Seminars in reproductive endocrinology最新文献

Reactive oxygen species derived from molecular oxygen are highly reactive metabolites. These species can be generated by cellular or acellular mechanisms. They react with all biological molecules such as protein, lipid, and carbohydrates. The reaction of these species with lipids, called lipid peroxidation, is a very well-studied phenomenon. Compounds, which scavenge these molecules, are called antioxidants. The disruption of the delicate balance between pro- and antioxidants has been implicated in the pathophysiology of many chronic diseases such as, for example, atherosclerosis. This article presents an introduction to what reactive oxygen species are and their reactions with various metabolites. It deals with lipid peroxidation in detail and with methods for measuring lipid peroxidation. This article also outlines the importance of these species in the pathology of various gynecological diseases.

Oxidative stress and free radical-mediated cell death have been linked to diseases such as atherosclerosis, Alzheimer's disease, and cancer. Estrogens may promote, or offer protection against these conditions, by acting both as an antioxidant and prooxidant. Estrogens are converted to catecholestrogens via an oxidation step. Catecholestrogens are precursors of quinones that undergo a reversible oxidation-reduction reaction yielding semiquinones and reactive oxygen species. These semiquinones and reactive oxygen species may act as prooxidants and result in DNA and protein damage that may play a role in initiating tumor growth. Estrogen may also stimulate the peroxidase reaction, thereby promoting prooxidant reactions catalyzed by estrogen. Such reactions may be involved in enhancing the oxidizability of low-density lipoproteins (LDL). This mechanism of oxidation of LDL in plasma may actually lead to increased clearance of LDL by the liver and thereby contribute to estrogens' antiatherogenic action. On the other hand, participation of catecholestrogens in iron redox cycling may contribute to the antioxidant action of estrogens. This action might be important in sites such as the subendothelial space where estrogens are thought to inhibit LDL oxidation. Estrogens may also exert antioxidant effects by acting on genes with response elements for antioxidants. This may in turn inhibit expression of certain proteins involved in disease processes such as atherogenesis. Thus, by acting as an antioxidant and prooxidant, estrogen may produce both beneficial and adverse effects important in the prevention and pathogenesis of disease.

Approximately 20 years ago the first child conceived with in vitro fertilization (IVF) and embryo transfer was born in England. Although overall pregnancy rates and delivery rates after IVF have improved over the years, success between IVF clinics can vary as much as tenfold. The factors that influence the success rate include type of patient, ovarian stimulation protocol, quality of oocytes, culture conditions, handling of gametes and embryos, quality of embryos, embryo transfer technique, and endometrial receptivity. Culture conditions and handling of gametes and embryos will be reviewed with the hope of improving success of human IVF. The ongoing clinical pregnancy rates in our program increased from about 30% in 1995 and 1996 to about 50% in 1997. Improved embryo culture conditions and embryo cryopreservation technology should not only increase fresh but also frozen-thawed embryo transfer pregnancy. This will make IVF efficient and cost-effective while achieving high overall pregnancy rates with lower multiple pregnancy rates.

Several years ago the hypothesis was advanced that alterations of endothelial function could explain much of the pathophysiology of preeclampsia. Since that time, extensive data have been generated to support the hypothesis. Markers of endothelial activation can be demonstrated in women with overt preeclampsia. More importantly, many of these markers precede clinically evident disease and disappear with resolution of the disease. The original postulate was that materials produced by the poorly perfused placenta, which is characteristic of preeclampsia, entered the systemic circulation and altered endothelial cell activity. This was proposed to change vascular sensitivity to circulating pressors, activate coagulation, and reduce vascular integrity resulting in the pathophysiological changes of preeclampsia. As data have accumulated it has become increasingly evident that the insult to the endothelium is neither toxicity nor nonspecific injury but rather can better be characterized as endothelial activation. Candidate molecules have been suggested but not established. It seems likely that the responsible agent(s) will not be unique molecules but rather usual molecules present in excessive amounts. The hypothesis has been expanded to invoke involvement of the maternal constitution in the generation of endothelial injury and injurants. This concept is stimulated by the observation that reduced placental perfusion per se is not sufficient to generate the maternal syndrome. Women with growth-restricted fetuses frequently are not preeclamptic. Placental bed biopsies from not only growth-restricted but also prematurely born infants demonstrate failure of the physiological remodeling of decidual vessels responsible for the reduced placental perfusion of preeclampsia. This has led to the concept that preeclampsia is secondary to an interaction of reduced placental perfusion and maternal factors. Interestingly these maternal factors, obesity, insulin resistance, black race, hypertension, and elevated plasma homocysteine concentration are all risk factors for atherosclerosis in later life.

This review addresses the general hypothesis that the pathogenesis of preeclampsia is related to an imbalance of increased oxidative stress and lipid peroxidation coupled to a deficiency of antioxidant protection. Evidence will be presented that this imbalance is present in both the maternal compartment and the placental compartment and that interactions between these two compartments result in the clinical manifestations of this disorder. We suggest the following as a scenario for the development of preeclampsia: Oxidative stress in the maternal compartment affects the placenta in such a way as to bring about a decrease in placental antioxidant enzyme protection. The oxidative stress in the maternal compartment may be preexisting (e.g., obesity, diabetes, hyperlipidemia) or may be caused by placental secretion of lipid peroxides. Decreased placental antioxidant enzyme protection leads to a cascade of events in the placenta of uncontrolled lipid peroxidation with increased thromboxane production and increased tumor necrosis factor (TNF-alpha) production. Increased placental secretion of lipid peroxides and/or TNF-alpha results in activation of leukocytes as they circulate through the intervillous space. The activated leukocytes serve as circulating mediators that link the increased oxidative stress of the placenta with a widespread increase in oxidative stress and endothelial dysfunction in the mother. In the third trimester, when the placenta is growing rapidly, the mother's antioxidant capacity is no longer able to compensate, and the clinical symptoms of preeclampsia appear.

Interest in the effects of androgens on the central nervous system (CNS) in postmenopausal women dates back to at least fifty years. The mechanisms of action of androgens on the CNS are extremely complex and multi-faceted. Much data has been accumulated in recent years that suggest a beneficial role of androgens in several aspects of CNS function. These include positive effects on mood, cognition, memory, and libido. The information continues to be preliminary in nature and requires further investigations. There is evidence of altered androgen metabolism triggered by exogenous postmenopausal estrogen therapy. While promising, the current body of evidence does not yet support the routine addition of androgens to postmenopausal hormone therapy.

Osteoporosis is one of the most common metabolic bone diseases in the adult population and its prevalence will continue to rise as our population grows older. In both sexes, hypogonadism is associated with accelerated loss of bone and development of osteoporosis. Adrenal and gonadal androgen levels decline with advancing age in both sexes. Androgens act by either directly binding to androgen receptors, or by aromatization of androgens to estrogens and subsequently interacting with estrogen receptors. Both pathways are important for skeletal health. Direct androgen binding to an androgen receptor may play a more important role in early skeletal development and determination of sexual dimorphic traits. While bone remodeling, which is important in maintaining healthy bone through life, is primarily stimulated by estrogen, studies in the rat and human support the complex action of androgens and estrogens in bone modeling and remodeling, and hence the development and maintenance of healthy bone. In postmenopausal females, the addition of androgens to hormone replacement therapy results in significant additional improvement in bone mineral density compared to estrogen replacement alone. Accumulating evidence indicate that androgens play an important role in the health of bone and the potential benefit of adding these agents to hormone replacement regimens.

The etiology of hyperandrogenic chronic anovulation is heterogeneous and relatively unknown in the majority of cases. Affected individuals in this latter segment are considered to have polycystic ovary syndrome (PCOS) of which 50 to 60% exhibit androgen excess of adrenal origin. An understanding of normal adrenal function provides insight into the factors that contribute to adrenal androgen excess in PCOS. Since pituitary ACTH secretion promotes developmental growth and overall steroidogenic efficiency within the adrenal cortex, it is probable that these actions of ACTH along with the adrenal's unique centripetal circulation play a major role in the induction of adrenarche. This latter phenomenon is characterized by alterations in adrenocortical morphology and steroidogenic enzyme activities culminating in increases in adrenal androgens to normal circulating adult levels. Thus, it is not surprising that adrenal dynamic testing has revealed increased 17,20 lyase activity or adrenal androgen hyper-responsiveness to ACTH as the two abnormalities leading to adrenal androgen excess in PCOS. Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological ACTH may be an intrinsic genetic defect, increases in 17,20 lyase activity and adrenal androgen hyper-responsiveness to ACTH in response to physiological ACTH may be promoted by the functional elevation of estrogen of ovarian origin in PCOS. The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a receptor mediated mechanism. Therefore, the currently available data indicate that adrenal androgen excess in PCOS is also heterogeneous in etiology.