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.

Embryonic stem (ES) cells are a primitive cell type derived from the inner cell mass (ICM) of the developing embryo. When cultured for extended periods, ES cells maintain a high telomerase activity, normal karyotype and the pluripotential developmental capacity of their ICM derivatives. Such capacity is best demonstrated by mouse ES cells which can contribute to all tissues of the developing embryo following either their injection into host blastocysts or tetraploid embryo complimentation (for a review see Robertson). For both practical and ethical reasons it is not possible to inject human ES cells into blastocysts for the development of a term fetus. However, when injected beneath the testicular capsule of severe combined immunodeficient (SCID) mice, human ES cells form teratomas comprising tissue representatives of all three embryonic germ layers (ectoderm, mesoderm and endoderm) thus attesting to their pluripotency. Based upon morphological criteria, neuronal, cardiac, bone, squamous epithelium, skeletal muscle, gut and respiratory epithelia are readily identifiable within the human ES-cell-derived teratomas. With the demonstrated capability to isolate and maintain pluripotent human ES cells in vitro, their ability to give rise to tissue representatives of all three embryonic germ layers and the technical advances made possible by research on mouse ES cells, a rapid increase in human ES cell research aimed at drug discovery and human cell and gene therapies has occurred. Indeed in the mouse, dissociated embryoid bodies (EBs) have already been demonstrated capable of repopulating the haematopoietic system of recipient animals (for a review see Keller) and mouse ES cells are currently being used in attempts to repair mouse neural degenerative lesions.

To prepare for the presence of a fetus, the uterus undergoes a critical process termed decidualisation that, in mice and probably humans, is required for reproductive success. This process involves phenotypic changes in uterine stromal cells that enable them to support implantation and placental development. Accompanying this transformation is the recruitment of a specialised population of maternal immune cells. These cells, termed decidual leukocytes, are a significant presence, composing up to 70% of cells in the uterus throughout early pregnancy. At first glance, the recruitment of immune cells to the site of implantation seems at odds with maternal tolerance. However, the unique characteristics of decidual leukocytes, particularly with regard to their abundance and distinct composition, suggest that they participate in protecting fetal tissues from immune attack. Thus, the mechanisms that recruit decidual leukocytes to the uterine wall provide an important component to successful pregnancy.

Malignant tumours of the female reproductive tract in childhood and adolescence are rare. The comparative frequencies of tumours in adults and children may be related to the relative accumulation of exposure to environmental factors. An example might be the relationship between exposure to human papillomavirus and the development of vulval, vaginal and cervical cancers. Some cancers in childhood are associated with factors specific to the time of life. Examples include in-utero stilboestrol exposure related to clear cell carcinoma and teenage pregnancy associated with gestational trophoblastic tumours. In childhood and adolescence, 67% of all ovarian tumours are germ cell in origin. This differs significantly to the distribution of ovarian tumours in adults.

Ovulation is the result of an integrated action of the hypothalamus, pituitary and ovaries. During the process, gonadal steroids, peptides and growth factors are produced and influence the synthesis and release of gonadotropin-releasing hormone (GnRH), follicle stimulating hormone (FSH) and luteinizing hormone (LH). These latter compounds play a crucial role in folliculogenesis and are frequently used in the management of infertility.

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.

According to Webster's Universal College Dictionary (Random House, 1997), normal means “conforming to the standard or the common type; usual regular, natural; free of any mental disorder; sane; free from disease or malformation”. On the basis of these various definitions, the answer to the question posed in the title of this review should be an unequivocal “no”. Incessant menstruation for years on end as it occurs today is certainly not natural, nor is it free of any mental disorder or free from disease. In fact, it conforms to no standard and it may cause serious dysphoric disorders and several diseases, of which anaemia and endometriosis are outstanding examples.

Fertility-promoting procedures are among the most frequently performed laparoscopic procedures. Some of the procedures have a relatively long history, with good documentation of technique, efficacy and effectiveness. On the other hand, many are experimental, in development or relatively new and lacking supportive clinical data.

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.

Human endometrium is composed of three layers: stratum compactum, stratum spongiosum and stratum basale. Stratum compactum is the superficial layer made up of openings of the uterine glands and some stromal cells. Stratum spongiosum is the middle layer containing mainly dilated glands and little stroma. Stratum basale is the deepest layer adjoining the muscularis. It consists of primordial glands and compact stroma. Stratum compactum and stratum spongiosum form stratum functionale which is subject to cyclic changes and is removed during menstruation.

Ovarian cancer is the commonest cause of death from gynaecological malignancy in the Western world. About 5000 new cases of this cancer are diagnosed each year in England and Wales (5% of all cancers), and it is the fourth commonest cancer in all women up to 85 years (after cancers of the breast, lung and large bowel). The life-time risk of developing ovarian cancer, in England and Wales, is 1 in 56, or 1.8% by the age of 85. Ovarian cancer incidence in England and Wales has increased gradually in the last two decades. Mortality rates are only slightly lower than the incidence rates – a reflection of its poor prognosis. In England and Wales, only 29% of women with the malignancy survive as long as five years after diagnosis although younger women do survive longer: 69% of those who are under 40 years old at diagnosis survive for five years compared to less than 20% for those aged 70 or more. Because of its high incidence and poor prognosis, ovarian cancer also represents the fourth most common cause of death from cancer among women in England and Wales, accounting for about 3600 deaths per year (7% of all cancer deaths).

Since the discovery of the structure and function of steroids over 60 years ago, it has long been recognized that synthetic antagonists of the natural hormones would have potential therapeutic uses. Antagonists of mineralocorticoids, androgens and oestrogens, for example spironolactine, cyproterone, flutamide and tamoxifen, have already found a place in the management of hormone dependent conditions. In 1982, chemists at Roussel UCLAF announced that they had synthesized mifepristone (RU486) 17β-hydroxy-11(p-(dimethylamino)phenyl)-17-(1-propynyl) estra-411, 9-dien-3-one) a derivative of norethindrone which had potent antiprogestogenic as well as antiglucocorticoid activity. Although it was immediately realised that this compound would potentially have wide clinical application, its development in the last 10 years has been dominated by its abortifacient action. In the original clinical report by Herrman and colleagues it was shown that bleeding occurred when it was given to female volunteers in the second half of the menstrual cycle. In addition, complete abortion occurred in eight of 11 women who took the drug in the early weeks of pregnancy. These findings, which demonstrated that mifepristone could be used as the basis of a medical method of inducing abortion, were immediately made the focus of groups opposed to abortion on moral grounds. Experience over the last 10 years has confirmed the promise of these early studies and mifepristone, in combination with a suitable prostaglandin, is now licensed in France, UK and Sweden for use as a medical method of inducing abortion in early pregnancy.

It is estimated that 50–80% of menstruating women experience some degree of physical and psychological premenstrual symptomatology and that 3–5% have symptoms of sufficient severity to disrupt social or psychological functioning. The diagnosis of clinically significant premenstrual syndrome (PMS) is applicable when at least one moderate to severe physical and psychological symptom occurs for up to two weeks prior to menses with remission by the end of the menstrual flow. Symptoms should cause functional impairment and must be documented prospectively for at least two consecutive menstrual cycles. Table 1 lists the American College of Obstetrics and Gynecology (ACOG) criteria set for the diagnosis of PMS.

Approximately 25% to 35% of couples that seek infertility services suffer from defects in ovulation.This diagnosis represents the single leading cause of infertility disorders, and makes medical ovulation induction the most common intervention for the treatment of infertility. There are two classes of correctable ovulation defects, and correct classification is correlated with treatment and prognosis. World Health Organization (WHO) I patients have ovulation defects associated with low estrogen and low gonadotropin levels and fail to exhibit withdrawal bleeding after progestin challenge. WHO II ovulation disorders occur in estrogenized/androgenized women who, in general, menstruate. Other names for these conditions include hypogonadotropic hypogonadism (WHO I) and polycystic ovarian disease (WHO II).

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.

Approximately 30–40% of couples seeking fertility treatments have male factor infertility. Their dysfunctions include azoospermia, oligozoospermia, asthenozoospermia and teratozoospermia. Those with azoospermia represent about 25% of the total, and of these about 30% have an obstructive process while the remaining have either primary or secondary testicular failure. In the obstructive azoospermia group, 25% of males have congenital bilateral absence of the vas deferens (CBAVD).

Hysteroscopy was first reported by Pantaleoni in 1869. He used a 12 mm diameter straight tube that was inserted into the uterine cavity with a concave mirror to reflect light into the uterus. Today, there are two main types of endoscopes in use: (1) the rigid endoscopie panoramic hysteroscope and (2) the flexible hysteroscope.

There has been an increase in the incidence of ectopic pregnancy to epidemic proportions in many developed countries in the past two decades. In 1989, ectopic pregnancy accounted for 1.6% of all pregnancies in the United States of America. This trend may be explained by an increase in the incidence of established risk factors as well as a dramatic improvement in diagnostic tools and advances in reproductive technology. Technologic advances such as highly sensitive radioimmunoassays for the β-subunit of human chorionic gonadotropin (βhCG), the development of high-resolution ultrasound and a heightened physician awareness have revolutionized the clinical management of ectopic pregnancy, leading to earlier and more consistent diagnoses and consequently reduced maternal mortality rates. 1,3–13 Unfortunately, ectopic pregnancy is still associated with a significant morbidity and mortality and contributes substantially to health-care costs. For example ectopic pregnancy complications accounted for 13% of all pregnancy-related deaths and were the leading cause of maternal mortality in African- American women in 1989. Financially, an estimated 1.1 billion dollars was spent in the United States of America alone for the management of ectopic pregnancy in 1990.

With hysteroscopic surgery, specific endoscopic approaches can be applied in selected cases avoiding the need for classical open surgery or even hysterectomy. The development of these surgical procedures has resulted in an increasing interest in the use of diagnostic hysteroscopy in order to identify that intrauterine pathology which is suitable for endoscopic treatment.

Ovarian folliculogenesis is an exponential process marked by dramatic proliferation and differentiation of the somatic and germ cell elements of the follicle. Although the central roles of gonadotropins and of gonadal steroids in this explosive agenda are well accepted, the variable fate of follicles afforded comparable gonadotropic stimulation suggests the existence of additional intraovarian modulatory systems. Accordingly, consideration must be given to another set (or sets) of regulatory principles that may provide these missing modulatory loops. The work of multiple contributors favors the hypothesis that these modulatory loops are comprised of a host of peptidergic principles which engage in situ in the modulation of ovarian growth and function. In its capacity as an intraovarian regulator, a given agent may be acting independently of, as an amplifier of, as an attenuator of, or even as a mediator of, gonadotropin action. Together, gonadotropins, steroids, and locally derived peptidergic principles form a triad that modulates the growth and differentiation of ovarian follicles (Figure 1).