Estrogens and SERMS as adjunctive treatments for schizophrenia

More than thirty years have passed since sex and gender differences were noted in the age of onset, course and outcomes for schizophrenia. The ‘estrogen hypothesis” was coined in the 1990′s to describe neuroprotective effects of estrogen.Intervention studies in schizophrenia patients with estradiol and selective estrogen receptor modulators (SERMs) are promising but psychiatrists and other health practitioners do not generally take up this useful adjunctive treatment for their female patients with schizophrenia. The reasons for this are manifold, but overall a cultural shift in the practice of psychiatry is needed to recognise the specific needs of women with schizophrenia and tailor treatments, such as hormone adjuncts to improve the outcomes for this significant population.The two main aims of this article are to review the evidence and theory of estrogen treatments in schizophrenia and to recommend translation of adjunctive estrogen treatment into clinical practice for women with schizophrenia.     

雌激素在膀胱癌发生发展中的作用及靶向治疗策略

雌激素是人体内一种基础性的性激素,在多种疾病的病理生理过程中发挥重要作用。雌激素在人体不同疾病的发生发展中扮演着不同的角色。膀胱癌是一种威胁人类健康的常见恶性肿瘤,在以男性病例为主的膀胱癌中,雌激素发挥了重要促瘤进展的作用,可作为重要的治疗靶点。此文就近年来雌激素在膀胱癌发生发展中的作用,以及靶向雌激素的抗癌治疗策略进行综述。     

Reproductive factors and clinical features of Parkinson's disease

BackgroundLiterature suggests that sex steroid hormones may modify the risk for Parkinson's disease (PD). We investigated the potential effect of reproductive factors on the clinical features of idiopathic PD (IPD) patients.MethodsAll IPD female patients admitted to and evaluated at our Institute over a 12-month period were included in the present cross-sectional study. We investigated the effect of the following parameters by multivariate linear regression analysis: age at menarche, age at menopause, length of fertile life, duration of exposure to endogenous estrogens and cumulative length of pregnancies, use of contraceptives and hormonal replacement therapy.ResultsIn total, 579 patients were evaluated and 497 reported menopause before PD onset. In this population, age at PD onset was positively associated with age at menarche and at menopause, length of fertile life and duration of estrogen exposure. Moreover, UPDRS motor score was inversely associated with age at menopause, length of fertile life and duration of estrogen exposure. Increasing age at menarche was also associated with predominant resting tremor at PD onset. In models refitted on patients with early PD (disease duration <5 years; N = 226) all the associations found were confirmed. The relationship between surrogates of estrogen exposure and UPDRS motor score actually became more significant.ConclusionsOur observations support the concept that hormonal exposure of the nigro-striatal network during life may influence its susceptibility to degenerative stimuli in later life, but the association does not seem to be unique? unidirectional. In particular, increased severity of PD signs correlates with shorter duration of estrogen exposure. The underlying mechanisms need to be clarified.     

雌激素通过受体介导的通路影响大鼠心脏心钠素表达

目的研究雌激素对卵巢切除大鼠心脏雌激素受体(ER)α和β的调控及对血压、心率、心肌细胞心钠素(ANP)基因表达、合成和释放的影响。方法成年雌性Wistar大鼠随机分成5组假手术组,卵巢切除组和卵巢切除不同剂量17β-雌二醇组(80、800、8000ng·g-1·d-1)。测量大鼠收缩期血压(SBP)、心率;采用半定量RT-PCR和Western印迹方法,探讨不同剂量的17β-雌二醇对卵巢切除大鼠心脏ERα和ERβmRNA、ER蛋白质的表达调控及对ANPmRNA表达的影响;放射免疫方法测定血浆和心房组织ANP含量。结果超生理剂量的17β-雌二醇能降低卵巢切除大鼠SBP,减慢心率;成年雌性大鼠心脏ERαmRNA高于ERβmRNA的表达水平,而心房ERαmRNA表达又明显超过心室;卵巢切除减少心房ERαmRNA和蛋白质的表达,下调ANPmRNA,使心房组织和血浆ANP含量明显降低[(121±19)ng/mg组织vs(184±12)ng/mg组织,(196±21)ng/Lvs(288±36)ng/L,P<0.01];生理剂量17β-雌二醇能逆转上述改变。随剂量增加,17β-雌二醇的这种作用在一定程度上呈剂量依赖性关系。但卵巢切除和17β-雌二醇替代并不影响心脏ERβmRNA、心室ERαmRNA表达。结论超生理剂量雌激素可降低卵巢切除大鼠SBP,心率;ERα的高水平表达说明ERα是雌激素对心脏调控的优势受体;雌激素对心脏作用的主要靶部位是心房;雌激素促进心房肌细胞ANPmRNA的表达、合成和释放,通过受体依赖的ANP介导的通路发挥作用。     

Causes and treatment of idiopathic benign paroxysmal positional vertigo based on endocrinological and other metabolic factors

The genesis of the Benign Paroxysmal Positional Vertigo (BPPV) seems to be related to some metabolic factors. These factors, such as vitamin D, glucocorticoids, and even thyroid and growth hormones, can affect bone metabolism and the mineralization of otoconia. It also seems to link to factors related to aging or nutritional habits. Besides, since the incidence of BPPV is quantitatively higher in women than in men, female sex steroids could be associated with this process. It could be useful to understand how these factors act in otoconial mineralization if we want to develop treatments aimed at preventing or delaying BPPV recurrences. In this review, we will analyze the role of these metabolic and hormonal factors in otoconial mineralization and in the treatment of BPPV.     

雌激素诱导胎儿血管平滑肌细胞基质金属蛋白酶-2分泌和活化

目的: 探讨雌激素对胎儿血管平滑肌细胞(HVSMC)基质金属蛋白酶-2(MMP-2)分泌及其活化的影响。方法: 分别以不同浓度的雌二醇与体外培养的HVSMC作用24h,明胶酶谱法检测细胞培养上清液中明胶酶活性。结果: 随着雌二醇剂量增加,MMP-2的酶原形式(pro-MMP-2)和MMP-2活性形式逐渐增强。0.1 nmol/L、1 nmol/L、10 nmol/L、100 nmol/L雌二醇组pro-MMP-2分别比对照组高9.4%±8.2%(P>0.05)、73.0%±13.7%(P<0.05)、229.2%±42.2%(P<0.01)、428.4%±72.3%(P<0.01), MMP-2活性形式分别比对照组高39.8%±12.9%(P>0.05)、127.2%±20.4%(P<0.01)、428.4%±37.6%(P<0.01)、683.4%±50.9%(P<0.01)。结论: 雌二醇以剂量依赖性方式促进pro-MMP-2分泌和活化。     

Gynecologic consequences of long-term, unopposed estrogen replacement therapy

We evaluated the gynecologic risks of unopposed, long-term estrogen use in postmenopausal women. Our medical record review showed that unopposed estrogen users (mean dose, 0.9 mg of conjugated estrogens) had a significantly higher (P < 0.001) incidence of abnormal vaginal bleeding, curettage, hysterectomy, and endometrial cancer. The ratios of occurrence of these events among users compared with non-users were 7.8, 4.9, 6.6 and 7.7. The prevalence of hysterectomy reached 28.2% of users compared with 5.3% of non-users, and endometrial carcinoma developed in 9.9% of users compared with 1.4% of non-users.     

The effect of hormone replacement therapy on bone mass in patients with ovarian failure due to bone marrow transplantation

Long permanent remissions in malignant hematopoietic disorders can often be achieved by autologous bone marrow transplantation (ABMT) or by allogenic bone marrow transplantation (BMT). Previous studies have shown that such therapies may induce osteoporosis due to iatrogenic ovarian failure. The administration of hormone replacement therapy (HRT) in these women could prevent the adverse effects of long-term ovarian failure without remarkable side effects. The aim of this study was to evaluate how the bone mass is affected by HRT in patients undergoing ABMT or BMT adjusting the results for age, weight, and height. Subjects and methods: Thirteen women with previous ABMT/BMT were treated with a standard dose (0.625 mg/day) of conjugated equine estrogen (CEE) or with 50 μg/day of 17-β-estradiol in transdermal therapeutic systems (TTS) plus 5 mg/day of medroxyprogesterone acetate sequentially added to the last 12 days of estrogen therapy. Bone mass was measured prior to and 12 months following HRT. Blood samples were collected before therapy and during the 6th and 12th treatment months. Results: The mean time elapsed between bone transplantation and HRT initiation was 13.0 months (range 3–26 months). Before treatment nine patients were osteopenic and after HRT bone mass increased in all cases. Following ABMT/BMT, hepatic hyperenzymemia was detected in three patients. After 6 and 12 months of treatment no significant changes were observed in hepatic enzymes. Conclusion: Although hepatic hyperenzymemia is commonly considered as a contraindication for HRT, our results suggest that HRT is safe for these patients and that such therapy should be initiated after transplantation in women to prevent adverse effects of long-term ovarian failure.     

雌激素对低氧大鼠颏舌肌肌型磷酸果糖激酶表达的影响

目的 探讨雌激素药物治疗对慢性间歇性低氧(chronic intermittent hypoxia,CIH)大鼠颏舌肌肌型磷酸果糖激酶(phosphofructokinase muscle-specific isoform,PFK-M)表达的影响,以期从能量代谢的角度探讨雌激素用于治疗阻塞性睡眠呼吸暂停低通气综合征(OSAHS)的可能机制.方法 选择2个月龄健康雄性SD大鼠50只,用随机排列表分为5组:正常对照组(NC)、慢性间歇性低氧组(CIH)、低剂量雌激素治疗组(LE)、中剂量雌激素治疗组(ME)、高剂量雌激素治疗组(HE),每组10只.后4组建立CIH模型(8 h/d,5周);后3组分别给予0.1、0.2、0.3 mg/kg的苯甲酸雌二醇肌肉注射,NC、CIH组给予无菌橄榄油肌肉注射.实时反转录聚合酶链反应(real-time RT-PCR)检测大鼠颏舌肌PFK-M mRNA表达;蛋白质印迹法分析PFK-M蛋白表达.结果 CIH组PFK-M mRNA和蛋白的表达量分别为(2.144±0.260)和(0.875±0.025),与NC组相比(1.000±0.259,0.413±0.013)均显著升高(P＜0.05).LE、ME、HE组PFK-M mRNA的表达量分别为(1.424±0.193)、(1.395±0.251)和(1.310±0.094),PFK-M蛋白的表达量分别为(0.638±0.015)、(0.576±0.017)和(0.505±0.021),与CIH组相比,3个雌激素治疗组的PFK-M mRNA和蛋白表达均显著降低(P＜0.05).3个雌激素治疗组间两两比较显示,HE组PFK-M蛋白表达量比LE组明显降低(P＜0.05),而PFK-M mRNA表达量的差异无统计学意义(P＞0.05).结论 CIH可导致大鼠颏舌肌内PFK-M转录和翻译水平的升高,而雌激素药物治疗可显著抑制PFK-M的过度表达,并呈现一定的剂量依赖趋势.