Seminars in reproductive endocrinology最新文献

A review of the literature of androgen actions affecting the circulatory system indicates early enthusiasm for use of testosterone in cardiac patients, subsequent disenchantment with androgens due to negative effects on lipid metabolism, and recent renewed interest as new technologies and understandings of the cardio-protective effects of estrogens has led to re-examination of the beneficial and adverse effects of androgens. Ovarian steroids, including androgens, have effects on lipid metabolism in the liver and direct effects in the arterial wall, which influence the development and progress of atherosclerosis. Androgens lower total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides but also decrease high-density lipoprotein (HDL) cholesterol levels. Androgen arterial-wall effects help maintain the mechanisms involved in vasodilation. Androgens alone appear to promote atherosclerosis but when administered with estrogens have the opposite effect in the arterial wall. Recognition of the cellular actions of androgens and the decrease in androgen production as women age after the menopause has led to increased use of androgen replacement therapy for postmenopausal women. Preliminary clinical findings in women using postmenopausal estrogen/androgen treatment indicate a good safety profile. However, in comparison to the many years and experience in evaluating the effects of estrogens, studies of androgen effects must be considered to be at a preliminary stage.

As infertility treatments evolve and techniques are developed to improve the fertilization and pregnancy rates, it is clear that the in vitro environment in which the gametes/embryos are cultured is less than perfect when compared to the in vivo counterpart. This becomes a serious problem for couples who seek to have children but are limited by unsuccessful attempts to become pregnant and a technology that is behind in mimicking the in vivo environment that would enhance gamete interaction and embryo development. In an attempt to begin to correlate the in vivo and in vitro microenvironment of the gametes/embryos and to recognize the potential of the fallopian tube as more then a highway for oocytes to transverse in their pathway to the uterus, coculturing of tubal cells along with gametes and embryos was introduced to the in vitro fertilization community. This report is an attempt to compile the research and results of those attempting to improve pregnancy rates by improving in vitro culture conditions via co-culture of cells with gametes and/or embryos.

The unusually high content of phospholipid-bound polyunsaturated fatty acids (PUFA) in the sperm plasma membrane drew attention to their potential physiological significance. Docosahexaenoic acid (22:6) is quantitatively the most important fatty acid. The high PUFA content of sperm membranes makes them vulnerable to peroxidative changes, since PUFA containing two or more double bonds are readily attacked by oxygen radicals. The effects of oxidation on sperm function have been suggested as detrimental as well as beneficial. Generation of reactive oxygen species (ROS) and peroxidation of sperm membrane can bring negative effects on motility, midpiece abnormalities, and sperm-oocyte fusion. ROS trigger sperm hyperactivation, and may support the capacitation of spermatozoa and fertilization. Spermatozoa are protected by various antioxidants and antioxidant enzymes in the seminal plasma or in spermatozoa itself. When the gametes are cultured in vitro, they become more susceptible to oxidative damage. Addition of antioxidants in the media brought beneficial effects in preventing loss of motility and inhibiting lipid peroxidation. Treating patients with antioxidants has shown to have a positive effect on improving fertilization in limited data. The mechanism of antioxidant effects on spermatozoa needs to be further studied.

Endothelial injury is common to all pathological features of preeclampsia. Neutrophil activation has been implicated in the pathophysiology of preeclampsia and requires binding and transmigration of neutrophils through the endothelium. This occurs via an interaction of endothelial adhesion molecules and surface receptors on neutrophils. Upon activation, neutrophil granules are released, the contents of which are capable of mediating vascular damage. In addition, leukotrienes are synthesized, and superoxide is generated in a respiratory burst. These products also provoke vascular damage. Neutrophil recruitment to the endothelium involves express of P-selectin and released of platelet activating factor from the endothelium. In preeclampsia there is evidence of an increase in neutrophil activation with up-regulation of neutrophil integrin expression and increased regulation of the protease elastase. Furthermore, these markers of neutrophil activation correlate with established markers of disease severity. The primary mechanism of neutrophil activation is unknown, but neutrophils in preeclampsia appear to have normal motor activity. Several potential mechanisms of neutrophil activation have been identified. They include up-regulation of cellular adhesion molecules on the endothelial surface, increased generation of tumor necrosis factor-alpha, and endothelial activation from hyperlipidemia. In additional to activation of neutrophils in preeclampsia, there may be involvement of the interleukin-6 and endothelin-1 in "priming" neutrophils for subsequent superoxide production. Activated neutrophils are likely to play a large part in the arteriopathy and endothelial damage associated with preeclampsia, but it is unclear whether neutrophil activation is the cause or the consequence of endothelial damage.

The ovaries are a major site of production of circulating androgens during the postmenopausal years. This includes the production of testosterone. Bilateral oophorectomy can lead to a reduction in circulating testosterone levels of nearly fifty percent. Several experimental conditions have confirmed that the postmenopausal ovarian androgen production is regulated through gonadotropins and that exogenous hormones can modulate this androgen production. The function of the postmenopausal ovaries must be considered in light of these data. This body of information introduces an important consideration in the debate over elective oophorectomy at the time of unrelated gynecologic surgery.

The etiology and pathogenesis of the pregnancy syndrome preeclampsia remain poorly understood. There is evidence that oxidative stress (am imbalance between oxidant and antioxidant forces in favor of oxidants) occurs in preeclampsia, and it has been hypothesized that reactive oxygen species or their metabolites ultimately comprise the "defensive" vasodilatory, antiaggregatory, and barrier functioning of the vascular endothelium. Oxidative stress may be point at which feto-placental and maternal factors converge, resulting in the protean manifestations of preeclampsia. This review highlights the evidence for maternal dyslipidemia and altered iron kinetics in preeclampsia and gives a critical assessment of their potential impact on disease progression. The theme is developed that interaction of maternal components, particularly neutrophils and oxidation-susceptible lipids, with placental cells and placental-derived factors engenders feed-forward cycles of oxidative stress that ultimately cause widespread endothelial cell dysfunction and its clinical manifestations.

During the past decade a new hypothesis has been formulated that explains many of the disparate findings associated with the pregnancy syndrome preeclampsia. With an increased awareness of the physiological significance of vascular endothelial cell function, the seemingly unrelated signs of hypertension, proteinuria, edema, and hypercoagulability have converged to provide clinical evidence of a unifying pathophysiological mechanism: systemic, maternal endothelial cell dysfunction. Investigators have attempted to test this hypothesis through two approaches. The first approach involves the identification of in vivo markers of vascular endothelial cell injury in women with clinically evident preeclampsia. The second approach focuses on the ability of circulating factors derived from the serum or plasma of patients afflicted with preeclampsia to perturb endothelial cell function in vitro. In this review we summarize the increasingly compelling evidence that maternal vascular endothelial cells are a critical target for toxic humoral activities that precipitate the multifaceted preeclampsia syndrome.

There is increasing interest in the use of menopausal androgen replacement therapy (MART) in symptomatic women undergoing natural or surgical menopause. However, the efficacy of MART in alleviating these symptoms compared to traditional estrogen/progestin hormone replacement therapy remains a subject of debate. Accordingly, attention must be focused on the side-effects of the various MART preparations. The dose, alkylation, and route of administration of these compounds influences the development of side effects. While all androgens are potential virilizing agents, alkylated compounds have an additional risk of inducing severe hepatic consequences, regardless of their route of administration. Fortunately, the lower doses administered to women compared to men has not resulted in significant hepatic events. Generation of an adverse lipoprotein profile is possible but is not addressed in this article. Thus, virilizing and cutaneous side effects remain the primary concern. While some observational studies indicate acne and/or hirsutism are evident in up to 38% and 36% of oral methyltestosterone-treated patients, respectively, other studies performed in a prospective fashion suggest a much lower incidence of approximately 5%. Other reported virilizing effects include deepening of the voice and clitoromegaly. Additional concerns are related to risks of developing endometrial hyperplasia when MART is used in conjunction with estrogens. Fortunately, concomitant progestin administration is protective. Finally, there is a theoretical concern that MART may increase the risk of developing breast cancer but this has not been demonstrated in clinical practice. Overall, the safety profile of MART appears to be acceptable when dosing avoids supraphysiologic testosterone levels.

This review focuses on the question of how oxidative stress in cells populating atherosclerotic lesions stimulates gene expression, cell proliferation, and cell death, and how these events contribute to the initiation, progression, and destablization of the lesions. It is hypothesized that oxidative stress in endothelial cells, macrophages, and smooth muscle cells occurs as a result of the depletion of the cellular content of reduced glutathione. Glutathione becomes oxidized in response to the accumulation of oxidized lipids, the formation of reactive oxygen species released from the mitochondria and generated as part of the activation-induced respiratory burst, and the generation of nitric oxide, peroxynitrite, and thiol radicals. Both in vitro and in vivo evidence suggests that these cells can take up modified lipoproteins that become trapped within the artery wall leading to the overaccumulation of oxidized fatty acids and oxidized forms of cholesterol. The cells also generate oxidized lipids via the activity of lipoxygenases, cyclooxygenases, and myeloperoxidase. A sublethal oxidative stress can activate redox-sensitive kinase cascades and transcription factors such as NFB and AP-1, with resulting increases in the expression of factors associated with an inflammatory response and cellular proliferation. There is also accumulating evidence that suggests that oxidative stress may be associated with the induction of cell death either via stimulation of apoptosis and/or necrosis and that increased cell death contributes to the formation of a necrotic core, the hallmark of an advanced, unstable lesion.

Cell-cell and cell-extracellular matrix interactions are fundamental processes involved in cell migration and tissue remodeling. Both the cyclic regeneration of the human endometrium during the menstrual cycle as well as the process of embryo implantation involve such dynamic interactions. It has become quite clear that integrin adhesion molecules expressed on the surface of cells play critical roles in the transmission of signals from the extracellular milieu to the cells. It is these signals that presumably regulate the behavior of these cells during major morphogenetic processes. In recent years, work in human endometrium and trophoblasts has uncovered both the regulated and constitutive expression of integrin subunits and their extracellular matrix ligands in these tissues. In addition, attempts have been made to correlate pathological states related to either infertility or abnormal pregnancy to the aberrant expression of several of these integrins. The purpose of the present review is to describe briefly our present state of knowledge of the expression of integrins in human endometrium and trophoblasts and provide the reader with the necessary background needed to understand, at the cellular and molecular levels, processes in reproduction such as embryo implantation.