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.

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.

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.

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.

Estradiol amplifies the amount of luteinizing hormone (LH) secreted in response to increasing doses of gonadotropin-releasing hormone by specifically augmenting the duration of evoked LH secretory events and hence their mass.

Amplification of LH release during the preovulatory LH surge could result from increased GnRH secretion and/or estradiol's facilitation of the dose-dependent actions of GnRH. We have investigated the mechanisms of estrogen's enhancement of GnRH action by evaluating LH release in response to four consecutive iv doses of GnRH (7.5, 25, 75, and 250 ng/kg) administered in randomized order followed by a fifth (maximal) dose of 750 ng/kg GnRH. The GnRH dose-response study was carried out before and after 10 days of estradiol treatment (0.2 mg/day percutaneously) in nine healthy postmenopausal women. Deconvolution analysis was used to quantitate specific measures of GnRH-stimulated LH secretion as well as estimate the half-life of endogenous LH. We found that 10 days of estradiol delivery did not alter the calculated half-life of immunoradiometric LH (126 +/- 10 min basally vs. 135 +/- 14 min during estrogen), but amplified the total mass of LH secreted in response to the five doses of GnRH; viz. 201 +/- 29 (control) vs. 406 +/- 58 IU/L (estrogen) (P < 0.001). Estradiol specifically enhanced the maximal value of the GnRH dose-LH secretory response curve; viz. from a mass of LH secreted of 46 (41-51) IU/L (basal) vs. 113 (93-139) IU/L (estrogen) (P < 0.001). Estradiol did not induce a significant leftward shift of the GnRH dose-LH secretory response curve, since the half-maximally effective dose of GnRH (ED50) was 9 (3.6-18) (control) vs. 19 (10-31) ng/kg (estradiol). The increased mass of LH secreted in the estrogen-rich milieu was due to a doubling of LH secretory burst duration, with no change in amplitude. We conclude that amplified LH secretory burst duration constitutes a novel neuroendocrine mechanism by which estradiol can promote GnRH self-priming of LH release by the previously estrogen-deprived human anterior pituitary gland in vivo.

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.

Patient satisfaction with psychiatric treatment of menopausal women in a multidisciplinary women's midlife center.

OBJECTIVE: Menopause may be associated with new onset psychiatric symptoms or may exacerbate or heighten preexisting psychiatric problems in women. We present a model center for midlife women, with a multidisciplinary approach to treating this population, and patients' perceptions of satisfaction with treatment received during referral visits to an outpatient psychiatry clinic. DESIGN: In this study, 59 patients were referred from their primary care provider at the midlife center for evaluation by a faculty psychiatrist in an outpatient setting. A brief telephone interview was administered within 1 year of initial evaluation, using items from the Client Satisfaction Questionnaire-8 (CSQ-8) to assess patient satisfaction with psychiatric services received during the referral visits. Findings were based on responses provided by 50 women who were successfully contacted by telephone for the follow-up assessment. RESULTS: For this sample, the mean total client satisfaction score was 27.8 (s = 5.4) of a possible score of 32, which indicated that most women who were referred for psychiatric services reported a positive experience with the services provided by outpatient psychiatrists and reported being very satisfied with their treatment. CONCLUSIONS: We feel that this model center represents a unique way to identify and treat psychiatric disorders in a patient population that may be at high risk for depression and other psychiatric disorders.

Adenosquamous carcinoma of the renal pelvis.

A case of adenosquamous carcinoma of the renal pelvis is reported, associated with multiple staghorn calculi, occurring in a 35-year-old woman. A review of the literature revealed only two previously reported cases. It is postulated that chronic irritation from the renal calculi had induced squamous and glandular metaplasia with subsequent adenosquamous neoplasia.

Intraoperative Doppler localization of intestinal arteriovenous malformation.

Arteriovenous malformations of the gastrointestinal tract have been identified as the cause of significant bleeding when other causes are obscure. A method of precise intraoperative localization using Doppler ultrasound technique is presented. The value of this method is shown in the management of an illustrative case of a rare arteriovenous malformation of the duodenum.

Fibrodysplasia with dissecting aneurysm of the hepatic artery.

The presentation and management of a patient with a symptomatic hepatic artery aneurysm is detailed. The aneurysm occurred secondary to fibromuscular hyperplasia of the hepatic artery and was associated with a limited area of dissection. This patient represents the second reported case of this type of aneurysm of the hepatic artery,

The use of monofilament suture in vascular surgery.

The blood lost through the suture line holes of vessels closed with braided polyester sutures is compared with that lost when a monofilament polypropylene suture is employed. In a retrospective analysis of blood replacement during saphenous vein aortorenal bypasses, twice as much blood replacement was required when the braided polyester suture was used. Further, ten dogs had one femoral artery reanastomosed with braided polyester suture and the other with monofilament polypropylene. Bleeding was three times greater and lasted six times longer when the braided polyester suture material was utilized.

Intestinal vascular malformations.

Eleven patients with intestinal vascular malformations (VMs), all diagnosed by angiography, are presented. Two of the VMs were incidental findings in patients treated for other problems; the other nine patients all presented with gastrointestinal hemorrhage, and all had resection of the portion of intestine containing the VM. None has rebled. The specimens from these nine patients revealed a variety of histological findings. One VM was the vasculature of small bowel leiomyoma. Three other specimens contained obvious VMs without associated findings, and one specimen contained no identifiable pathology. In the remaining four specimens, a variety of inflammatory conditions were found on histological study, including one case of Crohn's disease and another of ischemic colitis. In only one of these specimens did we identify the VM. None of these last four cases conforms to the degenerative lesions described by Boley and his colleagues. Therefore, we propose a fourth type of VM that is associated with or perhaps secondary to another disease of the intestine. We precisely localized one VM in the duodenum during operation with the Doppler ultrasonic flow detector, thus enabling us to limit the extent of the resection. We also propose the use of this technique for pinpointing the area where sections should be made for histological study.