NO EFFECT OF KININS ON DNA SYNTHESIS IN LNCaP PROSTATE CANCER CELLS

1. Prostate has kininogenase activity and expresses members of the tissue kallikrein gene family. The present study examined the effect of exogenous and endogenous kinins on growth of LNCaP prostate adenocarcinoma cells. 2. Rate of DNA synthesis was measured by incorporation over 4 h of [³H]-thymidine into a TCA insoluble fraction of LNCaP cells that had been cultured for 24 h. 3. Increased [³H]-thymidine incorporation was seen in response to 10 nmol/L testosterone (4– 103 ± 5 s.e.%), dihydrotestosterone (+ 113 ± 14%) and R 1881 (+64 ± 10%) (P± 0.001; n = 4). 4. In contrast 0.05, 5 and 1000 nmol/L lysyl-bradykinin had no effect (15 ± 4, 10 ± 9 and 5 ± 3 s.e.%, respectively; n = 7). Des-Arg⁹[Leu⁸]-bradykinin (a B₁ receptor antagonist) and/or d-Arg-[Hyp³,Thi^5,8,d-Phe⁷]-bradykinin (a B₂ receptor antagonist), 1 nmol/L, and indomethacin, 5 μmol/L, also had little or no effect. 5. In conclusion, kallidin and endogenous kinins and prostaglandins have little or no effect on DNA synthesis and therefore on the growth of LNCaP cells in comparison to the two-fold stimulation produced by androgens.     

Muscle dysfunction in male hypogonadism

Twenty-eight consecutive male patients with primary and secondary hypogonadism (14 each) were evaluated clinically and electrophysiologically for muscle dysfunction. Although generalised muscle weakness was initially reported by only 9 patients, on direct questioning, it was recorded in 19. Objective weakness was found in 13 patients and it involved both the proximal and distal limb muscles. Quantitative electromyography showed evidence of myopathy in the proximal muscle in 25 patients, i.e., reduced MUP duration and amplitude with increased polyphasia in the deltoid and the gluteus maximus. There were no denervation potentials. None of the patients showed clinical neuropathy or NCV abnormalities. Thus, the profile of muscle involvement in hypogonadism closely simulates limb-girdle muscular dystrophy and other endocrine myopathies. The incidence of muscle involvement was higher in secondary hypogonadism. Diminished androgens in primary hypogonadism and diminished growth hormone in the secondary hypogonadism are probably responsible for the myopathy.     

Endocrinology: Pattern of gonadotrophin secretion in patients with hyperandrogenaemic amenorrhoea before and after ovarian wedge resection

The follow-up of androgen and gonadotrophin concentrations afterovarian wedge resection is reported in two patients with hyperandrogenaemicamenorrhoea. Elevated testosterone concentrations decreasedimmediately and androstenedione after 3 months. In a patientwith polycystic ovarian disease, luteinizing hormone (LH) amplitudeswere reduced in the presence of unchanged pulse frequency. Smalldecreases in mean LH baseline values were accompanied by increasesin follicle stimulating hormone concentrations. Our data provideevidence that reduction of elevated ovarian androgen concentrationsleads (directly or indirectly) to a decrease of exaggeratedLH pulse amplitude in patients with hyperandrogenaemic amenorrhoea.     

Phase II study of flutamide as second line chemotherapy in patients with advanced pancreatic cancer

Androgen receptors are present in both pancreatic cancer tissue and cell lines. Flutamide is a potent antiandrogen widely used in clinical practice for patients with metastatic prostate cancer. This Phase II trial was undertaken to evaluate the impact of flutamide in patients with advanced pancreatic adenocarcinoma who had developed progressive disease following therapy with one 5-FU-based regimen. Fourteen patients were treated with flutamide, 250 mg orally three times per day. Therapy was generally well tolerated. No patient achieved objective tumor response. No patient had improvement in tumor-related symptoms as measured by improvement in pain intensity, analgesic requirement, performance status, or nutritional status. Median survival was 4.7 months. We conclude that flutamide is ineffective second line therapy for patients with advanced pancreatic adenocarcinoma.     

雌雄激素对中老年男性骨密度的影响

目的:研究中老年男性雄激素、雌激素水平和比值的变化及其与骨密度的关系。方法:将84例51～89岁中老年男性分为4个不同年龄组,测定其睾酮(T)、雌二醇(E2)水平并计算其比率(T/E2),分析不同年龄组各指标数值的变化。并测定其中24例的骨密度(BMD),与T、E2和T/E2进行直线相关分析。结果:各年龄组E2水平差别无统计学意义,T、T/E2随年龄增长逐渐降低,各年龄组的T、T/E2水平差别有统计学意义。24例不同年龄的男性的T、T/E2与BMD呈正相关,(r分别为0.80和0.92,P<0.01),E2与BMD无直线相关性。结论:在中老年男性因增龄而发生的骨量丢失中,雄激素的减少是比雌激素变化更为重要的因素。     

男性心力衰竭患者血清雄激素与细胞因子及活化蛋白的关系

目的探讨男性心力衰竭(心衰)患者血清雄激素与细胞因子及活化蛋白(activator protein-1,AP-1)的关系。方法选择160例男性心衰患者作为心衰组,心功能(NYHA)Ⅱ级40例,Ⅲ级55例,Ⅳ级65例,同期选择40例健康体检男性作为对照组,ELISA法检测外周血游离睾酮(FT)、总睾酮(TT)、去氢表雄酮(DHEA)、去氢表雄酮硫酸酯(DHEAS),白细胞介素(IL)-1β、IL-6、TNF-α、IL-10及AP-1的水平,进行相关分析。结果心衰组血清FT[(42.76±8.46)pmol/L vs(51.25±4.71)pmol/L]、TT[(14.26±3.65)nmol/L vs(17.98±2.59)nmol/L]、DHEA[(6.63±1.43)nmol/Lvs(6.39±1.39)nmol/L]、DHEAS[(1.77±0.59)nmol/Lvs(2.28±0.43)nmol/L]及IL-10水平显著低于对照组,随心功能Ⅱ级、Ⅲ级到Ⅳ级增加逐级显著下降(P<0.05,P<0.01)。心衰组血清IL-1β、IL-6、TNF-α、AP-1水平显著高于对照组,由心功能Ⅱ级、Ⅲ级到Ⅳ级增加而逐级显著升高(P<0.05,P<0.01)。心衰组FT、TT、DHEA、DHEAS与IL-1β、IL-6、TNF-α、AP-1呈负相关(P<0.05,P<0.01),与IL-10呈正相关(P<0.05,P<0.01);FT与AP-1独立负相关(P<0.01)。结论男性心衰患者血清雄激素水平减低,可能与致炎细胞因子增高、抗炎细胞因子减少及AP-1活化有关,低雄激素血症影响男性心衰的发生和发展。     

Expression of steroidogenic enzymes and sex-steroid receptors in human prostate

Identification of the cell types expressing the steroidogenic enzymes and sex steroid receptors in the human prostate has recently been performed using immunocytochemistry and in-situ hybridization. The enzymes 3beta-hydroxysteroid dehydrogenase (3beta-HSD), which converts dehydroepiandrosterone (DHEA) into androstenedione, and type 5 17beta-HSD, which catalyzes the reduction of androstenedione to testosterone, have been localized in basal cells of alveoli as well as in stromal cells and endothelial cells of blood vessels. On the other hand, type-2 5alpha-reductase, which converts testosterone into the most potent androgen dihydrotestosterone (DHT), has been mostly observed in the luminal cells in alveoli. Aromatase, which converts testosterone into estradiol, has also been found to be expressed in the luminal cells of the alveoli as well as in stromal cells. Androgen receptor (AR) has been localized in luminal cell nuclei of alveoli and a large number of stromal cells, while estrogen receptor beta has been detected in both basal and luminal cells in alveoli and also in stromal cells.     

The role of androgens on periodontal repair in female rats

1 Background

Testosterone replacement enhances cognitive function and musculoskeletal health in postmenopausal women. However, the biological role of testosterone on inflammation and bone metabolism in females is not well understood. Our objective was to measure the impact of androgens and their receptors on periodontal tissues during periodontal repair in female rats.

2 Methods

Seventy female Holtzman rats were divided into seven groups (n = 10/group): negative control; repair control; androgen receptor antagonist (flutamide, 50 mg/kg, every other day); estrogen receptor antagonist (fulvestrant, 1.5 mg/kg/day); testosterone supplementation (durateston, 250 mg/kg, weekly); aromatase inhibitor (anastrozole, 0.2 mg /kg/day); testosterone plus anastrozole. Cotton ligatures were kept for 13 days, when pharmacological treatment was initiated. On day 14, the ligatures were removed. The rats were euthanized on the 17^th or the 28^th day (n = 5/group/period) for the evaluation of markers related to inflammation and bone. The tissue and serum samples were evaluated using a multiplexed immunoassay for the inflammatory targets. Radiographic and histologic analyses were performed to assess changes in tissues.

3 Results

Blockage of androgen receptors had little effect on inflammatory cell count, although it tended to increase interleukin (IL)‐4, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) as well as decrease IL‐1β, tumor necrosis factor (TNF)‐α, and IL‐6. Flutamide also significantly impaired bone repair (P < 0.05) and had greater osteoclast count, although this last difference was not statistically significant. Testosterone supplementation significantly increased the inflammatory cell count, decreased the levels of IL‐4, IL‐10, IL‐1β, IL‐6, and TNF‐α; and increased VEGF and EGF.

4 Conclusion

The blockage of androgen receptors significantly impair bone repair in females through mechanisms that are different from those related to estrogen receptors.     

Intraprostatic testosterone and dihydrotestosterone. Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer

Owing to inconsistencies and methodological differences, the present peer-reviewed literature lacks conclusive data on the intraprostatic levels of androgens, in particular dihydrotestosterone (DHT), in untreated benign prostatic hyperplasia (BPH) and prostate cancer. To date, no difference has been shown between DHT concentrations in normal prostatic tissue and BPH, and nor has a difference been shown in DHT concentrations between the histologically distinct regions of the prostate. Recent literature has also failed to show a consistent difference in androgen level between BPH and prostate cancer. The role of intraprostatic DHT in the pathogenesis of BPH and in the initiation and progression of prostate cancer thus remains to be established. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels may lead to more optimized and more personalized forms of treatment, and probably new therapeutic targets as well.