shows that the term ‘lymphokine’ was first described in 1969 as the product of sensitized lymphocytes exposed to specific antigens. To eliminate the incorrect notion that such proteins can be produced only by lymphocytes, Cohen et al. (1974) proposed the term ‘cytokines’ to indicate their production also by nonlymphoid cells.2 After a long-persisting reluctance, it seems that ‘cytokine’ is becoming the prevalent term for these proteins. Meanwhile, a group of participants at the Second International Lymphokine Workshop held in 1979 proposed the term ‘interleukin’ in order to develop, ‘a system of nomenclature based on the protein's ability to act as communication signals between different populations of leukocytes’.3 They introduced the names IL-I and IL-2 for two important cytokines. Since then the number of described interleukins reached 16 and this number may increase. Furthermore, notwithstanding this previous notion, interleukins are now known to be produced in a variety of tissues other than leucocytes and affect the functions of many and diverse somatic cell types (e.g. IL-1 or IL-6). Therefore, while many cytokines are now termed as interleukins, others continue to be known by their old names [e.g. tumour necrosis factor-alpha (TNF-α)], suggesting that they had been recognized earlier, but all of them are included under the generic name of cytokines.

Estrogens are essential regulators of female fertility. Estrogen biosynthesis is dependent upon expression of the cytochrome P450 aromatase, the highest levels of expression of which are detected in the human placenta and the granulosa cells of the mature ovarian follicle. Consistent with this pattern of expression, in non-pregnant premenopausal women, the ovaries have been shown to be the primary source of estradiol. In recent years there has also been an increased interest in the role(s) played by estrogens in regulation of adipose tissue, the vasculature and bone and as paracrine regulators of tissue function in postmenopausal women. In the premenopausal years the uterus is a target for estrogen and the cyclical event of menstruation is a consequence of the sequential exposure of the endometrium to estrogen and progesterone (reviewed in references 5 and 6). Endometrial breakdown occurs as a consequence of progesterone withdrawal with the demise of the corpus luteum (CL) in the absence of pregnancy.

Group B streptococci (GBS), Streptococcus agalactiae, are Gram-positive bacteria occurring in pairs and short chains. S. agalactiae was originally investigated as a frequent cause of bovine mastitis; before the widespread use of penicillin, it accounted for as much as 90% of all bovine mastitis. It was first isolated from parturient women in 1935. Since the 1970s, GBS have emerged as important human pathogens and have remained the major cause of bacterial diseases in newborns in the western world. In 1990, there were approximately 7600 neonatal cases of invasive GBS disease in the USA. Since then, intense intrapartum use of antibiotics has decreased the incidence of neonatal early-onset GBS disease, to 2200 cases in 1998. Babies can be exposed to GBS during labour and delivery, when they swallow or inhale the bacteria while passing through the birth canal of the colonized mothers. Babies can also be exposed in utero. GBS infection in infants causes sepsis and meningitis, which can result not only in illness and death but also in long-term disabilities such as hearing loss, impaired vision, developmental problems and cerebral palsy. The direct costs of neonatal disease alone in the USA have been estimated at 300 million dollars annually. GBS is also an important cause of maternal illness and a risk factor for preterm delivery.

As early as 1500 BC, history records women using a variety of drugs, devices and manoeuvres in an attempt to prevent pregnancy after intercourse has taken place. It was not until the 1960s however that scientific efforts were made to develop effective postcoital contraception (PCC). Whilst it had been known for over thirty years that a variety of compounds would inhibit implantation and embryonic development and interrupt pregnancy in the rabbit and the rat, experiments with primates had been less successful. In 1966 however, Morris and Van Wagenen reported the prevention of pregnancy in 28 macaque monkeys treated with oestradiol, diethylstilboestrol or a synthetic compound (ORF 3858), administered after mating. In the same paper – and confessing that they embarked upon human experimentation ‘with some trepidation’ – the authors reported that 50 mg diethylstilboestrol (DES) given for four to six days appeared to be effective in preventing pregnancy after intercourse had taken place in an undisclosed number of women who were the victims of rape.

In contrast to the classic action of steroid hormones through cytoplasmic/nuclear receptors, there is an accumulating body of data which strongly suggests that they have a direct effect on cells mediated through putative membrane receptors, a so-called non-genomic action. Although such non-genomic effects were discovered 50 years ago it is only in the last 15 years that the subject has become an area of intense research.