Use Of Estrogen Replacement Therapy Research Articles

Psoralen and Isopsoralen, Two Estrogen-Like Natural Products from Psoraleae Fructus, Induced Cholestasis via Activation of ERK1/2.

With the increasing use of oral contraceptives and estrogen replacement therapy, the incidence of estrogen-induced cholestasis (EC) has tended to rise. Psoralen (P) and isopsoralen (IP) are the major bioactive components in Psoraleae Fructus, and their estrogen-like activities have already been recognized. Recent studies have also reported that ERK1/2 plays a critical role in EC in mice. This study aimed to investigate whether P and IP induce EC and reveal specific mechanisms. It was found that P and IP increased the expression of esr1, cyp19a1b and the levels of E2 and VTG at 80 μM in zebrafish larvae. Exemestane (Exe), an aromatase antagonist, blocked estrogen-like activities of P and IP. At the same time, P and IP induced cholestatic hepatotoxicity in zebrafish larvae with increasing liver fluorescence areas and bile flow inhibition rates. Further mechanistic analysis revealed that P and IP significantly decreased the expression of bile acids (BAs) synthesis genes cyp7a1 and cyp8b1, BAs transport genes abcb11b and slc10a1, and BAs receptor genes nr1h4 and nr0b2a. In addition, P and IP caused EC by increasing the level of phosphorylation of ERK1/2. The ERK1/2 antagonists GDC0994 and Exe both showed significant rescue effects in terms of cholestatic liver injury. In conclusion, we comprehensively studied the specific mechanisms of P- and IP-induced EC and speculated that ERK1/2 may represent an important therapeutic target for EC induced by phytoestrogens.

Estrogen replacement therapy and non-hormonal medication use among patients with uterine cancer

ObjectiveAs the prognosis for endometrial cancer is excellent, management of the effects of estrogen deprivation has an important influence on quality of life. We examined the trends in the use of estrogen replacement therapy (ERT) and non-hormonal medications among patients with uterine cancer following surgery. MethodsThe MarketScan Database was used to identify patients 18–49 years who underwent hysterectomy plus oophorectomy and those aged 50–75 years who underwent hysterectomy between 2008 and 2020. ERT and non-hormonal treatments of menopause were identified preoperatively and postoperatively. After propensity score balancing, difference-in-differences (DID) analyses were performed to compare the pre-and-postoperative changes in ERT and non-hormonal medication use between groups. The trends in postoperative use of ERT were assessed and tested using Cochran-Armitage trend tests. ResultsA total of 19,700 patients with uterine cancer and 185,150 controls were identified. Overall, postoperative ERT use decreased for both age groups and for patients with and without uterine cancer. The DID in ERT use between those with uterine cancer and those with benign pathology after hysterectomy was −37.1% (95% CI, −40.5 to −33.6%) for patients 18–49 years of age and − 10.4% (95% CI, −10.9 to −9.9%) for those 50–75 years. The DID for non-hormonal medication use between those with uterine cancer and those with benign pathology after hysterectomy was 11.2% (95% CI, 7.8 to 14.7%) for younger patients and 3.4% (95% CI, 2.9 to 4.0%) for those 50–75 years. The postoperative new ERT use has been declining over time in patients with uterine cancer in those 18–49 years of age (P = .02) and those 50–75 years of age (P < .001). ConclusionsThe use of ERT is uncommon and has declined over time in patients with uterine cancer. Conversely, non-hormonal medications are more commonly used among patients with uterine cancer.

Supraphysiologic doses of 17β-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism

Background17β-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown.MethodsIn this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC–MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro.ResultssE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression.ConclusionThese data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

The Effect of the Rate of Increase of Estrogen Replacement Therapy on Bone Mineral Density Accrual in Young Patients with Turner Syndrome

BackgroundTurner syndrome (TS) is caused by partial/complete X-chromosome monosomy with variable phenotypes, characterized by hypogonadism and short stature. To achieve pubertal changes, up to 50%-79% of patients with TS require estrogen replacement therapy (ERT), and 80% have low bone mineral density (BMD). Studies show that pubertal delays are associated with decreased BMD. Currently, guidelines suggest that ERT start at 12 years, increasing slowly, simulating pubertal progression. Many studies show that ERT increases BMD in adolescents with TS, but uncertainty remains as to how the rate of increase in ERT affects BMD. MethodsInstitutional review board approval was obtained from our institution for this retrospective chart review from 1991 to 2020. Charts were requested for the database using ICD 9-10 codes for TS and patients undergoing dual-energy X-ray absorptiometry. Biometric data and medical and treatment histories were extracted from charts. Multilevel random effects models were constructed to assess the time-dependent associations between ERT and bone density parameters. The primary independent variable of interest was the rate at which patients went from initiating ERT to reaching final doses. The primary dependent variables measured were total body BMD (tbBMD) and corresponding z-scores, calculated using dual-energy X-ray absorptiometry techniques. Analyses were done with SAS software (version 9.4, Cary, NC). ResultsTwenty-eight patients met the inclusion criteria. The mean age at TS diagnosis was 6.9 years; 8 patients had monosomy X, 16 had mosaic karyotypes, and 4 had unknown karyotypes. The average age for starting hormone replacement therapy was 14.1 years. Thirteen patients had spontaneous pubertal onset before starting hormone replacement therapy. tbBMD increased significantly with age (P = .03). However, change in BMD by age did not vary between patients who reached final adult doses of ERT within 0-2.5 years compared with patients who took 2.5-5.5 years (P = .7). Patients who took 2.5-5.5 years to reach final adult doses of ERT had a more negative trend in z-scores (−2.144) in comparison with patients who took 0-2.5 years (−1.776), although this difference did not reach statistical significance (P = .15). Future larger studies are needed to better understand the relationship between duration of ERT use and tbBMD. ConclusionBMD in adolescents with TS increases with age. Neither absolute tbBMD values nor tbBMD z-scores increased faster when ERT doses were maximized within 2.5 years. This study identified a cohort of children under 12 years with TS who had not had any ERT or BMD measurements, a potential population for future larger prospective studies.

LATE and potential estrogen-related risk factors collected 30 years earlier:The 90+ Study.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30 years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16-0.95) and recent use (0.39, 95% CI: 0.16-0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: A monocentric study

Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: A monocentric study

Association of menopausal hormone therapy with gastric and colorectal cancer risks in Korean women: A nationwide population-based cohort study

BackgroundMenopausal hormone therapy (MHT) has been associated with a decreased risk of gastric cancer (GC) and colorectal cancer (CRC); however, few studies have been conducted in diverse ethnic groups, particularly in the Asian population. Therefore, the current study evaluated if MHT is inversely associated with GC and CRC in East Asia using a representative population-based study in Korea. MethodsThis retrospective cohort study was conducted using the National Health Insurance Service–National Sample Cohort 2.0 in South Korea from 2002 to 2015. A total of 196,095 women aged ≥40 years were included in the study. The numbers of participants who did and did not use MHT were 19,063 (9.7 %) and 177,032 (90.3 %), respectively. Hazard ratios (HRs) and the corresponding 95 % confidence intervals (CIs) were estimated using a time-dependent Cox proportional hazards model. Age was considered as a time scale, and other confounding factors, including income levels based on insurance premiums, region of residence, and comorbidities, were included in the multivariable-adjusted model. ResultsThe total number of incident cases of GC and CRC were 1339 (0.68 %) and 1428 (0.73 %), respectively. We observed an inverse association of the use of estrogen replacement therapy (ERT; estrogen-containing therapy regardless of other regimen types) with GC [HR (95 % CI):0.68 (0.51–0.90)], CRC [0.57 (0.42–0.78)] and gastrointestinal cancer [GI, 0.63 (0.51–0.77)]. In the analyses by CRC subsite, the risks of both colon and rectal cancers were associated with ERT. In addition, both estrogen and combined estrogen and progestogen regimens were significantly associated with CRC and GI cancer. ConclusionERT was associated with a decreased risk of GC and CRC. Our findings support the protective effect of estrogen against GC and CRC in Korean women.

Trends in use of estrogen replacement therapy for premenopausal women with gynecologic cancer after surgical menopause (372)

<b>Objectives:</b> Estrogen replacement therapy (ERT) for pre-menopau- sal women who undergo oophorectomy and surgical menopause with gynecologic cancers remains controversial. ERT may not only prevent menopausal symptoms but also decrease the risk of longterm sequelae of estrogen deprivation, including osteoporosis and cardiovascular disease. We examined trends in the use of ERT among pre-menopausal women with gynecologic cancer who underwent bilateral oophorectomy. <b>Methods:</b> The IBM Watson Health MarketScan Database was used to identify women <50 years of age with gynecologic cancer who underwent bilateral salpingo-oophorectomy (BSO) from 2008-2019. ERT was defined as any prescription of estrogen with or without progesterone filled from six weeks prior to BSO to within three years of BSO. The cumulative rates of ERT use over time, time to initiation of ERT, and duration of ERT were examined. Performance of testing associated with estrogen deprivation in young women, including bone mineral density testing, lipid screening, and diabetes screening, was examined. Cumulative rates of ERT stratified by age groups were analyzed using Kaplan-Meier analyses. A multivariable log-linear regression model was developed to examine factors associated with ERT use. <b>Results:</b> A total of 4,972 women were identified. Overall, 1,952 (38.5%) women received ERT and 3,060 (61.5%) were not treated with ERT. The rate of ERT declined year over year from a peak of 45.9% in 2008 to 17.7% in 2019. Patients aged 18-29 years had the highest rate of ERT (62.9%) use, and those aged 45-50 years had the lowest rate (31.7%). The median time to initiation of ERT was 0.4 months after BSO (IQR: 0.1-2.5 months), and ERT was used for a median of 3.4 months (IQR: 1.0-10.3 months). The cumulative rate of ERT use at 12, 24, 36 months after BSO was 36.3%, 38.9%, and 40.3%, respectively. ERT was utilized in 30.4% of women with uterine cancer, 55.7% of women with cervical cancer, and 34.3% with ovarian cancer. In a multivariable model, younger age, Medicaid recipient, concurrent hysterectomy with BSO, and diagnosis of cervical cancer were associated with higher ERT rates. By the end of 36 months of BSO, bone mineral density testing was performed in 16.6% of women who received ERT compared to 16.9% not treated with ERT, while lipid testing was performed in 70.7% and 73.0% of women in these groups, respectively. Fig. 1 <b>Conclusions:</b> The rate of ERT after surgical menopause among premenopausal women with gynecologic malignancies has declined substantially. Testing for adverse events associated with estrogen deprivation is uncommon.

The risk of Parkinson's disease in women who underwent hysterectomy before the age of menopause.

IntroductionParkinson’s disease (PD) is the second most common neurodegenerative aging disorder. Oestrogen has been shown to have a neuroprotective effect against PD in animal models.This study aimed to detect the risk of PD in women who underwent hysterectomy before the age of menopause.Material and methodsSeventy-six women with PD (study group) were recruited for this retrospective study and compared to 80 controls. Collected data included the education level, smoking, age of menopause, type of menopause (natural or surgical), past surgical history of hysterectomy, type of hysterectomy (hysterectomy only or hysterectomy with oophorectomy [unilateral, bilateral]), and use of postmenopausal oestrogen replacement therapy. The collected data were analysed to detect the risk of PD in women who underwent hysterectomy before the age of menopause.ResultsThe odds ratio (OR) and relative risk (RR) of PD was significantly higher after surgical menopause in the study group (30 [39.5%]) compared to controls (17 [21.25%]), (OR 2.4 [95% CI: 1.19–4.8]; p = 0.01, RR 1.9 [95% CI: 1.12–3.1]; p = 0.016). In addition, the OR and RR of PD was significantly higher after bilateral oophorectomy in the study group (19 [25%]) compared to controls (8 [10%]), (OR 3.0 [95% CI: 1.22–7.4]; p = 0.016, RR 2.5 [95% CI: 1.16–5.4]; p = 0.01).ConclusionsThe risk of PD increased in women who underwent hysterectomy and bilateral oophorectomy before the age of menopause, and the risk of PD did not increase whether the menopause, either natural or surgical, occurred before 48 years of age.

Abstract P1-08-07: Risk factors for high-grade and low-grade DCIS in the cancer prevention study-II nutrition cohort

Abstract Background: Nuclear grade, believed to be established early in carcinogenesis, is an indicator of ductal carcinoma in situ (DCIS) prognosis. Women with high-grade DCIS have a higher risk of local recurrence compared to women with low-grade DCIS. Risk factors for DCIS overall are well-characterized but risk factors by grade are not. Given the prognostic capabilities of grade for DCIS, it is of interest to identify whether risk factors by DCIS grade differ. Methods: Among 75,630 women enrolled in the Cancer Prevention Study-II Nutrition Cohort in 1992-1993, we identified 422 who were diagnosed with low-moderate grade DCIS (i.e. grades 1 or 2) and 355 who were diagnosed with high-grade DCIS (i.e. grade 3) during follow-up through 2013. Beginning in 1997, biennial questionnaires were administered to update exposure status, including screening mammography in the previous two years. For this analysis, these questionnaires were used to partition follow-up time into approximately two-year intervals. Because screening is strongly linked to diagnosis of DCIS, contribution of person-time within a specific interval was conditional on reporting a screening mammogram in the interval prior. Multivariate joint Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the associations of known breast cancer risk factors with DCIS overall, and with high-grade and low-grade DCIS individually. Results: Parity (HR=0.70; 95% CI: 0.63-0.78, parous vs. nulliparous), smoking status (HR=0.69; 95% CI: 0.58-0.82, current vs. never smoking) and menopausal status (HR=0.79; 95% CI: 0.73-0.87, natural menopause &amp;lt;50 years vs. natural menopause ≥ 50 years) were inversely associated with risk of DCIS overall. Whereas, positive family history of breast cancer (HR=1.46; 95% CI: 1.36-1.57), personal history of benign breast disease (BBD) (HR=1.73; 95% CI: 1.62-1.85), and current use of combination estrogen and progestin hormone replacement therapy (HR=1.15; 95% CI: 1.04-1.28) were associated with higher risk of DCIS. In analyses stratified on DCIS grade, history of BBD was more strongly associated with higher risk of low-grade (HR=2.21; 95% CI: 1.81-2.70) than with high-grade DCIS (HR=1.29; 95% CI:1.04-1.60) (p for heterogeneity=0.001). Current combination estrogen and progestin hormone replacement therapy use was associated with a higher risk of high-grade DCIS (HR=1.40; 95% CI:1.03-1.90) but not low-grade DCIS (HR=1.02; 95% CI: 0.75-1.40), but the difference by grade was not statistically significant (p=0.5). Conclusions: In this study, which is the first to comprehensively assess risk factors by DCIS grade, the association between personal history of BBD and risk of DCIS appeared to differ by grade. Due to limited power for some risk factor analyses, future studies using larger prospective cohorts or pooled data should be conducted to better identify these associations. Citation Format: Puvanesarajah S, Gapstur SM, Gansler T, Patel AV, Gaudet MM. Risk factors for high-grade and low-grade DCIS in the cancer prevention study-II nutrition cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-07.

A Cross-Sectional and Longitudinal Analysis of Trabecular Bone Score in Adults With Turner Syndrome.

Turner syndrome (TS) is associated with short stature, gonadal failure, and fractures. Spinal trabecular bone score (TBS) is a novel bone imaging modality that has not been evaluated in TS. To evaluate TBS in TS and its association with bone mineral density (BMD), prevalent fracture, and risk factors. Longitudinal study of TS from a single tertiary hospital between 2006 and 2017. Fifty-eight subjects with TS aged 20 to 49 years who underwent dual-energy X-ray absorptiometry (DXA). TBS, DXA parameters, and prevalent fractures were investigated. Normal, partially degraded, and degraded TBSs were observed in 39 (67%), 15 (26%), and four (7%) subjects, respectively. High rates of prescribed estrogen replacement therapy (ERT) with stable TBS and BMD were observed during follow-up. TBS was positively correlated with spine and femoral neck (FN) BMD and Z-scores (all P < 0.05) and negatively correlated with age (-0.004 per year; P = 0.014) and delay in ERT initiation in women with primary amenorrhea (-0.010 per year; P < 0.001). Fractures were present in 17 (31%) subjects. Low TBS had a significantly higher area under the receiver operator curve for predicting prevalent fracture than low bone mass at either the spine or FN (P < 0.05). Subjects with no history of fracture were more likely to have a normal TBS (P = 0.023). BMD and TBS can be preserved with early initiation and continued use of ERT. TBS may provide additional fracture risk prediction to standard DXA parameters in TS and needs to be validated in larger prospective studies.

Oestrogen fuels the growth of endometrial hyperplastic lesions initiated by overactive Wnt/β-catenin signalling.

Unopposed oestrogen is responsible for approximately 80% of all the endometrial cancers. The relationship between unopposed oestrogen and endometrial cancer was indicated by the increase in the number of endometrial cancer cases due to the widespread use of oestrogen replacement therapy. Approximately 30% of the endometrial cancer patients have mutations in the Wnt signalling pathway. How the unbalanced ratios of ovarian hormones and the mutations in Wnt signalling pathway interact to cause endometrial cancer is currently unclear. To study this, we have developed a uterine epithelial cell-specific inducible cre mouse model and used 3D in vitro culture of human endometrial cancer cell lines. We showed that activating mutations in the Wnt signalling pathway for a prolonged period leads to endometrial hyperplasia but not endometrial cancer. Interestingly, unopposed oestrogen and activating mutations in Wnt signalling together drive the progression of endometrial hyperplasia to endometrial cancer. We have provided evidence that progesterone can be used as a targeted therapy against endometrial cancer cases presented with the activating mutations in Wnt signalling pathway.

Effect of estradiol on fibroblasts from postmenopausal idiopathic carpal tunnel syndrome patients.

Fibrosis of the subsynovial connective tissue (SSCT) is a characteristic finding in patients with idiopathic carpal tunnel syndrome (CTS). Idiopathic CTS frequently occurs in postmenopausal women; therefore, female steroid hormones, especially estrogens, may be involved in its development. In this study, we evaluated the effect of the estradiol on the expression of genes and proteins related to fibrosis of SSCT fibroblasts from patients with idiopathic CTS. This study included 10 postmenopausal women (mean age 76 years). Fibroblasts derived from SSCT were treated with estradiol (10-4 -10-12 M), and the expression levels of TGF-β-responsive genes were evaluated. The relationships between the expression of untreated estrogen receptor α (ERα) and ERβ and changes in gene expression due to estradiol treatment were examined by quantitative real-time polymerase chain reaction. The effects of 10-4 M estradiol on collagen type I (Col1) and collagen type III (Col3) protein expression levels were also evaluated by fluorescent staining. The relationships between ERα/β and Col1/3 expression were evaluated by immunohistochemical staining. The reduction in Col1A1 mRNA expression due to estradiol treatment was positively correlated with ERα expression (r = 0.903, p < 0.01). At the protein level, expression of Col1 and Col3 were down-regulated. These results indicated that ERα-mediated signaling may be involved in the regulation of Col1A1, and its regulatory effect may be dependent on the ERα expression level. The accurate evaluation of ERα expression level in the SSCT of individual patients with idiopathic CTS might guide the effective use of new estrogen replacement therapy.

The flavanol (−)‐epicatechin improves learning, memory and anxiety behavior in ovariectomized rats

The loss of gonadal function in women during menopause is known to contribute to impaired memory and learning performance. Conversely, menopausal women using estrogen replacement therapy (ERT) can evidence improvements on these endpoints. However, the long-term use of ERT has been show to have important health risks such as increased rates for certain cancers. Supplements, such as phytoestrogens and/or flavonoids have emerged as potential alternative treatments during menopause that may offer safer options. (−)-Epicatechin (Epi), is the most abundant flavonoid present in cacao seeds. Epi is related with a number of healthy cardiometabolic effects in preclinical models and in humans. Such effects include improvements in vascular, cardiac and metabolic function, stimulation of mitochondrial biogenesis and upregulation of enzymatic and non-enzymatic antioxidant systems in tissues such as the heart and skeletal muscle. These effects appear to be related to the binding/stimulation of Epi to the G-protein estrogen receptor (GPER). However, the effects of Epi in postmenopausal female model neurological endpoints including learning, memory and anxiety are poorly understood. In this study we evaluated the effect of Epi (0.01 and 1 mg/kg body weight) on memory, learning and anxiety behavior of ovariectomized (Ovx) rats, an accepted animal model of menopause. For this purpose, Ovx rats were evaluated using two behavioral tests, 1) object recognition task (ORT) (involving short and long term memory; STM, LTM respectively) and, 2) T-maze (anxiety model). As shown in the figure, in the ORT, Ovx rats evidenced significant improvement in short and long term memory with 0.01 mg/Kg of Epi. For anxiety T-maze measures, Epi significantly reduced delayed avoidance latency markedly with the dose of 1.0 mg/Kg and escape latency with both doses of Epi. These data suggest that low dose of Epi improves the recognition memory in Ovx rats and can also reduce anxiety. The underlying mechanisms may be related to the positive effects of Epi on regulators/stimulators of mitochondrial biogenesis and oxidative stress buffering systems which we have reported to occur in senile animals. These results warrant the implementation of future studies in human subjects using Epi. Support or Funding Information DoD 150090 to FV This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Eldecalcitol increases bone mass in patients with Turner syndrome who have insufficient bone mass acquisition after estrogen replacement therapy

Most patients with Turner syndrome (TS) exhibit amenorrhea due to premature ovarian failure. Therefore, estrogen replacement therapy (ERT) is required; however, even after undergoing ERT, it is not rare for bone mass acquisition to be insufficient. This study was conducted in two stages, involving a cross-sectional and a prospective interventional study. We recruited 52 TS patients undergoing ERT due to amenorrhea (categorized into low (LB group; n = 23), and normal (NB group; n = 29) bone mass groups) and 7 TS patients who maintained ovarian function (spontaneous menstrual cycle group (MC group)) as controls. We compared bone associated markers between the three groups (LB, NB, and MC). Furthermore, the LB group had concomitant treatment with eldecalcitol (ELD) and ERT for 12 months. The bone mineral density (BMD) of the lumber spine (L2-4) and the bone metabolism markers were then compared before and after the treatment. The bone metabolism markers were significantly higher in the LB group than the NB and MC groups. Furthermore, with the concomitant use of ELD and ERT in the LB group, BMD increased significantly (pre-treatment 0.710 ± 0.056 g/cm2 vs. 0.736 ± 0.062 g/cm2 after 12 months; p < 0.001). TS patients with insufficient bone mass acquisition even after ERT were characterized by a higher turnover in bone metabolism. Therefore, the concomitant use of ELD was considered an effective adjuvant therapy for increasing bone mass.

Prevention of breast cancer.

Modifiable lifestyle factors may reduce the risk of developing breast cancer. Obesity is associated particularly with post-menopausal breast cancer. Diet is important, and exercise equivalent to running for up to 8 hours each week reduces the risk of breast cancer, both in its own right and through reducing obesity. Alcohol consumption may be responsible for 5.8% of breast cancers in Australia and it is recommended to reduce this to two standard drinks per day. Drinking alcohol and smoking increases the risk for breast cancer and, therefore, it is important to quit tobacco smoking. Prolonged use of combined oestrogen and progesterone hormone replacement therapy and oral contraceptives may increase breast cancer risk and this must be factored into individual decisions about their use. Ionising radiation, either from diagnostic or therapeutic radiation or through occupational exposure, is associated with a high incidence of breast cancer and exposure may be reduced in some cases. Tamoxifen chemoprevention may reduce the incidence of oestrogen receptor positive cancer in 51% of women with high risk of breast cancer. Uncommon but serious side effects include thromboembolism and uterine cancer. Raloxifene, which can also reduce osteoporosis, can be used in post-menopausal women and is not associated with the development of uterine cancer. Surgical prophylaxis with bilateral mastectomy and salpingo-oophorectomy can reduce the risk of breast cancer in patients carrying BRCA1 or BRCA2 mutations. For preventive treatments, mammographic screening can identify other women at high risk.

Sulfotransferase 1A1 as a Biomarker for Susceptibility to Carcinogenesis: From Molecular Genetics to the Role of Dietary Flavonoids.

Sulfotransferase (SULT) 1A1 is a phase II metabolic enzyme that catalyzes sulfate conjugation of various phenolic compounds, including endogenous substances, such as estrogens and thyroid hormones, but also different xenobiotics. Although sulfation is classically considered as a detoxification event facilitating the excretion of more water soluble metabolites from the body, in some cases such bioconversion may also lead to bioactivation of promutagens, producing highly reactive intermediates which are capable of damaging DNA and promoting carcinogenesis. The most common polymorphism in SULT1A1 (Arg213His) has an important functional impact by affecting the capacity to sulfate diverse substrates and numerous case-control studies have shown associations between SULT1A1 variants and susceptibility to different malignancies. Several factors may significantly influence such relationships, including ethnicity, gender, parity, menopausal status, use of estrogen replacement therapy, exposure to tobacco smoke or occupational chemicals. In this review article, we show that one more important determinant should be considered as a stratifying factor in studies of possible associations between SULT1A1 variants and cancer risk, i.e., the dietary intake of different flavonoids. As sulfation of bioactive plant polyphenols can change their potential anticancer activities and, on the other hand, these phytochemicals are capable to behave also as potent SULT1A1 inhibitors, the regular dietary exposure of humans to these compounds can make a great contribution to the impact of sulfation capacity on individual susceptibility to carcinogenesis. The effect of specific flavonoids as well as their interactions with other factors on associations between SULT1A1 alleles and cancer risk certainly needs further thorough studies.

Bio-identical hormones replacement therapy and the quality of life for breast cancer patients.

87 Background: Many treatments for breast cancer block the estrogen receptor or the androgen conversion of estrogen to reduce the risk of relapse. This results in a change in the hormonal milieu. Although most women tolerate the change in hormonal status, problems can arise from this change. Without estrogen, clinical symptoms include hot flashes, sleeplessness, insulin sensitivity, and mood changes. Here, it is examined that the use of estrogen and progesterone bio-identical hormone replacement therapy (BHRT) for women in the normal physiological pattern of reproductive women is expected to coincide with increased well-being and better quality of life for women with breast cancer. Methods: This BHRT approach uses bio-identical estrogen and progesterone to restore the woman’s body to normal serum levels through twice daily transdermal application. Using real “bio-identical” or plant-derived human molecular hormones compounded via a standard formula, concentration, and packaging of transdermal creams (Estradiol E2) of 1 mg/0.1ml and progesterone P4 of 20 mg/0.1 ml). Furthermore, through an understanding of hormonal mechanisms, this BHRT mimics the female reproductive cycle by following a 28 day cycle. Results: Throughout the study, women were asked to how gauge their general well-being and quality of life. Most women reported resolution of menopausal symptoms, better sleep, decreased migraines and incontinence, increased focus, and increased libido. Most patients were pleased to be on the treatment and showed general improvement in the quality of life. Conclusions: We present the general mechanisms of action for BHRT and explain clinical trials conducted over the past decade have been examining the impact on the overall well-being and quality of life for 112 patients, as well as the impact on various cancers as well as other chronic conditions. Patients reported increased energy and overall well-being. BHRT provided resolution of most all of the patients subjective anti-estrogenic complaints. It is also observed that the recurrence rate of various breast cancers was no higher than national averages. Therefore, BHRT and rhythmic dosing seems to greatly improve well-being with no increase of cancer risk.

The Efficacy Evaluation of Danggui Buxue Tang (DBT) on Menopausal Symptoms: Clinical Trial Protocol Design and Considerations

Background: Almost two third women experience hot flushes after menopause. Conventional treatment is the use of oestrogen replacement therapy or hormone replacement therapy (HRT). Although HRT is considered the most effective treatment for hot flushes, it may increase the risk of breast cancer and thromboembolic disease. Danggui Buxue Tang (DBT) is a combination of Danggui A§Â•Â¶A¦Â­Â¸ (Radix Angelicae Sinensis) and Huangqi A©Â»ÂƒA¨ÂSÂa (Radix Astragali), which has been reported in ancient Chinese medicinal literature to relieve blood deficiency in female. The aims of the clinical studies were to proof the efficacy and to find out the optimal dose of DBT for menopausal symptoms. Methods/Design: The clinical studies were consisted of two stages. Stage I was designed as a single-center, randomized, double blind, placebo-controlled parallel study. Eligible subjects were randomized to one of two groups: DBT or placebo. Stage II was designed as a multiple-dose escalation clinical trial to look for the optimum dose for menopausal women. Eligible subjects were randomized to one of three dosage groups: low, middle and high dose. Results: Through the well-designed and well-conducted clinical trials, we found that in stage I trial, in analysis by severity of flushes, there was a significant reduction in the number of mild hot flushes in DBT group but not in the placebo group. In stage II trial, there were significant reduction in hot flushes and night sweats in high and middle dose groups after 3 months treatment, however, no significant changes were seen in low dose group. Conclusion: Our experiences suggested that it was feasible to perform a well-designed TCM clinical trial although there were challenges had to deal with, such as placebo preparation, outcome/endpoints determination and batch-to-batch consistency of the study medication.

17β-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner.

This study was undertaken considering that, despite the broad use of the unopposed estrogen replacement therapy in elderly women, data on estrogen influence on the functional capacity of dendritic cells (DCs), and consequently immune response are limited. We examined the influence of 17β-estradiol on phenotype, cytokine secretory profile, and allostimulatory and polarizing capacity of splenic (OX62+) conventional DCs from 26-month-old (aged) Albino Oxford rats matured in vitro in the presence of LPS, a TLR4 agonist, and R848, a TLR7/8 agonist. In the presence of 17β-estradiol, DCs from aged rats exhibited an impaired ability to mature upon stimulation with LPS, as shown by the lower surface density of MHC II and costimulatory CD80 and CD86 molecules. 17β-Estradiol alone enhanced CD40 expression in OX62+ DCs without affecting the expression of other costimulatory molecules, thereby confirming that the expression of this molecule is regulated independently from the regulation of other costimulatory molecules. However, although R848 upregulated the expression of MHC II and CD80 and CD40 costimulatory molecules on DCs, 17β-estradiol diminished the effect of this TLR agonist only on MHC II expression. In conjunction, the previous findings suggest that LPS and R848 elicit changes in the expression of costimulatory molecules via triggering differential intracellular signaling pathways. Furthermore, 17β-estradiol diminished the stimulatory influence of both LPS- and R848-matured OX62+ DCs on allogeneic CD4+ T lymphocyte proliferation in a mixed lymphocyte reaction (MLR). Moreover, as shown in MLR, the exposure to 17β-estradiol during LPS- and R848-induced maturation diminished Th1- and enhanced Th17-driving capacity and reduced Th1-driving capacity of OX62+ DCs, respectively. This suggests that LPS and R848 affect not only the surface phenotype, but also functional characteristics of OX62+ DCs triggering distinct intracellular signaling pathways. Collectively, the findings indicate that estrogen directly acting on OX62+ DCs, may affect CD4+ lymphocyte-dependent immune response in aged female rats.