The present review demonstrates that the availability of bioactive FSH and LH in PCOS is normal and that granulosa cells of PCO are not apoptotic and instead hyperexpress functional FSH receptors and may possess intact aromatase activity. Consequently, these cells respond excessively to exogenous FSH stimulation and produce high amounts of oestradiol both in vivo and in vitro. The altered developmental capacity of follicles from PCO in vivo is most likely due to the abnormal follicular milieu of PCO and the culminating effects of intrafollicular inhibitors and stimulators. The failure of ovarian oestradiol production and follicular maturation to dominance in vivo may be due to a mechanism that interferes with the function of FSH, such as intraovarian steroids and growth factors. It has previously been shown that EGF and TGFα have inhibitory actions on follicular development, aromatization and LH receptor formation. In contrast, EGF enhances early follicular recruitment and growth. Therefore, it is hypothesized that EGF/TGFα may have a causal relationship in the mechanisms of anovulatory infertility in women with PCOS. Thus, an aberration in the regulation of follicular fluid EGF and/or TGFα may result in reduced numbers of granulosa cells, cessation of follicle selection and ultimately in the creation and maintenance of PCOS. The exact mechanism by which the hyperfunction of EGF/TGFα occurs and the trigger for this hyperactivity in the ovary remain to be determined. An experimental animal model may be required to assist such investigations in the future.

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.

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).

Uterine fibroids are estimated to affect up to 25% of women of reproductive age and are a common cause of morbidity, being associated with menstrual dysfunction, iron deficiency anaemia, pregnancy wastage and subfertility. Their pathogenesis remains unknown but their association with ovarian function and oestrogen production is undisputed and supported by their occurrence only after puberty and the shrinkage observed after the menopause. This oestrogen dependency has recently been exploited therapeutically through investigation of the use of agents that induce a hypo-oestrogenic state, the gonadotrophin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) analogues.

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.

Male infertility is a frequent cause of childlessness, and, indeed, a comparison of the contributions to conception failure made by male and female factors shows them to be equally frequent. In practice, male infertility appears to be resistant to most treatments. However, the major reason for this may be that often attempts are carried out without knowing the cause of the problem. Unlike in women, obstructions and hormonal disorders are rare in male infertility. Rather, it would appear that sperm disorders are the most common cause, reflecting a variety of pathogenetic mechanisms. Defects in sperm morphology, defective sperm movement, deficient development or functional failure of the acrosome, and the excessive generation of reactive oxygen species are changes that are often seen in infertile semen, but little is known about their aetiology. In 5–10% of men being treated for infertilty, an autoimmune reaction against spermatozoa is observed. Although the correlation between the presence of systemic antisperm antibodies and fertility potential is poor, the appearance of sperm-bound antibodies of immunoglobulin class IgA in semen seems to be closely associated with infertility. Studies in laboratory animals and humans have shown that complementary adhesion molecules are located on the surface of oocytes and spermatozoa. These molecules interact and lead to gamete fusion. Abnormalities in these molecules on the sperm surface might be expected to contribute to male infertility. However, their clinical significance has not yet been documented, and the molecular basis of human gamete interaction is far from being understood. Therefore, the key to understanding male infertility may lie in basic research which directly targets the fundamental cellular and molecular biology of the human spermatozoon.

The lack of reliable methods to assess sperm fertilizing potential has been a long-standing problem for infertile couples and for their physicians. The most widely used tests, the measurements of sperm concentrations, motility, velocity and morphology in the ejaculate, are of limited utility. Indeed, following intrauterine insemination, a treatment that compensates for low motile sperm concentrations, there were no significant differences found in semen parameters among those who did or did not achieve pregnancies. Other available assays probing for selected sperm functions, such as membrane integrity, acrosome enzyme activity, bovine cervical mucus penetration test, zona-free hamster oocyte penetration test and sperm binding to various carbohydrates,10–13 have all failed thus far to consistently predict male fertility. It became increasingly obvious that there was a need to identify cellular markers of sperm quality and fertilizing potential.

Genomic imprinting is defined as the differential expression of a gene or chromosomal region according to the parental origin of inheritance. Both the maternal and paternal alleles are present, but while one is functionally active, the other is silenced (inactive) in somatic cells (Figure 1a). Genomic imprinting is reversible through successive generations. Inherited maternal and paternal “imprints” are erased during gametogenesis (gamete production) and new imprints established according to the sex of the parent. Genomic imprinting is an epigenetic phenomenon (not dependent on the DNA sequence itself, but rather on factors that regulate DNA activity). These factors include attachments of methyl groups to the DNA, which are set in the gamete and serve to distinguish the parental alleles in somatic cells post-fertilization.

In an effort to summarize the potential risks of therapeutic insemination by donor (TID), including a review of cases of disease attributed to donor semen, a MEDLINE literature search was conducted to identify all published case reports of transmissible diseases occurring in donor semen recipients published in English between 1975 and 1992. The reference list for each article was reviewed to locate additional published case reports. Pertinent case reports were compiled according to disease agent and classified into viral, bacterial and other categories.

Mammalian fertilization, whether it takes place within the female reproductive tract or within a laboratory dish, is comprised of many processes which must follow a specific sequence. The spermatozoon must bind to and pass through the zona pellucida, fuse with the oolemma and become incorporated into the cytoplasm of the oocyte. Fusion of the two gametes triggers oocyte activation, resulting in exocytosis of the cortical granules and completion of the second meiotic division of the oocyte. A block in one or more of these processes, due either to abnormalities in the spermatozoon or oocyte, may result in fertilization failure.

Ovarian stimulation protocols applied world-wide today may take several weeks per stimulated cycle, are complex, expensive and associated with a certain degree of risk. Gonadotrophin preparations are administered to stimulate multiple follicle development usually at daily doses of 150–300 IU (and sometimes higher) for one to three weeks. A premature rise in serum luteinizing hormone (LH) levels, generally believed to be detrimental for in vitro fertilization (IVF) outcome, is prevented by the co-administration of a gonadotrophin-releasing hormone (GnRH) agonist. This is usually initiated in the preceding cycle to allow for pituitary downregulation to occur before the initiation of exogenous follicle-stimulating hormone (FSH). Finally, the resumption of oocyte meiotic maturation is induced by a single bolus injection of human chorionic gonadotrophin (hCG) during the late follicular phase. In addition, the corpus luteum is supported during the luteal phase by repeated administration of hCG or supplemented by exogenous progesterone.

By 1959 it was recognized that the gene (or genes) responsible for initiating the human male phenotype were carried on the Y chromosome. But in subsequent years, few phenotypes were associated with the Y chromosome. Recently, using molecular techniques combined with classical genetics, the Y chromosome has been the focus of intensive and productive investigation. Some of the findings are unexpected and have extended our understanding of the functions of the human Y chromosome. The notion that the Y chromosome is largely devoid of genes is changing. At the present, over 20 Y chromosome genes or pseudogenes have been identified or cloned, a number that is rapidly increasing. A high proportion of Y chromosome sequences have been found to be related to X chromosome sequences: the assembly of a complete physical map of the Y chromosome euchromatic region (believed to carry all of the genes) has shown 25% of the region studied to have homology to the X chromosome.3 Several X-homologous genes are located in the X and Y chromosome pairing regions, an area predicted to have shared homology. Surprisingly, some of the Y-encoded genes that lie outside of the X and Y pairing region share high sequence similarity, and in at least one case, functional identity, with genes on the X chromosome.

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.

The term breakthrough bleeding (BTB) is rather poorly defined, but essentially describes the symptom of vaginal bleeding occurring with scheduled periods of withdrawal bleeding, in the absence of pelvic pathology in women taking exogenous sex steroids, usually contraceptives or hormone-replacement therapy (HRT). It may also describe occasional bleeding in those who are predominantly experiencing amenorrhoea due to these preparations. Rather confusingly, the term is sometimes used to describe intermenstrual bleeding in women who are not taking sex steroids, when structural or other pathological causes are more likely. In the absence of such pathology intermenstrual bleeding in the normal menstrual cycle is relatively uncommon, suggesting that exogenous sex steroids can profoundly disrupt the tight regulation of endometrial vascular development, function and breakdown. Intermenstrual bleeding also occurs spontaneously in some women and it is possible that this phenomenon has similar mechanisms to that seen in sex-steroid-related breakthrough bleeding.

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.

Lasers have now been used laparoscopically in infertility surgery for over a decase. Use of the CO2 laser at laparoscopy began independently in France, Israel and North America. Investigators have subsequently reported use of the argon, Nd-YAG, and the KTP lasers for laparoscopic laser surgery. All of these surgical lasers are now widely available and have been used clinically for many laparoscopic procedures. This review will examine the laparoscopic use of both infrared and visible laser light energy in the treatment of infertility and endometriosis.

The first attempts at in vitro fertilization (IVF) of human oocytes were performed during cycles utilizing human menopausal gonadotropin (hMG) and human chorionic gonadotropin (hCG). These early cycles resulted in a successful conception, which unfortunately ended as a tubal gestation. The birth of Louise Brown in 1978, the first successful IVF birth, was actually achieved following fertilization during a spontaneous cycle in which ovulation was triggered with endogenous luteinizing hormone (LH).However, due to the greater margin for error afforded by larger numbers of follicles, the practice of IVF rapidly evolved towards the use of controlled ovarian hyperstimulation (COH) to achieve higher pregnancy rates. It is easy to understand why this approach evolved. Oocyte harvesting was accomplished primarily by laparoscopy. Since oocyte yield per follicle was less than 100% and fertilization rates were limited, the relatively traumatic follicle aspiration process was more likely to result in embryo transfer if a greater number of follicles was present.

During the past decade, few fields in medicine have changed as dramatically as reproductive medicine and the treatment of male infertility. Whereas previously only men with obstructive azoospermia were candidates for treatment, either through surgical reconstruction or sperm aspiration, now even men with nonobstructive azoospermia are able to achieve pregnancies without having to resort to donor sperm. The extraordinary success of assisted reproduction after sperm retrieval for azoospermic men is the result of three important discoveries. First is the clinical observation that epididymal transit of sperm is not required for successful fertilization. Second is the recognition that significant heterogeneity in testicular biopsy specimens exists. Lastly is the advent of intracytoplasmic sperm injection (ICSI), which has enabled fertilization regardless of the degree of sperm impairment or retrieval source as long as sperm are viable. These three discoveries have enabled fertilizations and pregnancies for men previously referred for donor insemination or adoption, and have therefore broadened the indications for sperm retrieval. This review is intended to describe in detail the available techniques for the recovery of sperm, with emphasis on the latest technique, testicular microdissection for sperm retrieval in nonobstructive azoospermia.

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.

Only 50% of all conceptions result in a live birth (Figure 1). Human reproduction can therefore be viewed as being remarkably inefficient. However, the diametrically opposite opinion that it is in fact a very efficient and selective process, designed to optimize the outcome of pregnancy, deserves to be stated.

Between 65% and 90% of clinically recognized miscarriages are due to chromosome abnormalities, the occurrence of which is more closely related to basal follicle-stimulating hormone (FSH) levels rather than to maternal age alone. In contrast to women suffering a sporadic miscarriage, women who recurrently miscarry often, but not exclusively, lose pregnancies with a normal chromosome content. Using a combination of conventional Geimsa banding and the recently introduced technique of comparative genomic hybridization it has been reported that 54% of pregnancy losses amongst women with recurrent miscarriage are euploid. The challenge we face is to identify the causes of pregnancy loss amongst those couples who recurrently lose such euploid conceptions.

Whilst many conventionally held beliefs as to the aetiology and treatment of women with recurrent miscarriage have not withstood critical scrutiny, significant progress has been made. This progress is the subject of this review, which will also highlight potential areas of future research.