选择性雌激素受体调节剂与女性压力性尿失禁

雌激素疗法治疗女性尿失禁存在争议。本文综述雌激素与尿失禁的关系,及选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs)对尿失禁的临床观察及机制研究,为尿失禁的治疗提出新的前景。     

Selective estrogen receptor modulators inhibit the effects of insulin-like growth factors in hyperparathyroidism

BACKGROUND: Primary hyperparathyroidism (HPT) predominantly affects perimenopausal women, leading to speculations that an estrogen imbalance may be liable. We have previously demonstrated the importance of the insulin-like growth factor (IGF) axis in HPT. Because the antiestrogen tamoxifen has been shown to modulate the IGF axis, we examined the interactions of selective estrogen receptor modulators (SERMs) and IGF in HPT. METHODS; Estrogen receptors were evaluated by Western immunoligand blotting. Sixteen parathyroid glands from 19 patients were included. After adhesion, the cells were treated with IGF (I or II) +/- estrogen +/- SERMs (tamoxifen, ICI 182,780) for 96 hours in serum-free media. Proliferation was assessed by measuring tritiated thymidine incorporation. RESULTS: Both primary and secondary HPT express estrogen receptors alpha and beta. Primary and secondary HPT had comparable responses to SERMs, they were analyzed together. Compared with control (100%), IGFs (I and II) induced a significant increase in DNA synthesis. Estradiol at 10(-8) and 10(-7) mol/L (physiologic range) had no significant effects on IGF (I and II, P >.05). Both tamoxifen and ICI 182,780 inhibited basal DNA synthesis (P <.05) and abolished the effects of both IGF I and II (P <.05). CONCLUSIONS: SERMs are capable of reducing basal and IGF-stimulated DNA synthesis. This reduction in proliferation has implications for cancer biology and therapeutic potential for SERMs in HPT.     

Specific estrogen receptor modulators (SERMs)

PRINCIPLE CHARACTERISTICS: Specific estrogen receptor modulators (SERMs) are non-steroid molecules that maintain some of the agonist properties of estrogens on bone tissue and cardiovascular system, but not their stimulating effects on the gynecological sphere. OLD AND NEW MOLECULES: SERMs were formerly known as "antiestrogens" in reference to their primary inhibition of breast tumor growth. Hence, tamoxifen has been used for many years as adjuvant treatment of breast cancer. However, its long-term use is limited by the risk of endometrial hyperplasia, which has led to the development of new molecules devoid of this side effect. Among these molecules, raloxifen, more specifically reserved for the prevention of osteoporosis in menopausal women, has been the subject of major pre-clinical and clinical developments. THE EFFECTS OF RALOXIFEN: In the prevention of postmenopausal bone loss and vertebral fractures, the effects of raloxifen have been established in several randomized, double-blind studies against placebo, which were the basis of its current marketing authorization. Moreover, raloxifen has a favorable effect on lipid profile and, contrary to oral estrogens, does not increase the C-Reactive protein. Endometrial tolerance is good and it is associated with a significant reduction in the incidence of breast cancer in elderly osteoporotic women. ITS PLACE IN THERAPY: Raloxifen's properties raise the question of its place, together with hormone replacement therapy (HRT), in the management of menopausal women. Its absence of efficacy in the control of the climacteric syndrome does not a priori make it a treatment of choice at the beginning of postmenopausal phase. However, its effects in the prevention of vertebral fracture, its good gynecological tolerance and the fact that it is easy to administer, are arguments for its administration in the prevention of osteoporosis in 60 year-old women or in relay to HRT. Its safety on gynecological level privileges its use in all women exhibiting benign breast or uterine pathologies at the origin of poor tolerance to HRT.     

Platelet vasopressin receptor in patients with chronic renal failure

The vasopressin binding to intact platelet from patients with chronic renal failure (CRF) was investigated in relation to the abnormalities in platelet aggregation. The immunoreactive arginine vasopressin (AVP) in platelet-free plasma (PFP) but not in platelets was significantly higher in non-dialyzed patients with CRF than in normal subjects. Binding studies using [3H]AVP demonstrated a decreased number of binding sites (Bmax) on platelets from patients with CRF compared to normal controls with no significant difference in affinity (Ka). A significant diminution of the maximal percentage aggregation with AVP was found in patients with CRF. An inverse relation between Bmax and the PFP AVP levels and a highly significant relation between Bmax and the maximal percentage aggregation with AVP in patients with CRF and normal controls were observed. At 4 weeks after the introduction of hemodialysis in patients with CRF, the PFP AVP levels decreased and Bmax increased significantly, and the maximal percentage aggregation tended to increase. The present findings suggest that a reduced number of AVP receptors on platelets might account for decreased platelet aggregation with AVP, and the elevated plasma AVP levels might induce a down-regulation of the AVP receptor number on platelets in patients with CRF.     

Expression of scavenger receptor CD36 in chronic renal failure patients

BACKGROUND: Patients with chronic renal failure (CRF) are at increased risk of atherosclerosis development. One of the major steps in pathogenesis of atherosclerosis is formation of foam cells. Scavenger receptor CD36 is among the major receptors for oxidized low density lipoproteins (oxLDL) and therefore it plays a crucial role in foam cell formation. The aim of the present study was to investigate the expression of CD36 on blood monocytes of CRF patients. METHODS: Expression of CD36 on blood monocytes of CRF patients treated with hemodialysis (HD), peritoneal dialysis (PD), those not yet on dialysis (predialysis), and controls was assessed with the use of flow cytometry. Additionally, the major lipid peroxidation markers, malondialdehyde (MDA) and 4-hydroxyalkenals (HAE), were measured. Further, impact of treatment with HMG-CoA reductase inhibitors (statins) on CD36 expression in CRF patients was evaluated. RESULTS: Expression of monocyte CD36, measured as mean fluorescence intensity (MFI) was significantly higher in HD and PD patients, when compared to controls without renal insufficiency (respectively: 1011 +/- 288 and 1000 +/- 309 vs. 710 +/- 313; P < 0.01 for both groups). This was not the case in predialysis group (828 +/- 363 vs. 710 +/- 313). Higher concentrations of lipid peroxidation indicators, MDA and HAE were observed in all three subgroups of CRF patients (2.1 +/- 0.51, 2.02 +/- 0.27, and 1.81 +/- 0.53 microm in HD, PD, and predialysis group, respectively, vs. 1.13 +/- 0.59 microm in controls; P < 0.01). Patients treated with statins showed significantly lower CD36 expression than patients without statin therapy. CONCLUSIONS: The present study, for the first time, demonstrates increased expression of CD36 scavenger receptor in CRF patients. This may be a possible risk factor for accelerated atherogenesis observed in this group of patients.     

选择性雌激素受体调节剂所致绝经前子宫内膜增厚98例分析

目的探究以不同内膜厚度作为界值诊断选择性雌激素受体调节剂(SERM)所致子宫内膜病变的效果,以及分析SERM所致子宫内膜病变的可能危险因素。方法回顾性分析2001年5月至2016年5月98例口服SERM的绝经前乳腺癌患者因超声发现子宫内膜增厚行诊断性刮宫术或宫腔镜下子宫内膜活检术患者的临床资料。结果 98例患者中,4例(4.08%)出现子宫内膜增生性病变。以术前超声提示的内膜厚度≥10mm作为诊断标准,诊断的灵敏度为100%,特异度为28.72%,阳性预测值为5.63%,阴性预测值为100%;以≥15mm作为诊断标准,诊断的灵敏度为75%,特异度为68.08%,阳性预测值为9.09%,阴性预测值为98.46%。卡方分析提示年龄、用药时间、药物种类、停经史和症状等因素与内膜增生性病变无显著关联(P0.05)。结论绝经前乳腺癌患者应用SERM后可能导致子宫内膜厚度增加,但子宫内膜增生性病变风险并没有明显增加,提示患者可减轻用药期间因子宫内膜增厚而产生的顾虑;经阴道超声检查仍是首选的筛查手段,当内膜厚度≥15mm或内膜厚度≥10mm伴有其它危险因素时建议进一步处理。     

Antiestrogens and selective estrogen receptor modulators reduce prostate cancer risk

The development of chemoprevention strategies against prostate cancer would have the greatest overall impact both medically and economically against prostate cancer. Estrogens are required for prostate carcinogenesis. Estrogenic stimulation through estrogen receptor alpha in a milieu of decreasing androgens contributes significantly to the genesis of benign prostatic hyperplasia, prostate dysplasia, and prostate cancer. The ability of antiestrogens and selective estrogen receptor modulators (SERMs) to delay and to suppress prostate carcinogenesis is supported by preclinical, clinical, and epidemiological studies. SERMs have many features that make them attractive candidates for prostate cancer chemoprevention including their favorable safety profile and efficacy in preclinical prostate cancer models. The true clinical benefits of SERMs for chemoprevention to prevent prostate cancer, however, should continue to be investigated through human clinical trials. A phase IIb/III human clinical trial is currently evaluating safety and efficacy of toremifene, a SERM, in men who have high-grade prostatic intraepithelial neoplasia.     

Clinical results of selective estrogen receptor modulators (SERM)

The SERMs (selective estrogen receptor modulators) are a new class of molecules that bind to the estrogen receptor, resulting in an estradiol agonist or antagonist response according to the target tissue. Raloxifene, a new SERM, has been shown to prevent postmenopausal bone loss, to reduce the risk of vertebral fractures in osteoporotic women, to decrease serum cholesterol and its LDL fraction, and to reduce significantly the risk of breat cancer. Raloxifene is available in France for the prevention of post-menopausal osteoporosis.     

Endotoxemia in chronic renal failure

In the past years dialyzers have been improved, and consequently pyrogenic reactions have become rare. However, some patients in our dialysis unit have shown symptoms during hemodialysis which we suspected could be caused by endotoxins. These patients, as well as controls without similar symptoms, had elevated levels of circulating endotoxin. We therefore measured endotoxin in blood from patients with chronic renal failure and different kinds of treatment. Serum samples were analyzed with a sensitive method described in the literature, using a chromogenic substrate and Limulus amebocyte lysate. In patients on hemodialysis (mean +/- SEM) the endotoxin value in samples taken immediately before dialysis was 40 +/- 4.7 ng/l and significantly elevated (p less than 0.001) compared with the endotoxin value (7 +/- 0.6 ng/l) found in the healthy reference group. Increased endotoxin levels were also seen in patients on hemofiltration (19 +/- 7.5 ng/l) and in patients with conservative treatment and various degrees of renal insufficiency (17 +/- 2.5 ng/l). Patients on peritoneal dialysis and renal-transplanted patients had levels not different from the controls. The mechanism behind endotoxemia in uremia is unknown but may partly be explained by reduced endotoxin elimination due to impaired liver macrophage function. The differences in endotoxin levels in patients on peritoneal or hemodialysis treatment may reflect that extracorporeal circulation enhances endotoxin entrance to the circulation and/or that endotoxin clearance is dependent on the dialysis regimen.     

Myoglobinuria in chronic renal failure

Serum and urine myoglobin levels were determined on 14 patients with stable chronic renal failure. Serum myoglobin ranged from 38 to 350 ng/mL. Eleven patients had myoglobinuria between 15 and 250 ng/mL; none developed myoglobinuric renal failure. Fractional excretion of myoglobin in the myoglobinuric patients increased as creatinine clearance decreased, although there was no correlation between filtered load and excretion rate of myoglobin. This confirms that renal failure leads to hypermyoglobinemia and usually to myoglobinuria. Surviving nephrons tend to reabsorb less of the filtered load of myoglobin as renal function diminishes.     

Parathyroidectomy in chronic renal failure

Between 1978 and 1984, 19 patients at Royal Perth Hospital (RPH) underwent parathyroidectomy for secondary (renal) hyperparathyroidism. This represented 6.0% of the overall dialysis population treated at RPH during this period of time. The mean duration of pre-operative dialysis for these 19 patients was 48 months, compared with a mean duration of 30 months for the overall dialysis population. The principal indications for parathyroidectomy were symptomatic hyperparathyroid bone disease (10), hypercalcaemia (six), progressive lower limb ischaemia (two) and painful peri-articular calcification (one). The complications of chronic renal failure that were most consistently improved by parathyroidectomy were the clinical, radiological and biochemical manifestations of hyperparathyroid bone disease and hypercalcaemia. Features such as pruritus, soft tissue calcification, vessel wall calcification and peripheral ischaemia responded less predictably. Hyperparathyroid bone disease and hypercalcaemia remain the principal indications for parathyroidectomy in chronic renal failure. Profound postoperative hypocalcaemia was the major early postoperative management problem (seven patients) and was closely linked with the severity of pre-operative hyperparathyroid bone disease. It was also seen more frequently in those patients undergoing total parathyroidectomy with immediate autotransplantation of parathyroid tissue (TP-A), than in those in whom residual parathyroid tissue was left in situ (subtotal parathyroidectomy or STP). Recurrent hyperparathyroidism (four patients) was the major late postoperative complication, but was more frequently the result of a supernumerary or previously overlooked fourth parathyroid gland (three), than due to hyperplasia of residual parathyroid tissue (one). STP and TP-A were equally effective in controlling or reversing renal hyperparathyroidism, but the former was associated with a lower incidence of postoperative management problems and should be the preferred operation in this group of patients.     

Parathyroidectomy in chronic renal failure

Parathyroidectomy was carried out in 26 patients over a 14-year period. Excellent results were obtained in patients with severe hyperparathyroidism. Vascular calcification, hypercalcaemia and pruritus did not justify surgery unless associated with unequivocal hyperparathyroidism. 13 patients required intravenous calcium infusion for up to 2 weeks to control post-operative hypocalcaemia. Calcium requirements could be predicted from the pre-operative plasma alkaline phosphatase level. Following operation continued treatment with vitamin D was necessary to prevent hypocalcaemia. Hyperparathyroidism recurred in 1 patient after 8 years and 4 patients developed osteomalacia. Since parathyroid hormone may have toxic effects other than those on bone, maintenance of normal levels should be a long-term objective in the treatment of patients with chronic renal failure. Where large parathyroid glands are present, surgical reduction in gland mass is a logical prelude to long-term suppression of parathyroid hormone with vitamin D and phosphate-binding agents.     

Renoprotective effect of angiotensin II receptor antagonists in experimental chronic renal failure

We compared the antihypertensive and renoprotective effects of the angiotensin II receptor antagonist losartan and the calcium channel blocker verapamil in the rat with chronic renal failure. One month after five-sixths nephrectomy, male WKY rats were treated for 2 months with either losartan or verapamil. Both resulted in a similar reduction in blood pressure: from 147.1 to 112 mm Hg in losartan-treated and from 155 to 118 mm Hg (p = NS) in verapamil-treated rats. Losartan improved the creatinine clearance (difference + 17.1% as compared with + 6.6% for verapamil, p = 0.039) and prevented the increase in proteinuria: 12.26 +/- (SE) 2.33 mg/day before and 18.48 +/- 2.19 mg/day (p = NS) after therapy in the losartan-treated and 17.27 +/- 2.73 mg/day before and 32.27 +/- 10.29 mg/day after therapy (p = 0.0484) in the verapamil-treated group. In addition, losartan resulted in minimal mesangial proliferation and significantly less glomerular sclerosis and thickening of the small arterial and arteriolar walls. The changes in interstitial fibrosis and tubular hypertrophy, however, were similar in both the verapamil- and losartan-treated groups. Treatment with losartan 1 month after five-sixths nephrectomy in male WKY rats resulted in reduced blood pressure, similar to that of the verapamil-treated group. However, despite similar antihypertensive properties, losartan improved creatinine clearance and reduced proteinuria. The losartan-treated group also had a marked reduction in mesangial proliferation and less glomerular sclerosis and less reduced vascular wall thickness in renal small arteries and arterioles. However, losartan did not totally eliminate nephrosclerosis. The tubular and interstitial changes were fewer in the losartan-treated group. Thus losartan has an additional, although only partial, renoprotective effect when compared with verapamil.     

Hepatitis B vaccination and interleukin 2 receptor expression in chronic renal failure

Only 50 to 60% of dialysis patients develop anti-HBs antibodies following hepatitis B vaccination. The nonresponder state correlates with impaired monocyte function, decreased interleukin-2 (IL-2) production of T cells, and an upregulation of the IL-2 receptor system. In the present study we examined anti-HBs production after hepatitis B vaccination and the in vitro expression of IL-2 receptors in nondialyzed patients with various degrees of chronic renal failure. Forty-four patients with impaired renal function were immunized with 2 micrograms recombinant hepatitis B vaccine and boostered after one and six months. Prior to the first injection IL-2 receptor expression of activated T cells was studied by an in vitro proliferation assay. Sixty-four healthy subjects served as controls. After completion of the third vaccination 55.0% of the patients acquired antibody titers greater than 10 U/liter. The seroconversion rate did not differ between patients with lower (less than 3.5 mg/dl) and higher (greater than 3.5 mg/dl) creatinine levels. In nonresponders IL-2 receptor expression (stimulation index, SI = 10.09 +/- 1.80) was elevated compared to healthy controls (SI = 4.62 +/- 0.35, P less than 0.002) or patients who responded with a high antibody titer (greater than 50 U/liter, SI = 3.12 +/- 0.43, P less than 0.001). Patients who produced low antibody titers (less than 50 U/liter) also presented with enhanced IL-2 receptor expression. These data show that an impaired antibody production following hepatitis B vaccination and an enhanced IL-2 receptor expression of T cells may already be present in early stages of chronic renal failure.     

Fluoride-induced chronic renal failure

Renal fluoride toxicity in human beings is difficult to assess in the literature. Although experimental studies and research on methoxyflurane toxicity have shown frank renal damage, observations of renal insufficiency related to chronic fluoride exposure are scarce. We report a case of fluoride intoxication related to potomania of Vichy water, a highly mineralized water containing 8.5 mg/L of fluoride. Features of fluoride osteosclerosis were prominent and end-stage renal failure was present. The young age of the patient, the long duration of high fluoride intake, and the absence of other cause of renal insufficiency suggest a causal relationship between fluoride intoxication and renal failure.