Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders in females, reportedly affecting approximately 5–10% of women of reproductive age. The syndrome is characterized by oligo- or amenorrhoea, with clinical or biochemical hyperandrogenism, as evidenced by acne, hirsutism or alopecia; high serum levels of testosterone, androstenedione and dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) and/or low levels of sex-hormone binding globulin (SHBG) are typical biochemical findings. Lack of internationally agreed diagnostic criteria detract from comparisons between studies reported in the literature, the diagnosis in the USA relying more on abnormal ovarian appearances using ultrasound imaging. By contrast, the diagnosis in the UK rests more heavily on clinical and biochemical features with abnormal imaging not regarded as essential for the diagnosis. Polycystic ovaries on ultrasound are defined by the presence of eight or more subcapsular cysts ≤10 mm and increased ovarian stroma. False-negative scan reports may reflect inter-operator variability while the relatively high prevalence of typical polycystic appearances in asymptomatic women adds to the uncertainties of including ultrasound imaging as a major diagnostic criterion.
It was suggested by Ronald Fisher in 1931 that genes that benefit the male (including those required for spermatogenesis) would accumulate on the Y chromosome. Following the discovery that microdeletions of the Y chromosome were associated with diverse spermatogenic phenotypes, at least three intervals that contain one or more genes controlling male germ-cell differentiation have been identified in humans. These intervals, named AZFa , AZFb and AZFc , have been mapped, cloned and examined in detail for the presence of functional genes. In this review, I have discussed the genes that map to the AZF intervals and the evidence indicating which ones are the most likely candidates underlying Y-linked male infertility. In addition, I have considered the analysis of key intervals on the mouse Y chromosome, where it provides comparative data supporting the role of a candidate gene in an infertility phenotype.
Endometriosis is a benign and often progressive disease in which tissue originating in the uterine lining spreads locally by direct invasion, or through the blood vessels to distal sites. The disorder affects as many as 10–20% of women aged 30–40, although many women remain asymptomatic. Between 30% and 45% of infertile women are diagnosed with endometriosis.
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.
In the recent past, a diagnosis of cancer was often considered a terminal condition in the majority of patients. If one did not die quickly, the stigmatism associated with the disease often relegated one to a life without children. However, as oncology treatments improved, so did the prognosis, as well as the prospect of a 'survivor' being able to lead a healthy productive life.
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).
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.
Group B streptococci (GBS) are an important cause of neonatal sepsis and meningitis, and maternal infection. Although the pathogenesis of GBS infection is not well understood, several virulence factors have been identified. Two prevention strategies have been proposed: chemoprophylaxis and immunoprophylaxis. Implementation of selective intrapartum chemoprophylaxis on the basis of either screening or risk assessment has led to a substantial decrease in the morbidity and mortality of GBS disease in both mothers and infants. Penicillin remains the antibiotic of choice with no reported resistant GBS so far, whereas resistance of 10–20% of GBS to erythromycin and clindamycin has been reported in North America. Chemoprophylaxis based on screening requires optimal detection methods for GBS, which involve selective broth culture of combined vaginal and anal samples. Other conventional methods are useful for rapid identification of heavily colonised women, but are unreliable for the detection of light GBS colonisation because of poor sensitivity. GBS-specific polymerase chain reaction (PCR) assays using real-time PCR coupled with fluorescence-labelling technology offer powerful tools for sensitive and specific, yet rapid (less than 1 h), detection of GBS directly from clinical specimens at the time of delivery. The application of these assays to the current prevention strategies will simplify the prevention practice and rationalise the use of antibiotics. Immunoprophylaxis relies on the development of new vaccines against GBS, and active research is being conducted in this area.
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.
Interest in the investigation of male erectile dysfunction and male factor infertility has risen in recent years, due in part to the increased sophistication and high profile of new treatments associated with these conditions. The assessment and management of men presenting with erectile or fertility problems are usually achieved by collaboration between urology and other specialties. A radiologist is often a vital member of this multidisciplinary team. This article will review the imaging modalities currently available and discuss their current role in the investigation of these two key areas of andrology.
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.
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.
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.
Fertilization and early embryo development take place in the oviduct in vivo. Relative to studies in other reproductive organs, the importance of the oviduct has been ignored for many years because pregnancies can be obtained in assisted reproduction treatment using in-vitro fertilization (IVF) and embryo transfer to the uterus without involving the Fallopian tube. After the reports on the beneficial effect of oviductal cells on embryo development in sheep and subsequently in human, and a practical need to improve the success rates in clinical assisted reproduction, there was a period when more research was performed on the Fallopian tube. Many of these studies used in vitro coculture systems to emulate the in vivo environment in vitro, and to search for oviduct-derived embryotrophic factors. With the recent development of sequential culture to improve embryo development in vitro, the use of coculture in assisted reproduction and its related research declined because routine use of coculture is laborious and experience-dependent.
Angiogenesis is defined as the formation of new blood vessels from the existing vasculature. Angiogenesis occurs regularly in the endometrium throughout the reproductive life of females as part of the rapid growth and regression of this tissue that occurs during the menstrual cycle. It is now clearly evident that angiogenesis plays a key role in reproductive processes such as embryo implantation, placentation, endometrial regeneration after menstruation, and in the ovary during folliculogenesis and corpus luteum formation. Given the complexity and continual change of the endometrial milieu, it seems highly likely that aberrations in the angiogenic process may contribute to various disorders, including endometrial cancer, endometriosis, menorrhagia and breakthrough bleeding – all significant and common gynaecological pathologies. This review provides an update on the mechanisms and regulation of endometrial angiogenesis, with particular reference to the role of angiogenesis in implantation and placentation, as well as two endometrial pathologies – endometriosis and breakthrough bleeding.
Percutaneous trans-catheter embolization has been practised by radiologists for well over 20 years. In many different clinical situations a great variety of embolization materials or agents has been used in all parts of the body, but generally these procedures have been performed rarely. An important indication is severe bleeding not responding to conservative measures, where the alternative treatment would involve major surgery. Embolization has also been used in tumours, particularly where they are hypervascular, when the role has often been to debulk and devascularize immediately prior to surgery. The third main indication is in arteriovenous malformations and fistulae. Thus, it is somewhat surprising that it was not until 1995 that uterine artery embolization (UAE) was first advocated as a treatment for uterine fibroid disease.
Thyroid disorders are common in young women and are, therefore, amongst the commonest endocrine disorders to be encountered in pregnancy. Pregnancy outcomes for mother and fetus are usually good, but assessment and monitoring are required, often in conjunction with an endocrinologist, and, occasionally, serious complications are encountered.
Thyroid disorders are common in young women and are, therefore, amongst the commonest endocrine disorders to be encountered in pregnancy. Pregnancy outcomes for mother and fetus are usually good, but assessment and monitoring are required, often in conjunction with an endocrinologist, and, occasionally, serious complications are encountered.
The aim of preimplantation genetic diagnosis (PGD) is to give couples at risk of passing on a genetic disorder an alternative to standard prenatal diagnosis by enabling them to start a pregnancy that is known to be free of the familial disease. This can be achieved by generating embryos in vitro by standard in vitro fertilization (IVF) techniques and then removing one to two of the cells from the early embryo (embryo biopsy). Single cell polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) can then be used to diagnose single gene defects or chromosomal abnormalities respectively. Those embryos diagnosed as free from disease can then be considered for transfer to the womb and so the pregnancy is started knowing that the fetus is unaffected. This avoids the need to consider pregnancy termination in the quest for a healthy child. Originally it was thought that the major reason for referral would be the risk of passing on a single abnormal gene but an increasing proportion of couples are requesting PGD because of recurrent miscarriage due to parental chromosomal abnormality.
There have been a number of reviews on this topic over the past decade, starting with Carlsen et al. and including Irvine et al. and Murray et al., concerning declining male fertility. The most exhaustive has perhaps been that of Toppari et al. The main findings of these reviews are: (1) that in some countries of the world sperm production has halved in the last 60 years, (2) rates of testicular cancer have doubled, (3) rates of malformation of the male reproductive tract, such as hypospadias, have doubled, (4) rates of testicular maldescent have risen sharply and (5) these effects are largely linked geographically. Typically, endocrine disrupting chemicals (EDCs) in the environment have been regarded as the main candidates for these effects. A consistent problem with the field, however, is the difficulty in determining the accuracy of data relating to changes in men's health over the latter half of the 20th century. Advances in diagnosis and changing attitudes to the emotive issues surrounding deformity and male infertility inevitably render some of the mass of collected data suspect. Indeed a recent review of testicular and prostate cancer concluded that while the incidence of prostate cancer had increased, the epidemiological data were not suitable for concrete conclusions about causation to be drawn. However, in the case of testicular cancer the data suggested a limited number of major risk factors. In addition, assessing urogenital malformation retrospectively from patient notes is subject to considerable variation in classification. A recent review does however find evidence to suggest that trends of increasing incidences of hypospadias on a temporal and geographical basis may reflect an actual increase in incidence and require further study. On the other hand, there is a considerable body of evidence for EDC disruption of reproduction in wildlife (reviewed by Guillette & Gunderson, 2001).
