Estrogen In Prevention Research Articles

Abstract WP154: Estrogen Modulates Serotonin-induced Vasoconstriction Through Tyrisine Kinase Inhibition

Earlier onset of menopause may influence the risk of stroke. However, hormone therapy, estrogen, alone or with a progestogen, increases stroke risk. Thus, it is needed to clarify whether estrogens prevent or promote vasomotor symptoms, as well as the mechanism(s) involved. Recent study showed that serotonin enhancing drugs, including antidepressants, migraine therapies and diet pills, can trigger a stroke via vasoconstriction. In this study, we examined the modulatory mechanisms of estrogen in serotonin -induced vasoconstriction by using a combinatory approach of isometric tension measurements, molecular biology, and patch-clamp techniques. 17β-estradiol (E2) elicited a significant and concentration-dependent relaxation of serotonin-induced contraction in deendothelialized aorta strips isolated from male rats. E2 triggered a relaxation of serotonin-induced contraction even in the presence of tamoxifen, an estrogen receptor antagonist, suggesting that E2-induced changes were not mediated by estrogen receptor. Patch clamp studies in rat arterial myocytes showed that E2 prevented Kv channel inhibition induced by serotonin. Serotonin increased Src activation in arterial smooth muscle required for contraction, which is significantly inhibited by E2. The estrogen receptor-independent inhibition of Src by E2 was confirmed in HEK239T cells that do not express estrogen receptor. Taken together, these results suggest that estrogen exerted vasodilatory effects on serotonin-precontracted artery via Src, implying a critical role of estrogen in prevention of vascular hyperreactivity to serotonin.

Estrogen partially down-regulates PTEN to prevent apoptosis in VSC4.1 motoneurons following exposure to IFN-γ

PTEN is a tumor suppressor gene that is either mutated or deleted in a number of human cancers. PTEN acts as a negative regulator of the PI3K/Akt survival pathway and thus plays an important role in cell fate, proliferation, growth, and migration. Recent evidence suggests that PTEN may also be involved in the pathophysiology of neurodegenerative disorders such as spinal cord injury (SCI). Overexpression of PTEN appears to cause inactivation/dephosphorylation of Akt in neurons, resulting in increased cell death. Given this newly discovered role for PTEN, it has been identified as a potential molecular target for the development of novel therapeutic strategies against neurodegeneration. Motoneuron degeneration following SCI may occur due to up-regulation of pro-inflammatory and cytotoxic cytokines including IFN-γ. Exposure of VSC4.1 motoneurons to IFN-γ (10 ng/ml) for 24 h resulted in significant overexpression of PTEN and decreased levels of activated Akt. Up-regulation of PTEN following IFN-γ exposure was associated with decreased overall cell viability due to increased apoptosis, as assessed by Wright staining and analysis of cell death markers including Bax, Bcl-2, calpain activity, and caspase-3 activity, indicating a prominent role for PTEN in suppression of the PI3K/Akt survival pathway to promote motoneuron death. Addition of estrogen (100 nM) to VSC4.1 cells for 1 h prior to IFN-γ exposure partially decreased PTEN expression, allowing adequate activation or phosphorylation of Akt (p-Akt) to prevent apoptotic cell death. Thus, it appears that estrogen may mediate neuroprotection through decrease in PTEN expression. In conclusion, our studies suggest that PTEN inactivation may be used as an important parameter for evaluation of the efficacy of estrogen in prevention of neuronal loss in neurodegenerative disorders.

Pharmacologic treatment to prevent fractures: from markers to patients

Pierre Delmas made fundamental contributions to our understanding of the mechanisms of action of treatments for osteoporosis, played an important role in the design and publication of most of the agents in our armamentarium of treatments for osteoporosis, and provided evidence and guidance about the use of markers of bone turnover in clinical practice. The “BMD paradigm” that improvements in bone mineral density (BMD) directly translate into decreases in fracture risk was so strong that the FDA approved estrogen for prevention and treatment of osteoporosis based on trials showing that it significantly improved BMD. Two randomized trials undermined this paradigm. The first showed that sodium fluoride improved spine BMD by 10% but did not decrease the risk of fractures – indeed, it seemed to increase the risk of stress fractures. This forced a realization that histologically abnormal bone, as induced by fluoride, may improve BMD but not bone strength. The second assault on the BMD paradigm came from randomized trials of raloxifene. Pierre Delmas published the first results from a randomized trial showing that this new type of agent, a selective estrogen receptor modulator (SERM), improved BMD of the hip and spine, albeit by only 2–3% [1]. The subsequent MORE trial, with 4 year results led by Dr. Delmas, surprisingly showed that this modest increase in BMD resulted in about a 40% reduction in risk of vertebral fractures [2, 3]. This finding, in turn, led to analyses showing that the magnitude of treatmentinduced improvements in spine BMD accounted for less than 20%, and in the case of raloxifene less than 5%, of the effect of treatments on the risk of vertebral fracture [4]. Delmas and Seeman showed that changes in BMD could account for very little of the observed reduction in the risk of nonvertebral fractures by antiresorptive therapy [5]. Disenchantment with the BMD paradigm was accompanied by the rise of research on the effects of treatments on bone resorption and formation and development of the

Bazedoxifene: A Selective Estrogen-Receptor Modulator

Bazedoxifene is a third-generation selective estrogen-receptor modulator being developed for use alone or in combination with estrogen for prevention and treatment of osteoporosis in postmenopausal women. Preliminary clinical trials are encouraging. Bazedoxifene has been found to be efficacious in reducing bone turnover without adverse effects of breast pain. In Phase III studies, bazedoxifene was found to increase vasomotor symptoms when compared with placebo. This effect is similar to that of raloxifene. Lack of endometrial stimulation is another advantage. Current literature suggests that bazedoxifene is likely to be safe, well tolerated and effective for the treatment of postmenopausal osteoporosis. However, completion of Phase III clinical trials will further elucidate its safety and efficacy, as well as its advantages in comparison with other selective estrogen-receptor modulators.

Evaluation of a model for post-partum arthritis and the role of oestrogen in prevention of MRL-lpr associated rheumatic conditions.

Sixty-eight percent of female MRL-lpr mice developed a post-partum exacerbation of their mild spontaneous arthritis within 30 days of parturition. The flare became evident between 5 and 15 days after delivery. Histologically it was characterized by a significant increase of subsynovial inflammation and synovial hyperplasia without changes in the level of cartilage and bone erosion. Immunohistologically, marked subsynovial and frequent synovial staining of MHC class II bearing cells was noted, along with the sporadic presence of CD3, CD4, and CD43 receptor-bearing cells in the subsynovium. Injection of physiological levels (0.08 mg/kg) of estradiol on days 2, 3, 9, 15 and 20 post-partum delayed and reduced the flare to 23% of the animals. Administration of pharmacological amounts (0.4 mg/kg per day for 2 weeks following Freund's complete adjuvant injection) prevented adjuvant-enhanced arthritis, reducing the incidence from 67% to the baseline 21% level. Deleterious changes in the underlying systemic lupus erythematosus (SLE), as demonstrated by proteinuria and mortality rate increases, were elicited only by the employed pharmacological amounts of estradiol. These results indicate that the MRL-lpr mice might serve as a model for post-partum flare of arthritis in SLE and rheumatoid arthritis by providing an approach to study the complexity of the effects of pregnancy on autoimmune diseases, and to obtain further evidence for the involvement of oestrogen in arthritis.

Estrogen Agonists/Antagonists in Combination with Estrogen for Prevention and Treatment of Menopause-Associated Signs and Symptoms

For several decades, clinicians have been prescribing hormone therapy to postmenopausal women for approved indications, including the alleviation of vasomotor symptoms, relief of vaginal dryness and prevention of osteoporosis. Numerous publications have demonstrated that estrogen also induces favorable effects on lipids, the endothelium, cardiovascular outcomes, quality of life, cognition, skin and urinary incontinence. As a result of these findings, clinicians began adding each of these outcomes to their list of possible benefits of hormone therapy in postmenopausal women. Results from the Women's Health Initiative significantly changed this treatment paradigm and opened the door for new, innovative therapies for the prevention of clinical conditions encountered by women of menopausal age. One such treatment option is the estrogen agonist/antagonist. In this regard, investigators and clinicians alike seek a therapy that will act like estrogen in all the 'right' tissues and act as an estrogen antagonist in tissues in which estrogen action results in adverse events. This review describes the molecular actions of estrogen agonists/antagonists, discusses the current clinical data regarding the effect of these compounds on menopause-associated outcomes, and describes what is currently known about the effects of combining estrogen with an estrogen agonist/antagonist.

Commentary on "The Minimum Effective Dose of Estrogen for Prevention of Postmenopausal Bone Loss"

Commentary on "The Minimum Effective Dose of Estrogen for Prevention of Postmenopausal Bone Loss"

Use of estrogen for prevention and treatment of osteoporosis.

Two decades of experience leave no doubt that sustained administration of estrogen to menopausal women conserves bone throughout the skeleton. Such conservation should theoretically protect against osteoporotic fracture, and, indeed, epidemiological studies support the view that long-term estrogen replacement does afford women such protection. On the other hand, uncertainty remains about many aspects of this issue. Questions persist regarding the therapeutic schedule itself: the type, dose, and mode of administration of estrogen that is optimal. Other questions concern the individuals who will receive estrogen: the age at which treatment begins, its duration, and the consequence of adding progestins to the treatment regimen. The level of uncertainty for these questions grows considerably when the end point is fracture protection rather than bone mass. In this chapter, I discuss the therapeutic use of estrogen to prevent or treat osteoporosis.

Estrogen in Prevention and Treatment of Osteoporosisa

Estrogen has clearly been shown to decrease bone loss and frequency of osteoporotic fractures. Calcitonin has been shown in several studies to reduce the rate of bone loss, although no data are yet available demonstrating a reduction in fracture frequency. Studies of osteoporosis intrinsically assume that prevention of further loss, or increments in bone mass, will be associated with declines in fracture recurrence. That may not always be the case. Recent controlled studies in which fluoride was used to increase bone mass in vertebral bodies resulted in no significant decline in fracture recurrence, and there was even a suggestion of increased fracture risk at some sites. Thus further data on calcitonin will be important, even though calcitonin is not expected to alter bone quality as does fluoride. Alternative therapies to calcitonin and estrogen are being investigated in clinical studies since both are currently limited in their use. Because calcitonin currently requires nearly daily injections, estrogen remains the principal agent available for both prevention and treatment in spite of its wide effect on multiple body systems. Bisphosphonates, given continuously or intermittently, appear to be relatively safe oral alternatives to calcitonin. The long-term effects of these agents need to be evaluated in greater detail before they can be recommended for prevention, but a role in therapy of the established disorder seems likely. The skeletal effect of bisphosphonates is also inhibition of bone remodeling and therefore prevention of further bone loss. Thus, they add nothing to the other therapeutic regimens from this perspective and as with calcitonin therapy, documentation of decreased frequency of fracture is lacking. Agents to increase bone mass are purely investigational at this time and many years may elapse before efficacy can be shown for such interventions.

Estrogen/progestogen therapy: prevention and treatment of postmenopausal osteoporosis.

In original description of osteoporosis by Albright et al. (1), they highlighted the greater prevalence of oophorectomy among patients presenting with osteoporotic fracture, and established for the first time the importance of ovarian failure in the pathogenesis of bone loss. Since that time, considerable evidence has been accumulated documenting the rate of loss of ovarian function in the pathogenesis of osteoporotic fracture (2). This has led to the use of estrogen for prevention of bone loss and subsequent fracture (3) with dramatic success. However, about one decade ago, it became apparent that the uncontrolled use of estrogen in women who had an intact uterus led to an increased incidence of endometrial hyperplasia and malignancy. Concern that a therapeutic regimen that not only might afford protection against osteoporotic fracture, but also might reduce the frequency of ischemic heart disease, might increase the risk of other disorders, has led to a reevaluation of the use of estrogen among the post...

Postmenopausal estrogens in prevention of osteoporosis. Benefit virtually without risk if cardiovascular effects are considered

Postmenopausal estrogens can delay or prevent osteoporosis and decrease the frequency of fractures, but they also increase the risk of endometrial cancer. A decision analytic model was developed using a Markov process with 18 different states to estimate quality-adjusted life expectancy with and without estrogen therapy. The model considered fractures of the hip, wrist, pelvis, humerus and spine with potential outcomes of short-term morbidity, long-term disability, nursing home placement, and death. Quality adjustments were based on expert opinions. In sensitivity analyses, various risks of endometrial cancer and hysterectomy due to estrogens were examined. The effect of estrogen therapy on cardiac mortality also was considered. For a cohort of 50-year-old white women who would take estrogens for 15 years, the analysis showed a benefit of 0.47 years but 0.67 quality-adjusted years. For every five-fold increase in the relative risk of endometrial cancer, the benefit decreases by 0.07 quality years. The benefit would increase by 0.17 quality years for each 10 percent decrease in the fracture rate and 0.32 for each 10 percent decrease in cardiovascular mortality rate. Thus, estrogen therapy provides a significant gain in quality-adjusted life expectancy. In considering the efficacy of any drug, all the benefits of the drug as well as all its risks must be included. If the beneficial effect of estrogens on cardiovascular mortality is confirmed, it will overshadow all other effects. Any recommendation about postmenopausal estrogens with respect to osteoporosis that excludes their cardiovascular effects markedly underestimates the potential gains from therapy.

Postmenopausal gyn problems.

The conservative use of estrogens for prevention and treatment of osteoporosis is discussed. The author stresses the importance of thorough pelvic examination to detect inflammatory processes, possible generative tract prolapses, and/or growths.