Progestins used in hormonal replacement therapy display different effects in coronary arteries from New Zealand white rabbits

Objectives: The aim of this study was in an animal model to assess the vascular effects of different progestins commonly used in hormonal replacement treatment. Methods: Fifty-six non-atherosclerotic, ovariectomized New Zealand white rabbits were randomized into seven groups: (1) medroxyprogesterone acetate (MPA), (2) norethisterone acetate (NETA), (3) conjugated equine estrogens (CEE), (4) 17-β-estradiol (E2), (5) MPA+CEE, (6) NETA+E2, (7) or placebo (n=8) and given hormonal treatment through the diet for 4 weeks. Ring segments from the left proximal coronary artery and from the distal part of the left anterior descending coronary artery were microdissected and mounted for isometric tension recordings in a myograph. The vasoconstrictory responses induced by potassium, endothelin-1, calcium and N_w-nitro- -arginine methyl ester, and the vasodilatory response induced by acetylcholine and sodiumnitroprusside were investigated. The maximum contraction/relaxation (E_max) and the concentration required to induce half the maximum response (EC₅₀) were determined. EC₅₀ values were expressed as the negative logarithm to the molar concentration, pD₂=−log EC₅₀. Results: Treatment with MPA alone caused when compared to treatment with NETA an increase in tension development in the distal coronary artery after the addition of potassium (6.36±0.36 versus 4.31±0.42 P<0.005) (single dose response, mN/mm, mean±S.E.M.) and endothelin-1 (9.41±0.82 versus 6.43±0.73 P<0.05) (E_max, mN/mm, mean±S.E.M.). Treatment with MPA compared to placebo caused an endothelin-1 induced increase of E_max in the distal coronary artery (9.21±0.87 versus 6.51± 0.65 P<0.05) and a calcium induced increase of pD₂ in both coronary arteries (2.98±0.19 versus 2.42±0.12 P<0.05, proximal coronary artery) (3.26±0.09 versus 2.9±0.1 P<0.05, distal coronary artery) (pD₂, mean±S.E.M.). Treatment with NETA compared to placebo in the proximal coronary artery, after the addition of sodiumnitroprusside caused a decrease of pD₂ (5.33±0.19 versus 5.94±0.13 P<0.05). Treatment with E2 compared to treatment with CEE in the proximal coronary artery caused a decrease of pD₂ after the addition of sodiumnitroprusside (5.00±0.16 versus 5.77±0.28 P<0.05). No significant differences were found between MPA+CEE and NETA+E2. Conclusion: Treatment with MPA alone seems to enhance the contractile response to potassium and endothelin-1 in the distal coronary artery compared to NETA, indicating that different progestins used in hormonal replacement treatment may display different effects on contractile functions of coronary arteries.     

多囊卵巢综合征患者增生期子宫内膜ER、PR含量变化的研究

目的探讨多囊卵巢综合征（PCOS）患者增生期子宫内膜ER、PR含量的变化,为治疗提供理论依据。方法选择PCOS不孕患者32例为实验组,选同期输卵管性不孕患者20例为对照组,在宫腔镜下取子宫内膜标本,行病理学检查,分析免疫组化检测子宫内膜增生早、中、晚期雌激素受体（ER）和孕激素受体（PR）在子宫内膜腺体和间质细胞的细胞核内的表达变化。结果PCOS组中腺体细胞和间质细胞ER和PR的表达在增生早、中、晚期组的免疫组化积分3组间差异均无统计学意义（P〉0．05）。对照组中腺体细胞和间质细胞ER和PR的表达随月经周期子宫内膜增生而逐渐增加,差异均有统计学意义（P〈0．05）。增生早期,ER、PR在腺体细胞和间质细胞表达的免疫组化积分比较,2组差异均无统计学意义（P〉0．05）。但增生中期,ER在腺体细胞和间质细胞表达的免疫组化积分PCOS组均较对照组减少（P〈0．05）;增生晚期,ER、PR在腺体细胞和间质细胞表达的免疫组化积分PCOS组均较对照组减少（P〈0．05）。结论PCOS患者的ER、PR缺乏周期性改变;子宫内膜增生中期ER和增生晚期ER、PR含量减少。     

类固醇激素预处理在辅助生殖技术中的应用进展

在卵巢控制性促排卵（COS）过程中,窦卵泡对卵泡刺激素（FSH）的敏感性和充分利用率以及窦卵泡的协调生长是对促排卵效果起决定性作用的两个重要因素。越来越多的证据表明,类固醇激素预处理（复方口服避孕药、人工合成的雌二醇和孕激素）有效抑制或减弱早发的黄体期FSH抬头,使上述两个因素均受到积极影响,这些预处理措施可能对助孕结局产生决定性作用。然而,在COS前常规进行复方口服避孕药预处理或单独使用雌激素或孕激素预处理是否会提高体外受精（IVF）妊娠率和活产率,目前尚缺乏共识。汇总近年来相关临床研究进展,综述复方口服避孕药、雌激素及孕激素预处理在不同类型患者和不同卵巢刺激方案中的应用及其对辅助生殖技术助孕结局的影响。     

雌、孕激素对子宫内膜癌细胞株HEC-1B ERRα表达调控的研究

目的:探讨ERRα与雌、孕激素的相互作用及其在ERα阴性子宫内膜癌发病中的作用。方法:用MTT、实时定量PCR方法,检测不同浓度雌二醇(E2)、孕酮(P)作用于HEC-1B细胞后细胞增殖和ERRα mRNA的变化。结果:E2促进细胞增殖,E2(10-6～10-8mol/L)组OD值与对照组相比在48h时有统计学差异(P0.05);E2明显上调ERRα表达,且10-7mol/L时上调最明显,Pearson相关分析ERRα mRNA表达含量与相应细胞生长变化显示:24、48h呈正相关(P0.05),表明雌激素通过上调ERRα表达而诱导细胞增殖。P抑制细胞增殖,并具有浓度和时间依赖性,P(10-4～10-6mol/L)组OD值与对照组相比差异有统计学意义(P0.05);P明显下调ERRα表达,且10-4mol/L时下调最明显,Pearson相关分析ERRαmRNA表达含量与相应浓度细胞生长变化在24h呈正相关(P0.05),表明孕激素通过下调ERRα表达而抑制细胞增殖。结论:ERRα在ERα阴性子宫内膜癌的发生中发挥一定作用。     

Effect of progestins on immunity: medroxyprogesterone but not norethisterone or levonorgestrel suppresses the function of T cells and pDCs

Objectives

The potential effect of hormonal contraception on HIV-1 acquisition and transmission represents an important public health issue. Several observational studies have suggested an association between the use of hormonal contraception, in particular injectable depot medroxyprogesterone acetate (DMPA), and an increased risk of HIV-1 acquisition and transmission. We and others have previously demonstrated that DMPA acts as a potent inhibitor of innate and adaptive immune mechanisms. The study presented here addresses the immunomodulatory properties of several common progestins with a potential to replace DMPA.

Study design

To identify safe alternatives to DMPA, we tested the effect of commonly used progestins on the function of human primary T cells and plasmacytoid dendritic cells (pDCs) obtained from the blood of healthy premenopausal women.

Results

Medroxyprogesterone acetate (MPA) inhibited the activation of T cells and pDCs in response to T cell receptor- and Toll-like receptor-mediated activation at physiological concentrations. Etonogestrel exerted a partial suppressive activity at high concentrations. In sharp contrast, norethisterone (NET) and levonorgestrel (LNG) did not exhibit detectable immunosuppressive activity.

Conclusion

Evidence indicating the immunosuppressive properties of DMPA strongly suggests that DMPA should be discontinued and replaced with other forms of long-term contraception. Since NET and LNG do not exert immunosuppressive properties at physiological concentrations, these progestins should be considered as alternative contraceptives for women at high risk for HIV-1 infection.

Implications

The presented data suggest that, at physiological levels, the progestins NET and LNG do not suppress cytokine production by immune cells and should be considered as alternatives to DMPA; however, more in vivo testing is needed to confirm this data.     

早期子宫内膜癌及子宫内膜重度不典型增生给予口服大剂量孕激素的妊娠结局分析

目的探讨大剂量孕激素保守治疗早期子宫内膜癌及子宫内膜重度不典型增生的妊娠结局及相关影响因素。方法2008年6月至2013年1月收治的早期子宫内膜癌（58例）及子宫内膜重度不典型增生（33例）共91例患者,采用连续口服大剂量孕激素治疗,每3个月诊刮了解子宫内膜变化情况,病理检查证实完全缓解后给予个体化的后续治疗。回顾性分析其妊娠结局及相关影响因素。结果91例中87．9％（80／91）患者获得完全缓解,迫切要求生育且随诊时间满12个月者有61例。共有29例患者成功妊娠35次,妊娠率为47．5％（29／61）;22例获得活产儿,生育率为36．1％（22／61）。妊娠与否与患者年龄、治疗前合并症、治疗时间及治疗前子宫内膜病理诊断结果（子宫内膜重度不典型增生还是子宫内膜癌）无关（P〉0．05）。采用体外受精-胚胎移植助孕、口服促排卵药物及未助孕治疗期待自然妊娠者妊娠率分别为13／13,12／29和4／19,三者比较差异有统计学意义（P〈0．05）。结论连续口服大剂量孕激素保守治疗早期子宫内膜癌及子宫内膜重度不典型增生可获得较高的完全缓解率;助孕技术可显著提高治疗后的妊娠率。     

Progestins in the menopause in healthy women and breast cancer patients

At present, more than 200 progestin compounds are synthetized, but their biological effects are different: this is function of their structure, receptor affinity, metabolic transformations, the target tissues considered, dose. The action of progestins in breast cancer is controversial; some studies indicate an increase in breast cancer incidence, others show no differences, and yet others indicate a decrease. Many studies agree that treatment with progestins plus estrogens at a low dose and during a limited period (less than 5 years) can have beneficial effects in peri- and post-menopausal women. It was demonstrated that various progestins (e.g. nomegestrol acetate, medrogestone, promegestone), as well as tibolone and its metabolites, can block the enzymes involved in estradiol bioformation (sulfatase, 17β-hydroxysteroid dehydrogenase) in breast cancer. Progesterone is converted into various metabolic products: in normal breast tissue the transformation is mainly to 4-ene derivatives, whereas in the tumor tissue 5α-pregane derivatives are predominant. Aromatase activity is the last step in the formation of estrogens by the conversion of androgens. In recent studies it was shown that 20α-dihydroprogesterone, a metabolite found mainly in normal breast tissue and having anti-proliferative properties, can act as an anti-aromatase agent. The data suggest the possible utilization of this compound in breast cancer prevention. In conclusion, in order to clarify and better understand the response of progestins in breast cancer (incidence and mortality), as well as in hormone replacement therapy or in endocrine dysfunction, new clinical trials are necessary using other progestins in function of the dose and period of treatment.     

输卵管妊娠发病机制的最新研究进展

输卵管妊娠是最常见的异位妊娠,约占异位妊娠的98%,其病因及发病机制至今尚不明确。长期以来,输卵管手术和生殖道感染等各种高危因素导致输卵管内膜形态异常、炎性粘连、管腔狭窄甚至闭塞的解剖形态学异常改变被认为是输卵管妊娠的主要病因。最近研究发现,输卵管受精卵转运异常（包括各种因素导致的输卵管平滑肌收缩或输卵管纤毛摆动改变,以及输卵管微环境改变等功能性异常）可能是导致输卵管妊娠发生的重要机制。此外,免疫因素及细胞因子也可能在输卵管妊娠形成过程中起到一定作用。     

年轻早期高分化子宫内膜样腺癌患者保守治疗新进展

子宫内膜癌（EC）是常见的妇科恶性肿瘤,对年轻未生育的早期高分化子宫内膜样腺癌患者来说,保守治疗显得尤为重要。传统保守治疗药物包括孕激素、促性腺激素释放激素类似物（GnRHa）和芳香化酶抑制剂（AIs）等。宫腔镜电切术联合孕激素治疗是年轻子宫内膜样腺癌患者保留生育功能的新型治疗方式,在缓解率、妊娠率、不良反应发生率和复发率等方面优于传统保守治疗,但目前关于手术操作及术后激素治疗尚无统一标准。肥胖EC患者应治疗肥胖以降低复发风险,其中以减重手术效果最为显著、持久。现已证实减重手术对体质量指数（BMI）≥35 kg/m2的早期高分化子宫内膜样腺癌患者是有效干预。建议BMI≥35 kg/m2或BMI≥30 kg/m2且合并代谢综合征/2型糖尿病的年轻早期高分化子宫内膜癌患者,若经非手术治疗肥胖疗效不佳,可考虑以减重手术作为辅助治疗