Bailliere's clinical obstetrics and gynaecology最新文献

The clinical management of thrombo-embolic disease in obstetrics and gynaecology is hampered by the paucity of firm evidence on which to base clinical decisions. This is particularly so in obstetrics where there have been no randomized controlled trials of thromboprophylaxis in pregnancy or the puerperium of sufficient size to detect differences in the incidence of clinical thrombo-embolic events. The incidence of osteoporosis and bleeding complications associated with heparin have not been precisely defined in pregnancy and we are already using low-molecular-weight heparin in place of unfractionated heparin when we do not know whether either heparin is preferable to nothing. In gynaecology, the various thromboprophylactic modalities for use in relation to surgery need to be compared. The small randomized comparisons that have been performed suggest that relatively non-invasive procedures may be just as effective as heparin in preventing thrombo-embolism without the associated complications. Recent controversies concerning the effect of the OCP and HRT on the risk of thrombo-embolic disease indicate that the present methods we use to evaluate these interventions needs to be urgently addressed so that safety rather than efficacy becomes the principle outcome.

Oral contraceptives have been linked to an increased incidence of thrombovascular disease. This may be mediated by their effects on the haemostatic system. An increase in the activity of coagulation Factors VII, X and fibrinogen occur with pill usage. Increased Factor VII levels are dependent on both the oestrogen and progestogen component of the oral contraceptive. A reduction in antithrombin III levels has also been observed in some but not all studies. Increased fibrinolysis has also been shown in oral contraceptive users which should balance the changes in the coagulation pathway. The increase in fibrinolytic potential is thought to be due to a decrease in the levels of plasminogen activator inhibitor I combined with an increase in the levels of plasminogen; tissue plasminogen activator antigen is decreased in most studies. The increased levels of endpoints of coagulation and fibrinolysis in pill users indicate that enhanced activity of both systems is occuring in vivo. The increased coagulation activity appears to be balanced by the rise in fibrinolytic activity, so preserving haemostatic balance. Enhanced platelet activity has also been shown in women taking oral contraceptives. Thrombus formation can result, however, when local vascular wall damage exists, or when other risk factors for thrombo-embolism, such as older age and smoking, coexist and create a local activation resulting in a thrombus. In these situations, the small differences in levels of coagulation factors in women taking different oral contraceptive formulations may be important. Pills containing the lowest doses of oestrogen (20 μg ethinyloestradiol) have shown the least changes in haemostatic factors. The progestogen component of the pill modifies the effect of oestrogen on the haemostatic system.

Recent data have indicated that hormone replacement therapy (HRT) is associated with an increased risk of venous thrombo-embolism. Although the relative risk is significantly higher, the absolute risk remains small. Epidemiological studies on which the increased risk was based may have been open to biases, including those of referral, investigation and diagnosis. None the less, the association appears real albeit the mechanism poorly understood. Potential mechanisms include unmasking of an underlying thrombophilia or combination with other recognized risk factors for venous thrombo-embolism. The implications of these findings have to be placed firmly in the clinical context and weighed against the established benefits of hormone replacement therapy, including relief of menopausal symptoms, prevention of osteoporosis and arterial-vascular disease. Patients with a personal or family history of venous thrombo-embolism should be screened for underlying thrombophilia and such screening may be extended to relatives. However, the risk of venous thrombo-embolism following initiation of HRT is not yet known. None the less, HRT should be used with caution in this situation and may be best avoided, unless associated with concomitant antithrombotic therapy, in certain thrombophilias, expert advice should be sought. Patients without risk factors should be advised of the small increase in risk of venous thrombosis which is greatest during the first year. Where additional risk factors are present the situation will have to be assessed on an individual basis for each patient. For example, the beneficial effects of HRT in an obese patient at risk of arterial disease may outweigh the small risk of thrombosis. Patients already on HRT should have some assessment of the risk of venous thrombosis made and where there are features suggestive of thrombophilia screening performed.

A number of putative paracrine factors are now thought to interact with FSH in the control of ovarian steroidogenesis. The relative importance of these factors remains to be determined, but the presence of the insulin-like growth factors and their binding proteins and the mechanism of control of the latter through the local production of proteases suggests a role for this system in folliculogenesis.

We have demonstrated over-production of steroid hormones in tissue from women with polycystic ovaries. Theca cells in monolayer culture produced excessive amounts of progesterone and androstenedione and granulosa cell oestradiol production was considerably enhanced in response to FSH. Recent evidence points to a genetic defect in the expression or translation of steroidogenic hormones as a cause of excess androgen production, but the gene or genes involved has not been established. Data from our group suggest that granulosa cells from anovulatory polycystic ovaries are prematurely matured and we hypothesize that this is due to the interaction of the raised circulating insulin levels with LH in these follicles, an interaction that results in arrested follicular growth.

The last few years have witnessed an acceleration in our understanding of the regulation of the human pilosebaceous unit. Recombination and histochemical experiments are beginning to elucidate the role of homeotic genes, transcription factors, growth factors and adhesion molecules in pilosebaceous embryology. Histochemical studies, experiments in genemodified animals, and in vitro studies on growing human hairs, have identified a number of growth factors that are central to normal hair growth. Thus epidermal growth factor and transforming growth factor-α appear to be involved in the triggering of both anagen and categen. Insulin-like growth factor-I appears to sustain normal anagen growth, transforming growth factor-β will inhibit anagen growth, while interleukin-1-α and tumour necrosis factor-α will induce matrix cell death. These complex growth factor effects are beginning to be moulded into an integrated model of pilosebaceous regulation. The role of steroid hormones in modulating these growth factor effects is also beginning to be understood.

The reticularis and fasciculata zones of the adrenal cortex are the predominant sources of dehydroepiandrosterone (DHEA) and DHEA-sulphate and contribute directly or indirectly 60–75% of androstenedione and testosterone in women. The specific control of adrenal androgens remains unclear. While ACTH stimulates adrenal androgen secretion, the dissociation of cortisol and androgens occurring during adrenarche and under pathological conditions suggests other factors are involved. Recent studies using human adrenal cells in vitro have demonstrated that the ratio of androgen to cortisol produced is substantially independent of the age and gender of the adrenal, indicating that extra-adrenal factors are of greater importance. β-endorphin and joining peptide have been shown to stimulate androgen production in human adrenal cells and to influence ACTH-stimulated steroidogenesis in a manner that promotes adrenal androgen production. The activity of these proopiomelanocortin-derived peptides may explain the physiological and pathological dissociations of androgens and cortisol.

Polycystic ovary syndrome (PCOS) may be loosely defined as unexplained hyperandrogenism, with variable degrees of cutaneous symptoms, anovulatory symptoms, and obesity. The vast majority of patients with the full-blown Stein-Leventhal syndrome have functional ovarian hyperandrogenism (FOH). However, FOH often occurs without the LH excess or polycystic ovaries of classic PCOS. Functional adrenal hyperandrogenism (FAH) is often found in the syndrome, but it is less closely associated with anovulatory symptoms than is FOH. The vast majority of FOH seems to arise from abnormal regulation (dysregulation) of ovarian androgen secretion. This typically is due to escape from desensitization to luteinizing hormone (LH); this appears to occur because of a breakdown in the processes that normally coordinate ovarian androgen and oestrogen secretion so as to prevent hyperoestrogenism. Similar dysregulation of adrenal androgen secretion in response to ACTH seems to account for most FAH. Dysregulation of androgen secretion may affect the ovary alone (isolated FOH), the adrenal alone (isolated FAH), or both together. Modest insulin resistance is common in PCOS/FOH, and the resultant hyperinsulinaemia is a major candidate as the cause of the dysregulation. The hyperinsulinaemia may arise from either ‘nature’ (genetic defects) or ‘nurture’ (exogenous obesity). Although hyperinsulinaemia alone does not have an obvious effect on steroidogenesis, it may act in genetically predisposed women as a ‘second hit’ to unmask latent abnormalities in steroidogenesis. The ovary, the adrenal cortex, and several other organs paradoxically function as if responding to the hyperinsulinaemic state in spite of resistance to the effects of insulin on glucose metabolism.

PCOS should be viewed as an early manifestation of a hyperinsulinaemic condition that will predispose to cardiovascular and metabolic complications later in life. A subset of PCOS patients appear to have not only insulin resistance but also β-cell secretory dysfunction, which may indicate a relationship of the disorder to NIDDM. The fundamental genetic defects remain to be elucidated.

Up to 40% of women with polycystic ovary syndrome (PCOS) demonstrate some degree of glucose intolerance, either impaired glucose tolerance (IGT) or non-insulin dependent diabetes mellitus (NIDDM). Defects in insulin action have long-been recognized as characteristic in these women. Recently, evidence has been obtained which documents that insulin secretory dysfunction also contributes significantly to the observed glucose intolerance. This chapter will focus on the recent evidence supporting the specific roles of disordered insulin secretion and action, in the development of glucose intolerance in PCOS. In addition, the use of pharmacological agents that modify insulin action as therapeutic options for women with PCOS, will be discussed.