Managing vasomotor symptoms in women after cancer.

Women with estrogen-sensitive cancer or survivors of these neoplasms are generally not candidates for systemic menopausal hormone therapy or tibolone for the treatment of bothersome vasomotor symptoms (hot flashes or night sweats). However, menopausal symptoms negatively affect quality of life and need to be addressed by clinicians. For mild vasomotor symptoms, optimizing lifestyle changes or mind-brain behavior may be sufficient. For women with moderate to severe vasomotor symptoms unresponsive to these measures, non-hormone pharmacologic therapy may be needed. Randomized controlled trials have shown efficacy for vasomotor symptoms with selective serotonin reuptake inhibitors (paroxetine, citalopram, and escitalopram) and serotonin-norepinephrine reuptake inhibitors (venlafaxine and desvenlafaxine), as well as gabapentin, pregabalin, and clonidine. Therapies in development include neurokinin B inhibitors (neurokinin 3 receptor), stellate ganglion blockade, and a natural estrogen, estetrol. Individualizing therapy is important. As the physiology of menopausal hot flashes becomes better understood, it will drive development of future non-hormone pharmacotherapies.

Beyond estrogen: advances in tissue selective estrogen complexes and selective estrogen receptor modulators.

Selective estrogen receptor modulators (SERMs) are synthetic non-steroidal agents which have variable estrogen agonist and antagonist activities in different target tissues. Tamoxifen is an anti-estrogen in the breast used for treatment and prevention of breast cancer, with estrogen agonist activity in the uterus. Raloxifene prevents and treats osteoporosis and prevents breast cancer, and can be safely combined with vaginal but not systemic estrogen. The tissue selective estrogen complex combines conjugated equine estrogens (CEE) with the SERM bazedoxifene (BZA). The five Selective Estrogen Menopause and Response to Therapy studies, with up to 2 years of data, demonstrated that CEE/BZA 0.45 mg/BZA 20 mg improved vasomotor symptoms and vulvovaginal atrophy, prevented bone loss, and was neutral on breast tenderness, breast density, with breast cancer incidence similar to placebo. Protection against estrogen-induced endometrial hyperplasia and cancer was found, with similar amenorrhea rates to placebo. Ospemifene is approved to treat dyspareunia, with potential benefits on bone and the breast, while lasofoxifene is being developed to treat resistant estrogen receptor-positive breast cancer in women. Estetrol is an estrogen synthesized exclusively during pregnancy by the human fetal liver and initially considered a weak estrogen, but it appears to have dual weak estrogenic/anti-estrogenic features.

Revised global consensus statement on menopausal hormone therapy.

The following Consensus Statement is endorsed by The International Menopause Society, The North American Menopause Society, The Endocrine Society, The European Menopause and Andropause Society, The Asia Pacific Menopause Federation, The International Osteoporosis Foundation and The Federation of Latin American Menopause Societies.

Treatment of symptoms of the menopause: an Endocrine Society Clinical Practice Guideline

OBJECTIVE: The objective of this document is to generate a practice guideline for the management and treatment of symptoms of the menopause. PARTICIPANTS: The Treatment of Symptoms of the Menopause Task Force included six experts, a methodologist, and a medical writer, all appointed by The Endocrine Society. EVIDENCE: The Task Force developed this evidenced-based guideline using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews of published data and considered several other existing meta-analyses and trials. CONSENSUS PROCESS: Multiple e-mail communications, conference calls, and one face-to-face meeting determined consensus. Committees of The Endocrine Society, representatives from endorsing societies, and members of The Endocrine Society reviewed and commented on the drafts of the guidelines. The Australasian Menopause Society, the British Menopause Society, European Menopause and Andropause Society, the European Society of Endocrinology, and the International Menopause Society (co-sponsors of the guideline) reviewed and commented on the draft. CONCLUSIONS: Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures.

Tissue selective estrogen complex combinations with bazedoxifene/conjugated estrogens as a model.

The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator (SERM) with one or more estrogens. Different TSECs are associated with distinct gene expression profiles in mammary gland and endometrial tissue according to the individual SERM and estrogen components. Few TSECs have been evaluated outside the laboratory. In preclinical trials, bazedoxifene (BZA) was distinct from other SERMs, with a neutral effect on mammary gland and endometrial tissue, and an antagonist effect on these tissues when combined with conjugated estrogens (CE). The only TSEC in an advanced stage of clinical development pairs BZA with CE. In large, randomized clinical trials, two doses, BZA 20 mg/CE 0.45 and 0.625 mg, reduced menopausal symptoms and prevented bone loss in postmenopausal women with a favorable safety profile on the breast, endometrium, and ovary, and with cardiovascular and venous thrombosis events similar to placebo. Improvements were seen in sleep, health-related quality of life, and treatment satisfaction. Compared with traditional, progestogen-containing hormone therapy, BZA/CE had higher rates of amenorrhea and reduced breast pain, with changes in breast density from baseline similar to placebo. Future TSECs identified in preclinical studies need to be tested in rigorous phase-3 clinical trials for effectiveness, safety and tolerability.

Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis prevention.

Postmenopausal women with vasomotor and vaginal symptoms are commonly treated with estrogens or combined estrogen/progestin therapy (hormone therapy). However, hormone therapy is associated with some safety and tolerability concerns and its benefit/risk profile may vary for women based on their time since menopause. The tissue selective estrogen complex (TSEC) pairs a selective estrogen receptor modulator with one or more estrogens, with the goal of relieving menopausal symptoms and preserving bone mineral density without stimulating the breast or endometrium. Bazedoxifene/conjugated estrogens (BZA/CE) is the first TSEC in clinical development. BZA 20 mg/CE 0.45 and 0.625 mg have been shown in phase-3 clinical trials to significantly improve hot flushes and vulvar/vaginal atrophy measures in symptomatic postmenopausal women and to prevent bone loss in postmenopausal women at risk for osteoporosis while ensuring endometrial safety. These doses of BZA/CE have also demonstrated significant improvements in quality-of-life scores, sleep parameters, and treatment satisfaction compared with placebo. BZA 20 mg/CE 0.45 and 0.625 mg showed high cumulative rates of amenorrhea and low rates of breast pain, similar to those with placebo. The favorable treatment effects seen with BZA/CE were generally consistent in women < 5 or ≥ 5 years since menopause. Based on its demonstrated efficacy and safety in women both closer to or further from menopause, BZA/CE may be an appropriate alternative to hormone therapy for the treatment of menopausal symptoms and the prevention of osteoporosis.

Soil Solarization as a Component of an Integrated Program for Control of Raspberry Root Rot.

Field and growth chamber studies were conducted during 2000 to 2005 to determine the efficacy of soil solarization for the control of Phytophthora root rot of raspberry (PRR). The exposure time that was lethal to Phytophthora rubi cultures on V8 juice agar plates was evaluated at intervals up to 240 h and at a range of temperatures from 20 to 35°C. Colonies incubated at 20 and 25°C nearly covered the plates in 240 h, while radial growth slowed at 27°C and ceased at temperatures ≥29°C. The exposure times required to kill P. rubi were estimated to be 222 h at 29°C, 168 h at 31°C, 108 h at 33°C, and 52 h at 35°C. Previous exposure to shorter durations at temperature ≥29°C slowed growth of colonies when they later were incubated at 20°C. Field trials were established in 2000 and 2003 at three locations in Washington State to evaluate soil solarization for the management of PRR. Cumulative hours with soil temperatures >29°C at 30 cm soil depth in solarized plots exceeded 200 h in each trial. In the 2000 trial, combinations of solarization, bed shape, and amendments of gypsum were evaluated. Over the 3 years after planting PRR-susceptible raspberry 'Malahat' and 'Willamette', primocane growth and survival were greater (P < 0.05) in raised bed plots that were solarized than in solarized and nonsolarized flat bed plots or hilled bed plots with gypsum. In 2003, trials were initiated to evaluate solarization in combination with applications of mefenoxam and fosetyl-Al. In 2004, solarization increased (P < 0.05) primocane growth of 'Malahat' and 'Qualicum' raspberries at both locations compared to application of fungicides alone and nontreated control plots. At both locations in 2005, density and growth of 'Qualicum' primocanes were greatest in solarized plots, while canes in solarized and fungicide only plots of 'Malahat' were similar. Incidence of diseased canes was lowest in plots that received fungicides. Primocane survival and fruit yields were very low at both locations in the third season because of favorable conditions for PRR and plant stress in late spring. These results indicate that soil solarization can be an effective component of integrated management of PRR in the Pacific Northwest, especially when combined with raised beds and gypsum amendments.

Maternal bisphenol-A levels at delivery: a looming problem?

OBJECTIVE: The objective was to determine whether bisphenol-A (BPA) is found in maternal circulation of pregnant women in the US population and is related to gestational length and birth weight. METHOD: Circulating levels of BPA were quantified by high performance liquid chromatography-tandem mass spectrometry at delivery in 40 southeastern Michigan mothers and correlated with gestational length and birth weight of offspring. RESULT: Maternal levels of unconjugated BPA ranged between 0.5 and 22.3 ng ml(-1) in southeastern Michigan mothers. There was no correlation between BPA concentrations and gestational length or birth weight of offspring. CONCLUSION: This is the first study to document measurable levels of BPA in maternal blood of the US population. Long-term follow-up studies of offspring are needed to validate or refute concerns over human fetal exposure to synthetic exogenous steroids.

Epidemiology of Xiphinema americanum and Tomato ringspot virus on Red Raspberry, Rubus idaeus.

Population dynamics of Xiphinema americanum and transmission of Tomato ringspot virus (ToRSV) were studied in a red raspberry field in Washington State. Population densities of X. americanum were highest in the winter, lowest in the summer, and were correlated with precipitation (R2 = 0.42). All nematode stages were present throughout the year. Gravid females were observed only in the spring, indicating one generation per year. The sequence of the coat protein of the ToRSV from this field was similar to those of other raspberry isolates from the Pacific Northwest. Cucumber seedlings were planted in soil collected monthly from the field and were evaluated for nematode transmission of ToRSV by enzyme-linked immunosorbent assay (ELISA). The proportion of assay plants infected with ToRSV was negatively correlated with nematode densities (R2 = 0.31). In another study, ToRSV was detected by ELISA in fine roots of raspberry plants 5 months after planting in field soil infested with viruliferous nematodes, in all subterranean portions of plants after 12 months, and in all aerial portions the second year. The rate of spread of ToRSV in a raspberry field was 70 cm per year. These results suggest that the rate of ToRSV spread is limited by systemic spread of virus in plants when nematode-infested soil is not transported in the field.

Effects of Mesocriconema xenoplax on Vitis vinifera and Associated Mycorrhizal Fungi.

Previous surveys of vineyards had indicated that Mesocriconema xenoplax was present in 85% of vineyards in western Oregon, but yields were not depressed in established vines. Microplot studies were initiated in 1997 in a Willamette Valley vineyard to determine the impact of M. xenoplax on vine establishment. Plots were infested with 0.03, 0.6, and 3.0 M. xenoplax g(-1) soil and planted with self-rooted Chardonnay and Pinot Noir vines. In November 2000, four growing seasons after planting, pruning weights, fine root weights, and fruit yield of vines planted in infested soil were reduced by 58%, 75%, and 33%, respectively, relative to control vines (planted in noninfested soil). In 1998 with ca 2000 degree-day base 9 degrees C accumulation, population densities increased 32-fold and 44-fold on 1-year-old Chardonnay and Pinot Noir vines, respectively. Nematode population dynamics and pruning data suggested that the carrying capacity of vines in microplots was 5 to 8 M. xenoplax g(-1) soil. In November 2000, more than 80% of the fine root length was colonized by arbuscular mycorrhizal fungi in all treatments. The frequency of fine roots containing arbuscules (the site of nutrient transfer between plant and fungus), however, was depressed from 5% to 65% in plants infested initially with M. xenoplax as compared to controls. Competition for photosynthate within the root system is proposed as a possible mechanism by which nematodes suppressed arbuscule frequency.

Use of alternatives to estrogen for treatment of menopause.

Women frequently chose alternatives to hormone replacement therapy (HRT) for treatment of menopause even though medical indications for estrogens may be present. Prior breast cancer or fear of breast cancer is a major consideration. This review of alternatives to estrogen discusses the evidence linking breast cancer to HRTs and compares potential risks and benefits of HRT to nonHRT alternatives for relief of vasomotor symptoms, vaginal atrophy, neurocognitive changes and prevention of heart disease and osteoporosis. Practical guidelines are suggested for use of alternatives for each problem.

The Use of Soil Solarization for the Management of Soilborne Plant Pathogens in Strawberry and Red Raspberry Production.

Root rot caused by Phytophthora fragariae var. fragariae and P. fragariae var. rubi are major concerns in strawberry and raspberry production in the Pacific Northwest. Of lesser importance is black root rot of strawberry, caused by a complex of fungi and nematodes. Soil solarization was evaluated in 1997 in a strawberry planting and in 1998 in a raspberry planting for: (i) enhancing plant health and growth, and (ii) reducing population densities of root-destroying pathogens. Plots were solarized from mid-July to mid-September. Maximum and mean soil temperatures in solarized plots recorded at 10 cm depth were 48 and 33°C in the strawberry plots and 46 and 29°C in the raspberry plots. These temperatures were 7 to 17°C higher than temperatures recorded in nonsolarized plots. Soil collected after solarization was assayed by growing bait plants, cv. Totem strawberry or cv. Qualicum raspberry, at 15°C for 6 weeks in saturated soil to promote infections. Root health and plant growth were evaluated after 6 weeks. Solarization significantly reduced (P < 0.05) root necrosis and increased root weight of bait plants compared to plants grown in soil from nonsolarized plots. Infection of strawberry roots by P. fragariae, Pythium, Rhizoctonia, and Cylindrocarpon spp. was reduced (P < 0.05) by solarization in sampled soil. Disease was reduced in cv. Hood strawberries and Qualicum and Skeena red raspberries planted in solarized field plots. In the second growing season, total number and number of healthy primocanes of Qualicum plants were greater (P < 0.05) in solarized plots compared to nonsolarized plots. Solarization combined with applications of mefenoxam was no more effective in controlling diseases than solarization alone, but better than mefenoxam alone. Skeena plants responded similarly, but the differences were not significant. Red raspberry plants growing in solarized soil yielded more fruit than plants growing in nonsolarized soil in the third year after solarization. Solarization has potential as a component in an integrated pest management program of root diseases in raspberry and strawberry production, particularly within the first 2 years following planting.

Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVE: To evaluate the efficacy of lower doses of conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) for relieving vasomotor symptoms and vaginal atrophy. DESIGN: A randomized, double-blind, placebo-controlled trial (the Women's Health, Osteoporosis, Progestin, Estrogen study). SETTING: Study centers across the United States. PATIENT(S): Two thousand, six hundred, seventy-three healthy, postmenopausal women with an intact uterus, including an efficacy-evaluable population (n = 241 at baseline). INTERVENTION(S): Patients received for 1 year (13 cycles; in milligrams per day) CEE, 0.625; CEE, 0.625 and MPA, 2.5; CEE, 0.45; CEE, 0.45 and MPA, 2.5; CEE, 0.45 and MPA, 1.5; CEE, 0.3; CEE, 0.3 and MPA, 1.5; or placebo. MAIN OUTCOME MEASURE(S): Number and severity of hot flushes and Papanicolaou smear with vaginal maturation index (VMI) to assess vaginal atrophy. RESULT(S): In the efficacy-evaluable population, reduction in vasomotor symptoms was similar with CEE of 0.625 mg/d and MPA of 2.5 mg/d (the most commonly prescribed doses) and all lower combination doses. CEE of 0.625 mg/d alleviated hot flushes more effectively than the lower doses of CEE alone. VMI improved in all active treatment groups. CONCLUSION(S): Lower doses of CEE plus MPA relieve vasomotor symptoms and vaginal atrophy as effectively as commonly prescribed doses.

From bipedalism to bicyclism: evolution in energetics and biomechanics of historic bicycles.

We measured the metabolic cost (C) and mechanical work of riding historic bicycles at different speeds: these bicycles included the Hobby Horse (1820s), the Boneshaker (1860s), the High Wheeler (1870s), the Rover (1880s), the Safety (1890s) and a modern bicycle (1980s) as a mean of comparison. The rolling resistance and air resistance of each vehicle were assessed. The mechanical internal work (W(INT)) was measured from three-dimensional motion analysis of the Hobby Horse and modern bicycle moving on a treadmill at different speeds. The equation obtained from the modern bicycle data was applied to the other vehicles. We found the following results. (i) Apart from the Rover, which was introduced for safety reasons, every newly invented bicycle improved metabolic economy. (ii) The rolling resistance decreased with subsequent designs while the frontal area and, hence, aerodynamic drag was fairly constant (except for the High Wheeler). (iii) The saddle-assisted body weight relief (which was inaugurated by the Hobby Horse) was responsible for most of the reduction in metabolic cost compared with walking or running. Further reductions in C were due to decreases in stride/pedalling frequency and, hence, W(INT) at the same speeds. (iv) The introduction of gear ratios allowed the use of pedalling frequencies that optimize the power/contraction velocity properties of the propulsive muscles. As a consequence, net mechanical efficiency (the ratio between the total mechanical work and C) was almost constant (0.273 +/- 0.015s.d.) for all bicycle designs, despite the increase in cruising speed. In the period from 1820 to 1890, improved design of bicycles increased the metabolically equivalent speed by threefold compared with walking at an average pace of ca. + 0.5 ms(-1) per decade [corrected]. The speed gain was the result of concurrent technological advancements in wheeled, human-powered vehicles and of 'smart' adaptation of the same actuator (the muscle) to different operational conditions.