Seminars in reproductive endocrinology最新文献

As women undergo menopause, circulating concentrations of estrogen decrease. The relative estrogen deprivation in postmenopausal women is associated with physiological changes and increased risk of several diseases, including cardiovascular disease. Studies in animals have shown that exogenous estrogen inhibits atherosclerosis, the underlying cause of cardiovascular disease. Ongoing clinical trials will soon provide data for the effect of exogenous estrogen on cardiovascular disease in postmenopausal women. Estrogen has a number of effects that could influence atherogenesis and cardiovascular disease. Estrogens have favorable effects on lipoproteins, but such effects can only account for part of the protection from cardiovascular disease that appears to be conferred by estrogen. Evidence suggests that estrogens can have both prooxidant and antioxidant effects. However, the available evidence suggests that in vivo physiological concentrations of estrogen may have a modest antioxidant activity, and prooxidant activity is unlikely. The antioxidant activity of estrogens and inhibition by estrogens of cellular processes that are thought to promote atherosclerosis are likely to be additional mechanism(s) by which estrogen inhibits atherosclerosis and cardiovascular disease, but more work is needed. Studies of some effects of estrogens on atherogenic processes in isolated cells need to be extended to the whole animal. The influence of estrogen receptors on inhibition of atherosclerosis by estrogen needs to be clarified. Future studies should be designed to investigate separately the estrogenic and antioxidant activities of estrogens and estrogen analogs. Investigations of the antioxidant activities of estrogens should include careful consideration of the interaction of estrogens with endogenous antioxidants and fatty acid saturation, and more attention should be paid to the potential for estrogens to inhibit intraarterial oxidation.

Evidence continues to accumulate that oxidative stress is a mediator of endothelial cell dysfunction and thus contributes to the cardiovascular complications of preeclampsia. The mechanisms for the interaction of oxidative stress and endothelial cell function have not been well defined. This review explores potential vasoactive pathways that may be affected by oxidative stress and have been reported to be altered in women with preeclampsia. In pathologic conditions of oxidative stress, increased production of superoxide peroxide anions and nitric oxide has been recognized to inactivate the nitric oxide as a vasorelaxant as well as produce peroxynitrite, a potent oxidant. Increase prostaglandin H (PGH) synthase activity resulting in vasoconstriction predominates in models of oxidative stress. Peroxynitrite increases PGH synthase activity in vitro, providing a potential, but as yet untested, link between oxidative stress, nitric oxide, and PGH synthase pathway, leading to reduced relaxation and increased constriction in the vasculature of women with preeclampsia. Other vasoconstrictors (such as isoprostanes and endothelin) that may be interrelated with oxidative stress and altered endothelial cell function in preeclampsia are also discussed.

Because changes in lipids, lipoprotein, and other metabolic processes, such as hyperinsulinemia and hyperuricemia, found in preeclampsia resemble the main features of the insulin resistance syndrome, it has been proposed that insulin resistance may be the common denominator for such metabolic changes. Several groups, using euglycemic-hyperinsulinemic clamping or intravenous glucose tolerance tests (Bergman's minimal model technique), have demonstrated insulin resistance during late pregnancy. Women with preeclampsia had higher fasting insulin levels, but also exaggerated hyperinsulinemia, in response to an oral glucose tolerance test, which is consistent with increased insulin resistance in preeclampsia. No direct measurement of insulin sensitivity (clamp or minimal model) has as yet been performed during preeclampsia. Increased insulin resistance can activate the sympathetic nervous system and lead to an increase in expression of receptors for endothelin, both of which events lead to increased blood pressure. Hyperinsulinemia can also induce hypertriglyceridemia, leading to endothelial dysfunction and reduction of prostacyclin production. This hyperinsulinemia can persist for as long as 17 years after preeclamptic pregnancy and may contribute to a woman's increased risk of cardiovascular disease. Insulin resistance may not be the cause of preeclampsia, but is one of the pathogenic factors, especially in genetically predisposed women.

There is widespread evidence of inflammatory cell and antioxidant activity in preeclampsia. However, it is difficult to disentangle the pathological changes from the normal physiological responses to the pathological process. The site at which the measurements are taken, and the severity of disease, alter the results. The interaction between the mother and the fetus needs to be considered separately, especially when the genetics of preeclampsia is considered. It is clear that within the placenta, there is an increase in tumor necrosis factor-alpha (TNF-alpha) and lipid peroxide production. These changes are associated with a reduction in the various placental antioxidants. This suggests there may be a failure of the normal fetal protection systems. Lipid peroxidation is also increased in the peripheral blood, as well as IL-6, IL-8, and TNF-alpha, which are of monocytic origin. Stimulated monocytes produce free radicals, which can cause oxidative damage. Maternal cells protect themselves with both plasma and intracellular antioxidants. There is an imbalance between oxidant and antioxidant activity in preeclampsia. Changes in membrane oxidation can lead to changes in the membrane stability. Genetic difference in the production of TNF-alpha and nitric oxide may also modify the disease process, demonstrating the role for "moderator genes."

Cryopreservation stands as an ongoing evolution in the field of assisted reproductive technologies. Face with increasing numbers of fertilized oocytes and early embryos, cryopreservation avails the ART program of a useful means to preserve embryos for future use without exposing patients to the risks of multiple pregnancies. This article examines some of the clinical and laboratory issues critical to a successful cryopreservation program.

The process of fertilization and the role that each gamete plays in that process have been the subject of investigation in a large number of species and for many years. However, while much is now known for some species relatively little is known for others. Indeed, the specific events that are required to occur in the human male and female gametes and that facilitate fertilization are still somewhat ill-defined. For example, as of today, there have been numerous biomolecular processes that have been put forth as playing an important role in the sequence of events during which sperm acquire fertilizing ability, yet the actual significance of many of these remains suspect. This article will summarize what is presently best known about prefertilization processes occurring in human spermatozoa. For those interested in nonhuman mammalian and nonmammalian species, articles addressing this and other topics can be found in the many review articles cited herein.

The concentration of androgens in the blood peaks in early adulthood. While the concentrations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) decline steadily, the concentrations of androstenedione (A) and testosterone (T) decline just before or at the menopause. DHEAS is bound strongly to albumin, resulting in a very low metabolic clearance rate (MCR) of about 12 L/day. DHEA and A are bound weakly to albumin and their MCRs are 1800 to 2000 L/day. T is bound strongly to sex hormone-binding globulin (SHBG), and the MCR of T is about 500 L/day. There are no significant changes in the MCRs at the menopause or with age. The pathways of metabolism are not altered at the menopause but aromatization of DHEA, A, and T to estrone and estradiol all increase with age. Thus, androgen metabolism in general is affected more by age than by the menopause itself.

In women, testosterone (T) is increasingly recognized as a steroid with multiple non-reproductive effects. Testosterone deficiency in menopausal women is more common than appreciated, particularly in patients on hormone replacement or with surgical menopause. Replacement of T is an established therapy for male hypogonadism, and as a result innovative new delivery systems have evolved to optimize physiologic delivery. However, in women, modalities of T replacement remain underdeveloped and at present provide artificial and/or supraphysiologic androgen levels. This review discusses the androgen replacement modalities presently available for women, and those being developed for future use.

In recent years, there has been increasing interest in the potential of androgen replacement in menopausal women and specifically adrenal androgen replacement. There is unfortunately increasing unmonitored use of dehydroepiandrosterone (DHEA) among adults in the United States with only limited and preliminary human data. An extensive body of literature in laboratory animals exists to suggest DHEA used in extremely large doses has multifaceted effects; though the inapplicability of this data to humans is not appreciated, as the physiology of adrenal androgens in humans and a few primates is unique. Currently, there is much international and multidisciplinary interest in the physiology and use of DHEA "replacement" in men and menopausal women. The scientific community anxiously await the results of these investigations, but in the interim DHEA and/or DHEA-Sulfate (DHEAS) supplementation is not recommended as a therapeutic option in menopause outside of clinical trials.

The dominating hypothesis of the preeclampsia syndrome (PES) is that placentally derived factors are released to the maternal circulation. These factors are believed to alter endothelial properties resulting in disturbed vasomotor function, increased endothelial permeability, and activation of thrombogenic factors. However, the impact of placentally derived factors on the endothelial cells is influenced by another major variable: the "sensitivity" of the maternal endothelium to the placental factors. Several maternal factors may play a role in determining this sensitivity. They include chronic hypertension, diabetes, and hyperlipidemia. In this article we discuss the possible role of hyperlipidemia (especially high free fatty acids and hypertriglyceridemia) in the pathogenesis of preeclampsia, viewed from this perspective. Pregnancy in general, preeclamptic pregnancy in particular, is associated with a marked hyperlipidemia. We suggest a parallel to atherosclerotic diseases, wherein hyperlipidemia induces endothelial dysfunction, probably by promoting oxidative stress in the arterial wall. The hyperlipidemia of pregnancy may have a similar effect on the endothelial cells. When placentally derived endothelial disturbing factors, like lipid peroxides and trophoblastic components, are released into the maternal circulation, their effects on the endothelium may be enhanced because of hyperlipidemia-mediated activation or "sensitization" of the endothelial cells. Alternatively, placentally derived factors like peroxides may combine with lipoproteins, forming complexes that are more disturbing to cells than the placental factors or lipoproteins are individually. We also discuss the possible role of maternal hyperlipidemia in aggravating placental insufficiency caused by poorly transformed spiral arteries. The hemodynamic flow pattern may be markedly different in completely and incompletely transformed spiral arteries. By analogy to the fundamental role of hemodynamic factors in development of atherosclerosis, we pose the hypothesis that abnormally transformed spiral arteries have an "atherogenic" blood flow pattern that promotes lipid deposition and "acute atherosis".