Effects of estradiol and progestogens on human breast cells: Regulation of sex steroid receptors

ObjectivesTo examine the effects of 17β-estradiol (E₂) and progestogens, used in hormone therapy, on estrogen receptors (ER), progesterone receptors (PR), and human breast tumor cell growth.Materials and methodsMCF-7 cells were incubated in pure E₂ (1 nM and 10 nM) as well as in E₂ in conjunction with 10 nM progestogens, including progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone acetate (NET), and cyproterone acetate (CPA). Cell proliferation, apoptosis, expression of caspase-3, and both ER and PR isoforms were evaluated.ResultsCaspase-3 was significantly diminished in cultures with only E₂, whereas ERα significantly increased. A significant increase of caspase-3 in addition to the entire abolishment of E₂-induced augmentation of ERα was observed in 1 nM E₂ plus MPA and 10 nM E₂ plus NET, whereas PR isoform B (PRB) was significantly increased. The ratios of apoptosis: proliferation significantly increased in 1 nM E₂ plus progestogens (except P4) and 10 nM E₂ plus NET. The changes of the PRA/PRB ratio were inversely related to the changes of the apoptosis to proliferation ratio. Significant increase of ERβ and PRB was noted in the E₂ plus MPA or NET, in addition to a significant increase of ERα and decrease of PRA in the E₂ plus CPA, as well as an increase of ERα and decrease of PRA and PRB in the E₂ plus P4.ConclusionsThe combination of E₂ and various progestogens resulted in diverging effects on ERs and PRs expressions, which induced different effects on MCF-7 cell growth. Compared with P4, aberrant hormone and biological activity of synthetic progestin, by way of altered receptor expression, may be an important factor in affecting breast cell growth.     

子宫内膜异位症孕酮抵抗机制研究进展

子宫内膜异位症（EMs）中异位内膜周期性出血形成的病灶导致女性严重的盆腔疼痛与不孕.EMs是一种雌二醇（E2）依赖性疾病,孕酮是拮抗E2的经典药物.EMs患者血清孕酮水平正常,但子宫内膜对孕酮的反应性却明显下降,导致着床期子宫内膜容受性下降,不孕症发生率增加.在临床治疗中,多数EMs患者对孕酮治疗呈现低反应或无反应,这些都称为EMs的孕酮抵抗现象.孕酮抵抗机制涉及孕酮受体（PR）的缺陷,PR辅激活子的改变,基因和环境因素的变化以及雌激素受体亚型的改变等.综述有关EMs孕酮抵抗的相关机制,为克服EMs孕酮抵抗提供理论基础.     

Biomarker assessment and molecular testing for prognostication in breast cancer

Current treatment of breast cancer incorporates clinical, pathological and molecular data. Oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) define prognosis and identify tumours for targeted therapy, and remain the sole established single‐molecule biomarkers defining the minimum breast cancer pathology data set. Ki67 remains one of the most promising yet controversial biomarkers in breast cancer, implemented routinely in some, but not all, pathology departments. Beyond the single‐molecule biomarkers, a host of multigene expression tests have been developed to interrogate the driver pathways and biology of individual breast cancers to predict clinical outcome more accurately. A minority of these assays have entered into clinical practice. This review focuses on the established biomarkers of ER, PR and HER2, the controversial but clinically implemented biomarker Ki67 and the currently marketed gene expression signatures.     

Mechanism of bisphenol AF‐induced progesterone inhibition in human chorionic gonadotrophin‐stimulated mouse Leydig tumor cell line (mLTC‐1) cells

Bisphenol AF (BPAF) has been shown to inhibit testicular steroidogenesis in male rats. However, the precise mechanisms related to the toxic effects of BPAF on reproduction remain poorly understood. In the present study, a mouse Leydig tumor cell line (mLTC‐1) was used as a model to investigate the mechanism of steroidogenic inhibition and to identify the molecular target of BPAF. Levels of progesterone and the concentration of cyclic adenosine monophosphate (cAMP) in cells exposed to BPAF were detected, and expression of key genes and proteins in steroid biosynthesis was assessed. The results showed that BPAF exposure decreased human chorionic gonadotrophin (hCG)‐stimulated progesterone production in a dose‐dependent manner. The 24‐h IC₅₀ (half maximal inhibitory concentration) value for BPAF regarding progesterone production was 70.2 µM. A dramatic decrease in cellular cAMP concentration was also observed. Furthermore, BPAF exposure inhibited expression of genes and proteins involved in cholesterol transport and progesterone biosynthesis. Conversely, the protein levels of steroidogenic acute regulatory protein (StAR) were not altered, and those of progesterone were still decreased upon 22R‐hydroxycholesterol treatment of cells exposed to higher doses of BPAF. Together, these data indicate that BPAF exposure inhibits progesterone secretion in hCG‐stimulated mLTC‐1 cells by reducing expression of scavenger receptor class B type I (SR‐B1) and cytochrome P450 (P450scc) due to the adverse effects of cAMP. However, StAR might not be the molecular target in this process.     

Bacteria-induced or bacterial product-induced preterm parturition in mice and rabbits is preceded by a significant fall in serum progesterone concentrations

Bacterial products are thought to induce labor by stimulating the production of pro-inflammatory cytokines and prostaglandins in gestational tissues, leading to the onset of preterm parturition. Progesterone withdrawal is a prerequisite of parturition in many species. Yet a role for progesterone in the mechanisms responsible for preterm parturition, in the setting of infection, is unclear. The current studies were conducted to determine if a fall in serum progesterone concentrations occurs before the onset of bacterial product-induced preterm parturition in animals.

Accordingly, pregnant mice at day 15 (70% gestation) were injected i.p. with Escherichia coli lipopolysaccharide (LPS; 50 μg/mouse) and timed-pregnant rabbits were inoculated transcervically with a suspension of E. coli to cause an ascending intrauterine infection. Control animals in both groups received equal volumes of sterile phosphate-buffered saline (PBS) solution. Blood specimens were collected at regular intervals and serum progesterone levels were determined by RIA. Within 14 h of LPS administration, mice delivered their pups. The median concentrations of serum progesterone were significantly lower at 1 h, 4 h, 10 h, and at the onset of preterm parturition (11–12 h) after LPS injection, compared to that in animals given PBS. Similarly, E. coli-inoculated rabbits delivered 1–2 days posttranscervical inoculation and demonstrated 60% decrease in serum progesterone within 12–24 h of inoculation compared to those given PBS. Parturition in both control groups occurred at term, following typical progesterone withdrawal. It is concluded that LPS administration to pregnant mice and ascending intrauterine infection in pregnant rabbits is associated with a dramatic fall in serum progesterone concentrations prior to the onset of parturition.     

EMAb、血清β-HCG及黄体酮联合预测早孕先兆流产结局

目的 探讨抗子宫内膜抗体(EMAb)、人绒毛膜促性腺激素(β-HCG)、黄体酮联合检查预测早孕先兆流产结局的价值.方法 将早孕先兆流产120例病例根据保胎治疗后的妊娠结局分为两组,即保胎成功组78例、保胎失败组42例,分别检测治疗前后两组血清中EMAb,β-HCG及黄体酮的含量,以评价早孕先兆流产的预后.结果 检测两组患者血清中EMAb阳性率,保胎成功组为7.69%,保胎失败组为38.10%,保胎成功组中EMAb阳性率低(P<0.05);检测两组患者血清中β-HCG及黄体酮水平,在治疗前后保胎成功组均较保胎失败组高(P<0.05);两组患者经保胎治疗后血清β-HCG均较治疗前升高(P<0.05),而黄体酮无明显变化.结论 EMAb、β-HCG、黄体酮联合检查可更准确预测先兆流产结局,为临床诊疗提供理论依据.     

孕激素受体膜元件1在颗粒细胞中的功能及女性生殖中的作用

孕激素受体膜组件1(PGRMC1)是近年来新发现的特殊受体,属于膜相关的孕激素受体(MAPR)蛋白家族。PGRMC1介导孕酮(P4)的抗有丝分裂和抗凋亡作用,并参与了颗粒细胞合成甾体激素的过程。在临床上,PGRMC1的异常表达与卵巢早衰(POF)及多囊卵巢综合征(PCOS)相关。本文就PGRMC1对颗粒细胞功能的影响、与卵泡发育的关系以及在人类生殖中的作用展开综述。