Reduced Estrogen Levels Research Articles

Endometriosis and physical exercises: a systematic review.

Regular physical exercise seems to have protective effects against diseases that involve inflammatory processes since it induces an increase in the systemic levels of cytokines with anti-inflammatory and antioxidant properties and also acts by reducing estrogen levels. Evidence has suggested that the symptoms associated with endometriosis result from a local inflammatory peritoneal reaction caused by ectopic endometrial implants. Thus, the objective of the present review was to assess the relationship between physical exercise and the prevalence and/or improvement of the symptoms associated with endometriosis. To this end, data available in PubMed (1985–2012) were surveyed using the terms “endometriosis and physical exercises”, “endometriosis and life style and physical exercises” in the English language literature. Only 6 of the 935 articles detected were included in the study. These studies tried establish a possible relationship between the practice of physical exercise and the prevalence of endometriosis. The data available are inconclusive regarding the benefits of physical exercise as a risk factor for the disease and no data exist about the potential impact of exercise on the course of the endometriosis. In addition, randomized studies are necessary.

Ovariectomy enhances mechanical load-induced solute transport around osteocytes in rat cancellous bone

To test if osteoporosis alters mechanical load-induced interstitial fluid flow in bone, this study examined the combined effect of estrogen deficiency and external loading on solute transport around osteocytes. An in vivo tracer, FITC-labeled bovine serum albumin, was injected into anesthetized ovariectomized and control female Sprague–Dawley rats before the right tibia was subjected to a controlled, physiological, non-invasive sinusoidal load to mimic walking. Tracer movement through the lacunar–canalicular system surrounding osteocytes was quantified in cortical and cancellous bone from the proximal tibia using confocal microscopy, with the non-loaded tibia serving as internal control. Overall, the application of mechanical loading increased the percentage of osteocyte lacunae labeled with injected tracer, and ovariectomy further enhanced movement of tracer. An analysis of separate regions demonstrated that ovariectomy enhanced in vivo transport of the injected tracer in the cancellous bone of the tibial epiphysis and metaphysis but not in the cortical bone of the metaphysis. These findings show that bone changes due to reduced estrogen levels alter convectional transport around osteocytes in cancellous bone and demonstrate a functional difference of interstitial fluid flow around osteocytes in estrogen-deficient rats undergoing the same physical activity as controls. The altered interstitial fluid flow around osteocytes is likely related to nanostructural matrix–mineral level differences recently demonstrated at the lacunar–canalicular surface of estrogen-deficient rats, which could affect the transmission of mechanical loads to the osteocyte.

ChemInform Abstract: Computational Methods for the Design of Potent Aromatase Inhibitors

AbstractReview: 103 refs.

Abstract 2519: Is accelerometer-measured physical activity associated with urinary estrogens and estrogen metabolites among postmenopausal women?.

Abstract Studies suggest that higher levels of physical activity may reduce the risk of breast cancer among postmenopausal women, potentially by lowering endogenous estrogen levels. However, few studies have assessed the influence of physical activity on estrogen metabolism; these studies mainly used self-reported measures and focused on only two metabolites, 2-hydroxyestrone and 16α-hydroxyestrone. Estrogen metabolism occurs via hydroxylation at the C-2,-4, or -16 positions, resulting in at least 13 metabolites with potentially different genotoxic and mitogenic effects. In the NCI Polish Breast Cancer Study, we previously reported significant reductions in breast cancer risk with objective measures of activity. Here we present the first study to date to assess the role of accelerometer-measured physical activity on a comprehensive profile of 15 urinary estrogens and estrogen metabolites (EM) among postmenopausal women (N=540) ages 40 to 74 years, not currently on menopausal hormone therapy. Participants were controls from a population-based case-control study conducted in Warsaw, Poland from 2000 to 2003. Women wore an accelerometer on their waist during waking hours for 7 days and provided a 12-hour urine sample. Overall activity was defined by counts per day and was averaged for monitored days with at least 10 hours of wear time. Urinary EM were measured using liquid chromatography-tandem mass spectrometry; EM were standardized by creatinine, assessed by enzyme linked immunoassay. EM were log transformed and analyzed individually, in metabolic pathways (C-2, -4, or -16), and as ratios relative to the parent estrogens (estradiol and estrone). Geometric means of EM by tertiles of activity, adjusted for age and body mass index, were computed based on linear models. Statistical heterogeneity in mean EM levels across activity tertiles was assessed using a Wald test (p-het). High overall activity was associated with lower mean levels of estrone (p-het=0.02) and estradiol (p-het=0.009). With regard to individual metabolites, high activity was inversely associated with 2-methoxyestrone (p-het=0.02), 2-methoxyestradiol (p-het=0.04), estriol (p-het=0.03), and 17-Epiestriol (p-het=0.03). No other significant associations were observed for the individual EM. Examination of specific hydroxylation pathways relative to the parent estrogens revealed that women in the highest tertile of activity had increased hydroxylation at the C-2, -4, and -16 sites (p-het ≤ 0.03). Analyses by intensity of activity and sedentary behavior are ongoing. Our findings with accelerometer-measured physical activity are consistent with prior studies reporting a reduction in estrogen levels with increased activity. Furthermore, our results suggest that increased physical activity may lower endogenous estrogens by increasing hydroxylation, and subsequent metabolism, of estrogens. Citation Format: Cher M. Dallal, Louise A. Brinton, Charles E. Matthews, Ruth Pfeiffer, Terryl Hartman, Jolanta Lissowska, Roni Falk, Montserrat Garcia-Closas, Xia Xu, Timothy D. Veenstra, Gretchen L. Gierach. Is accelerometer-measured physical activity associated with urinary estrogens and estrogen metabolites among postmenopausal women?. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2519. doi:10.1158/1538-7445.AM2013-2519

Advances in menopausal therapy: The tissue‐selective estrogen complex

Most menopausal women experience vasomotor symptoms, vulvar-vaginal atrophy, and/or bone loss. Although available estrogen and progestin therapies are effective in treating menopausal symptoms and preventing bone loss, some women may seek a therapy that provides symptom relief and has an improved tolerability profile. One option is a tissue-selective estrogen complex (TSEC), or the pairing of estrogen(s) with a selective estrogen receptor modulator (SERM) to achieve the benefits of each component with fewer side effects. The first TSEC in clinical development combines the SERM bazedoxifene (BZA) with conjugated estrogens (CEs). The purpose of this article is to review published data for BZA/CE. Data were obtained from phase 3 BZA/CE clinical trial study articles. Daily BZA 20 mg/CE 0.625 mg or 0.45 mg effectively relieved hot flushes, maintained or increased bone mineral density, treated vulvar-vaginal atrophy, and improved quality of life. Further, BZA prevented stimulation of the endometrium by CE, and resulted in rates of amenorrhea and breast pain similar to placebo. These results support the use of a TSEC consisting of BZA/CE as a promising therapy for managing the signs and symptoms from reduced estrogen levels associated with menopause.

Metabolic Dysfunction Under Reduced Estrogen Levels

Loss of estrogen function leads to the development of metabolic dysfunction that spans numerous tissues. In this review, we explore the concept that estrogens are critical for defining metabolic function in adipose and hepatic tissues and also the possibility that exercise training should be considered a substitute for estrogen replacement therapy in women with impairments in estrogen levels.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Alterations in the osteocyte lacunar–canalicular microenvironment due to estrogen deficiency

While reduced estrogen levels have been shown to increase bone turnover and induce bone loss, there has been little analysis of the effects of diminished estrogen levels on the lacunar–canalicular porosity that houses the osteocytes. Alterations in the osteocyte lacunar–canalicular microenvironment may affect the osteocyte's ability to sense and translate mechanical signals, possibly contributing to bone degradation during osteoporosis. To investigate whether reduced estrogen levels affect the osteocyte microenvironment, this study used high-resolution microscopy techniques to assess the lacunar–canalicular microstructure in the rat ovariectomy (OVX) model of postmenopausal osteoporosis. Confocal microscopy analyses indicated that OVX rats had a larger effective lacunar–canalicular porosity surrounding osteocytes in both cortical and cancellous bone from the proximal tibial metaphysis, with little change in cortical bone from the diaphysis or cancellous bone from the epiphysis. The increase in the effective lacunar–canalicular porosity in the tibial metaphysis was not due to changes in osteocyte lacunar density, lacunar size, or the number of canaliculi per lacuna. Instead, the effective canalicular size measured using a small molecular weight tracer was larger in OVX rats compared to controls. Further analysis using scanning and transmission electron microscopy demonstrated that the larger effective canalicular size in the estrogen-deficient state was due to nanostructural matrix-mineral level differences like loose collagen surrounding osteocyte canaliculi. These matrix-mineral differences were also found in osteocyte lacunae in OVX, but the small surface changes did not significantly increase the effective lacunar size. The alterations in the lacunar–canalicular surface mineral or matrix environment appear to make OVX bone tissue more permeable to small molecules, potentially altering interstitial fluid flow around osteocytes during mechanical loading.

P-1101 - Meizitang, oestrogen levels and psychosis in a transsexual - case report and literature review

The authors would like to report on, what we believe is the first reported case in the United Kingdom, of a 29 year old transsexual, who developed an acute psychotic episode due to a fall in Oestrogen levels and intake of Meizitang. We discuss the aetiology of his presentation, the protective effects of Oestrogen and the psychotic effects of Meizitang. Case-report, Literature review and Discussion. AB was a 29 year old transsexual admitted with a two week history of paranoid delusions and auditory hallucinations. He had recently reduced his Oestrogen tablets from 4 mg to 2 mg per day. He had also been taking Meizitang “a natural herbal” slimming pill, bought online. He presented with paranoid, persecutory delusions, first and third person auditory hallucinations and poor insight. He was treated with Quetiapine, recovered completely within 2 weeks and was discharged. We propose that the reduction in Oestrogen levels, the intake of Meizitang and the cognitive dissonance associated with his gender identity contributed to the development of psychosis. Our literature review revealed several studies that implicated Sibutramine (which Meizitang is known to be adulterated with) as an aetiological factor for psychosis. We also report on studies that demonstrated the anti-psychotic effects of Oestrogen. This case highlights the need for further studies on both the protective effects of Oestrogen in psychosis and the psychogenic effects of Meizitang. We recommend increased awareness amongst clinicians about the potential risk of psychosis associated with Meizitang.

Pre-Eclampsia and Breast Cancer Risk: “Fertile” Ground for Elucidating New Mechanisms of Prevention?

associated with breast cancer (with an odds ratio of 0.7 and 95% confidence interval of 0.5 to 1.0); the reported association was found to be even stronger among women who had multiple occurrences of preeclampsia (with an odds ratio of 0.3 and 95% confidence interval of 0.1 to 0.9), more pronounced among postmenopausal women, but was unrelated to gestational length. Vatten et al. [21] reported a cohort study combining information both the Medical Birth and the Cancer Registries in Norway, and found that, as compared with other parous women, those with pre-eclampsia and/or hypertension diagnosed in their first pregnancy had 19% lower risk (with 95% confidence interval from 9 to 29%) for breast cancer, after adjustment for attained age, time of diagnosis, age at first birth, and parity, and was similar for both preand postmenopausal women. A key review by Innes and Byers has explored several possible intracellular mechanisms from endogenous hormone generation in pre-eclampsia which may impact each other and thus breast cancer development [22]. These include reports of reduced estrogen levels in pre-eclamptic pregnancies as compared with uncomplicated pregnancies, concomitant with a deficiency in placental aromatization of the androgen precursors dehydroepiandrosterone (DHEA) and androstenedione to estrogen, and resultant buildup of these levels. Placental tissue itself from hypertensive pregnancies has shown decreased ability to aromatize these precursor androgens [23]. While the relation of androgens to the development of breast cancer is less clear in the literature than is the impact of estrogen, some epidemiologic studies have shown that androgen levels and breast cancer may be inversely related, especially in premenopausal women and those with a family history of breast cancer [24], and therefore further clarification is required. These androgenic alterations may even impact normal breast development. Forman [25] specifically reported that a cohort of offspring of preeclamptic pregnancies and of normotensive pregnancies followed from birth through 12.8 years showed lower estrogens levels in puberty compared to their normotensive offspring; high dehydroepiandosterone- sulfate levels (DHEAS) but low testosterone levels were found in girls aged 10 years, and by 13 years, daughters of pre-eclamptic pregnancies had a 20% lower risk of mature breast tissue development (with odds ratio of 0.80 and 95% confidence interval from

Putting the Cardiovascular Safety of Aromatase Inhibitors in Patients with Early Breast Cancer into Perspective

In the adjuvant setting, the third-generation aromatase inhibitors (AIs) anastrozole, letrozole and exemestane are recommended at some point during treatment, either in the upfront, switch after tamoxifen or extended treatment setting after tamoxifen in postmenopausal patients with hormone receptor-positive early breast cancer. AIs have demonstrated superior disease-free survival and overall benefit-to-risk profiles compared with tamoxifen. Potential adverse events, including cardiovascular (CV) side effects, should be considered in the long-term management of patients undergoing treatment with AIs. AIs reduce estrogen levels by inhibiting the aromatase enzyme, thus reducing the levels of circulating estrogen. This further reduction in estrogen levels may potentially increase the risk of developing CV disease. This systematic review evaluated published clinical data for changes in plasma lipoproteins and ischaemic CV events during adjuvant therapy with AIs in patients with hormone receptor-positive early breast cancer. The electronic databases MEDLINE, EMBASE, Derwent Drug File and BIOSIS were searched to identify English-language articles published from January 1998 to 15 April 2011 that reported data on AIs and plasma lipoproteins and/or ischaemic CV events. Overall, available data did not show any definitive patterns or suggest an unfavourable effect of AIs on plasma lipoproteins from baseline to follow-up assessment in patients with hormone receptor-positive early breast cancer. Changes that occurred in plasma lipoproteins were observed soon after initiation of AI therapy and generally remained stable throughout the studies. Available data do not support a substantial risk of ischaemic CV events associated with adjuvant AI therapy; however, studies with longer follow-up are required to better characterize the CV profile of AIs.

Aromatase inhibitors in the treatment of breast cancer in post-menopausal female patients: an update

Estrogen and its metabolites play a significant role in the proliferation of hormone receptor-positive breast cancer. In postmenopausal women, aromatase inhibitors can significantly reduce estrogen levels by blocking enzyme-mediated estrogen synthesis within tissues. Third-generation aromatase inhibitors have now surpassed tamoxifen as first-line therapy for postmenopausal women with metastatic, hormone receptor-positive, breast cancer, showing improved response rates and time to progression. Aromatase inhibitors have shown incremental improvements in disease-free survival, lower local recurrence rates, lower metastatic recurrence rates, and a lower incidence of contralateral breast cancer over tamoxifen when used in the adjuvant setting. Aromatase inhibitors are recommended to be used as adjuvant therapy within the first 5 years of hormonal therapy and may be used either upfront for 5 years or sequenced with tamoxifen. No superiority of one aromatase inhibitor over another has yet been shown. The side effect profiles of aromatase inhibitors have some key differences compared with tamoxifen. These differences may influence treatment choices as well as impact compliance.

Endometriotic Implants Regress in Rat Models Treated With Puerarin by Decreasing Estradiol Level

Phytoestrogens, which have a weak estrogenic effect, bind to estrogen receptors (ERs), thereby competing with estradiol, have an antiestrogenic effect on women of reproductive age with high estrogenic level. Herein, we examined the ability of the phytoestrogen Puerarin to treat endometriosis in rat models of endometriosis. In total, 75 adult, mature female Sprague-Dawley rats in which endometriotic implants were successfully induced by transplanting autologous endometrial tissue to ectopic sites were used in this study. Oral gavage of Puerarin (at doses of 600, 200, or 60 mg/kg per day) or Danazol (80 mg/kg per day) started 4 weeks after implantation. Control model rats received vehicle alone. After administration for 4 weeks, the weight of the ectopic implants, estradiol concentration, as well as ER-α and Aromatase P450 (P450arom) expression in different groups of rat tissues were evaluated after treatment. The endometriotic tissue weight and serum estrogen levels were significantly lower in high, medium, low dose of Puerarin and Danazol treatment groups than that in control group (P < .05 or P < .01). Low-dose Puerarin inhibited P450arom expression and significantly reduced estrogen levels in endometriotic tissue (P < .01). Three doses of Puerarin had no adverse effects on liver, kidney, and ovary, whereas high-dose Puerarin administration caused thinner bone trabecula with distortion and breakage and Danazol administration caused mild or moderate hepatic cell damage. These data demonstrate that Puerarin was able to effectively suppress the growth and development of ectopic endometrium in the rat endometriosis model, even at low doses, suggesting it may be an effective treatment for endometriosis.

A dose-finding clinical trial of mushroom powder in postmenopausal breast cancer survivors for secondary breast cancer prevention.

1582 Background: We have shown that extract from Agaricus bisporus, the common white button mushroom (WBM), contains phytochemicals that suppress aromatase activity, inhibit breast cancer (BC) cell proliferation, and decrease mammary tumor formation in vivo. We now report a translational clinical trial to determine the optimal dose to induce this effect in humans. Methods: WBM were freeze-dried and pressed into a tablet containing 500mg of powdered extract, each roughly equivalent to 5g of whole WBM. Postmenopausal women diagnosed with BC at least 5 years prior, who were at least 3 months off therapy and recurrence-free, were treated with a 12-week course of 5, 8, 10, or 13g of mushroom extract daily. Aromatase inhibition was evaluated with serial serum sex steroid hormone and ex vivo plasma aromatase activity (AA) assays. Response was defined as a ≥50% decrease in free estradiol (FE2). Because immunologic effects have been reported with medicinal mushrooms, cytokines were also measured. Results: WBM extract up to 13g per day was well tolerated, with a median adherence of 95%, 96%, 95%, and 98% on the four escalating doses, respectively (n==6 each). Although no patients met the pre-defined response criterion, FE2 was observed to trend upward over the 12-week treatment course for the 5g and 8g dose groups and remain stable among the 10g and 13g dose groups (p==.05). AA measurements were able to detect a consistent post-prandial peak in activity in the 5g and 8g dose groups (p==.003 and <.001, respectively), which diminished in the 10g group and disappeared in the 13g group. Among patients with detectable baseline cytokine levels, IL-1β, IL-2, and IL-6 decreased on treatment, but there was no clear dose effect. Conclusions: High doses of WBM extract are well tolerated. An ex vivo assay of aromatase activity developed in our lab is sensitive to short-term changes and demonstrated suppression of post-prandial fluctuations with a 10g or 13g daily dose of WBM extract. These results suggest that anti-aromatase phytochemicals are present in plasma with daily consumption of 100-130g whole WBM, but not at high enough concentrations to significantly reduce estrogen levels from baseline in 12 weeks.

Inhibitory Effects of Calcitriol on the Growth of MCF-7 Breast Cancer Xenografts in Nude Mice: Selective Modulation of Aromatase Expression in vivo

Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ERα levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.

Effects of Produced Water on Reproductive Parameters in Prespawning Atlantic Cod (Gadus morhua)

Produced water (PW) discharged from offshore oil industry activities contains substances that are known to contribute to a range of mechanisms of toxicity. In the present study selected reproductive biomarkers were studied in prespawning Atlantic cod (Gadus morhua) exposed to PW. The fish were exposed for 12 wk within a continuous flow-through system at realistic environmental near-field concentrations. Concentrations of polyaromatic hydrocarbon (PAH) and alkylphenol (AP) compounds were analyzed by gas chromatography with mass spectrometric detection measurement, as were PAH and AP metabolites in fish bile for verification of exposure conditions and presence of compounds in PW. A suite of reproductive biomarkers (vitellogenin, zona radiata protein, and plasma steroid concentrations) and histological alterations of the gonads were determined. Results showed that exposure to sufficiently high levels of PW produced an increase in vitellogenin levels in female fish compared to the control. Impaired oocyte development and reduced estrogen levels were also observed in PW-exposed female fish. In male fish testicular development was altered, showing a rise in amount of spermatogonia and primary spermatocytes and a reduction in quantity of mature sperm in the PW-exposed fish compared to control. Data indicate that sufficiently high levels of PW have the potential to adversely affect the reproductive fitness of cod.

Estrogen and Energy Balance

Nonclassical estrogen signaling mediates estrogen’s effect on metabolism.

Impaired TGF-β signaling and a defect in resolution of inflammation contribute to delayed wound healing in a female rat model of type 2 diabetes

Wound healing (WH) impairment is a well-documented phenomenon in clinical and experimental diabetes. Sex hormones, in addition to a number of signaling pathways including transforming growth factor-β1 (TGF-β1)/Smads and TNF-α/NF-κB in macrophages and fibroblasts, appear to play a cardinal role in determining the rate and nature of WH. We hypothesized that a defect in resolution of inflammation and an enhancement in TNF-α/NF-κB activity induced by estrogen deficiency contribute to the impairment of TGF-β signaling and delayed WH in diabetes models. Goto-Kakizaki (GK) rats and full thickness excisional wounds were used as models for type 2 diabetes (T2D) and WH, respectively. Parameters related to the various stages of WH were assessed using histomorphometry, western blotting, real-time PCR, immunofluorescence microscopy and ELISA-based assays. Retarded re-epithelialization, suppressed angiogenesis, delayed wound closure, reduced estrogen level and heightened states of oxidative stress were characteristic features of T2D wounds. These abnormalities were associated with a defect in resolution of inflammation, shifts in macrophage phenotypes, increased β3-integrin expression, impaired wound TGF-β1 signaling (↓p-Smad2/↑Smad7) and enhanced TNF-α/NFκB activity. Human/rat dermal fibroblasts of T2D, compared to corresponding control values, displayed resistance to TGF-β-mediated responses including cell migration, myofibroblast formation and p-Smad2 generation. A pegylated form of soluble TNF receptor-1 (PEG-sTNF-RI) or estrogen replacement therapy significantly improved re-epithelialization and wound contraction, enhanced TGFβ/Smad signaling, and polarized the differentiation of macrophages toward an M2 or "alternatively" activated phenotype, while limiting secondary inflammatory-mediated injury. Our data suggest that reduced estrogen levels and enhanced TNF-α/NF-κB activity delayed WH in T2D by attenuating TGFβ/Smad signaling and impairing the resolution of inflammation; most of these defects were ameliorated with estrogen and/or PEG-sTNF-RI therapy.

Abstract P5-11-01: The Effect of Zoledronic Acid on Aromatase Inhibitor Associated Bone Loss in Postmenopausal Women with Early Breast Cancer Receiving Adjuvant Letrozole: The ZO-FAST Study 5-Year Final Follow-Up

Abstract Background: Letrozole (LET) is an accepted adjuvant endocrine therapy for hormone receptor-positive (HR+) postmenopausal early breast cancer (EBC) with superior efficacy to tamoxifen. Long term aromatase inhibitors (AI) treatment reduces estrogen levels well below postmenopausal levels leading to acceleration of bone loss. Zoledronic acid (ZOL), effectively inhibits osteoclastic bone resorption in both benign and malignant bone disorders. The primary analysis at 12 months of the Z-FAST, ZO-FAST and E-ZO-FAST studies demonstrated that lumbar spine (LS) bone mineral density (BMD) loss secondary to LET can effectively be prevented by ZOL. In addition, the 36 month (mo) follow-up for ZO-FAST demonstrated ZOL improved disease free survival (DFS). This 5 yr analysis of ZO-FAST reports the final BMD results, long term safety and DFS. Additionally, we examine the characteristics of patients in the delayed arm who required ZOL to maintain BMD. Materials and Methods: 1065 postmenopausal women (PMW) hormone receptor positive (HR+) EBC receiving LET (2.5 mg qd x 5 yrs) with a BMD T-score ≥-2 were randomized to immediate ZOL arm (IMZOL, n=532) vs delayed ZOL arm (DZOL, n=533). ZOL was initiated in DZOL when postbaseline T-score decreased to &amp;lt;-2 SD, a non-traumatic or asymptomatic fracture occurred. Patients were followed for disease recurrence (DR) and survival until 5 years after the closure of enrollment. Results: At 60 mo, LS BMD is maintained with IMZOL with a mean percent change from baseline of 4.3 vs -5.4 in DZOL (least square difference of 10%, P&amp;lt;0.0001). 144 pts (26.9%) in the DZOL started ZOL at a median of 12.8 mo (range 0.9-62.1 mo). Patients on the DZOL who started ZOL were 81/165 (49%) initially osteopenic (-2≤ Tscore &amp;lt;-1.0) and 63/370 (17%) had a normal BMD (Tscore &amp;gt;-1.0). Additional risk factors regarding bone health were evaluated in a subset of patients. The fracture rate for the two arms is 39 (7.4%) in IMZOL and 38 (7.1%) DZOL. A total of 104 patients (31 DR and 11 deaths in the IMZOL vs. 48 DR and 14 deaths in the DZOL) experienced a DFS event. The hazard ratio for the comparison is 0.66 with a 95% confidence interval (0.44, 0.97), (p = 0.034). In the IMZOL, there were 29 patients (5.5%) with a distant recurrence vs 41 (7.7%) in the DZOL. Patients with local recurrences were 5 (0.9%) vs 12 (2.3%) in the respective arms. Over the 5 year study duration, osteonecrosis of the jaw (ONJ) was found in 4/669 patients who received ZOL (0.6%). Adverse events remain as previously reported and are consistent with the known safety profile of both study drugs. Conclusion: The 5 yr final analysis confirms the primary endpoint that ZOL 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in HR+ PMW with EBC. With longer follow up, the data continues to demonstrate a significant DFS benefit in the upfront ZOL arm supporting the antitumor efficacy of ZOL seen in several tumor types. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-01.

Estrogen dependence of the renal vasodilatory effect of nicotine in rats: Role of α 7 nicotinic cholinergic receptor/eNOS signaling

Aims We recently reported that acute exposure to nicotine vasodilates the renal vasculature of male rats via facilitation of endothelial nitric oxide synthase (eNOS). In this study, we investigated whether this effect of nicotine is sexually dimorphic and the role of estrogen in modulating the nicotine effect. Main methods Nicotine-evoked vasodilation was evaluated in phenylephrine-preconstricted perfused kidneys obtained from male, proestrus female, ovariectomized (OVX) and estrogen-replaced OVX (OVXE 2) rats. Key findings Nicotine infusion (5 × 10 − 5 , 1 × 10 − 4 , and 5 × 10 − 4 M) produced greater concentration-dependent reductions in the renal perfusion pressure (RPP) in an isolated kidney from proestrus females than from males. Inhibition of NOS by N G-nitro- l-arginine abolished the nicotine-evoked reduction in RPP and abolished the gender difference in the nicotine effect. Nicotine vasodilation was also attenuated in kidneys isolated from OVX and diestrus rats, models characterized by reduced estrogen levels. Further, estrogen or l-arginine supplementation in OVX rats largely restored the renal vasodilatory response to nicotine. Estrogen receptor blockade by tamoxifen abrogated the enhanced nicotine-evoked vasodilation elicited by E 2 in OVX rats. The nitrite/nitrate levels and protein expressions of eNOS and α 7 nicotinic cholinergic receptor (α 7 nAChRs) were significantly higher in renal tissues of OVXE 2 compared with OVX rats, suggesting a facilitatory effect for E 2 on α 7 nAChRs/eNOS signaling. Significance Estrogen-dependent facilitation of NOS signaling mediates the enhanced vasodilator capacity of nicotine in the renal vasculature of female rats. Preliminary evidence also suggests a potential role for α 7 nAChRs in this estrogen-dependent phenomenon.