Effects of menopausal hormone therapy-based on the role of estrogens,progestogens,and their metabolites in proliferation of breast cancer cells

Menopausal hormone therapy(MHT)has been widely used for the clinical treatment of symptoms associated with menopause in women.However,the exact nature of the relationship between MHT and the increased risk of breast cancer has not been fully elucidated.The results of the Women’s Health Initiative’s randomized controlled clinical studies showed that estrogen monotherapy was associated with a lower incidence of breast cancer as compared to estrogen-progesterone combined therapy,with an elevated risk of breast cancer.The evidence currently available from randomized trials and observational studies is based on data from different populations,drug formulations,and routes of administration.Even though the risks of MHT and breast cancer have received a great deal of attention,information regarding the unpredictable toxicological risks of estrogen and progestogen metabolism needs to be further analyzed.Furthermore,the diversity and complexity of the metabolic pathways of estrogen and different progestogens as well as the association of the different estrogen and progestogen metabolites with the increased risk of breast cancer need to be adequately studied.Therefore,this review aimed to describe the biological effects of estrogen,progesterone,and their metabolites on the proliferation of breast cancer cells,based on relevant basic research and clinical trials,to improve our understanding of the biological functions of estrogen and progestogen as well as the safety of MHT.

Optimizing menopausal hormone therapy:for treatment and prevention,menstrual regulation,and reduction of possible risks

Menopausal hormone therapy(MHT)is used to treat menopausal complaints including the genitourinary syndrome of menopause,to prevent osteoporosis,and to treat bleeding problems.Since these can be the indications also in young women,especially with POI(premature ovarian insufficiency)or with surgical menopause(bilateral oophorectomy),also the old term"Hormone Replacement Therapy(HRT)”is still used.The effective component is the estrogen component without relevant difference in the efficacy of the various MHT-preparations.Additional preventive benefits are reduction of cardiovascular disease(including prevention of diabetes mellitus and metabolic syndrome),reduction of colon cancer,and perhaps also Alzheimer's disease,if started within a Kwindow of opportunity",i.e.in perimenopause or within 6-10 years after menopause.Primary indication for progestogen addition is to avoid the development of estrogen-dependent endometrial cancer,i.e.addition not recommended in hysterectomized women.Two main schedules,sequential-or continuous-combined estrogen/progestogen regimens,are used for treatment of bleeding problems.For this and for optimizing menstrual regulation detailed recommendations are given including proposed dosages for the available different progestogens if added to oral or transdermal estradiol in different estrogen dosages.The WHI-study demonstrated the main risks using MHT within a“worst-case scenario",i.e.start of MHT in old women with high risk for breast cancer and cardiovascular diseases,whereby only^conjugated equine estro-gens”and^medroxprogesterone acetate”have been tested.One main result was that the progestogen component is decisive for the risk of breast cancer,which according to own experimental research and observational studies may be reduced using the physiological progesterone or its isomer dydrogesterone.In addition we propose to push forward research for screening patients with increased breast cancer risk like we have done in the past decade demonstrating that certain membrane-bound receptors in breast cancer tissue or blood can increase this risk.To reduce the risk of venous thromboembolism and stroke,transdermal estradiol(gels,patches,)should be used,in free combination with progesterone or dydrogesterone as"golden standard"in patients with increased risk.To increase the compliance in our patients without special risks we mostly use the available fix-combinations of estradiol/dydrogesterone getting strong efficacy,good menstrual regulation or amenorrhea,respectively,but also other combinations may be indicated to take advantage of for example androgenic or antiandrogenic progestogens.

Expression of p73, ER and PR in esophageal carcinoma and precancerous lesions

Objective： To test the expression of mutant p73, p53, ER and PR proteins in the esophageal normal mucosa, hyperplasia, dysplasia and squamous cell carcinoma, and research the clinically pathological significance and the correlation, for the early diagnosis, prognostic measure and therapy in clinic. Methods： With Immunohistochemistry, it was examined to show these tumor markers＇ expression in different epithelial lesions of 40 esophageal squamous cell carcinomas, 14 dysplasias, 14 hyperplasias and 14 normal mucosas. Results： The expression of p73 was 55%, 21%, 0% and 0% in the esophageal carcinoma, dysplasia, hyperplasia and normal mucosa, respectively. The significant difference in expression of p73 （P〈0.001） was observed between the esophageal normal mucosia, hyperplasia, dysplasia and esophageal squamous cell carcinoma with Fisher＇s exact test. Difference in expression of p73 （P〈0.05） was observed between the esophageal squamous cell carcinoma and dysplasia with X^2 test. The expression of p73 showed non-correlation with the patient＇s age, sex, tumor＇s grade, lymph-node metastasis and invasive depth （P〉0.05）; Similarly, the expression of mutant p53 was 67.5%, 35.7%, 7% and 0%, respectively; In like manner, the expression of ER was 55%, 21.4%, 14.2% and 0%, respectively; The expression of PR was 57.5%,14.28%, 0% and 0%, respectively. The significant difference in expression of PR （P〈0.001） was observed with Fisher＇s exact test. Difference in expression of PR （P〈0.05） was observed between the esophageal squamous cell carcinoma and dysplasia with x2 test. The expression of PR （P〈0.05） was correlated with lymph-node metastasis, and showed non-correlation with the patient＇s age, sex, tumor＇s grade, and invasive depth （P〉0.05）. Moreover, over-expression of mutant p53 and p73 showed significant correlation with ER and PR protein＇s positive expression （P〈0.05）. Conclusion： P73 protein may become a new tumor＇s marker to diagnose esophageal squarnous celt carcinoma. Because the expression of p73 protein was closely correlated with ER and PR, they could be simultaneously examined to help to early diagnose, prognosticate and cure esophageal carcinoma.

Expression of ΔDNMT3B Variants and Its Association with Estrogen/Progestogen Receptor Status in Breast Cancer

Objective： Our previous study has showed that △DNMT3B is the predominant form of DNMT3B in non-small cell lung cancer （NSCLC）. In this study, we aimed to explore the expression patterns of the △DNMT3B variants in breast cancer and to identify whether the pattern was similar to that in NSCLC or not and its clinical significance. Methods： Expression of seven △DNMT3B variants in 59 breast cancer and the corresponding normal tissue was measured using RT-PCR. The correlations between the expressions of △DNMT3B variants and the clinical parameters including ER/PR status, clincopathologic feature and survivals were analyzed. Results： There were significant differences in the expression ratios of △DNMT3B1-7 variants between breast cancer tissues and normal tissues （P〈0.001）. The positive ratio of △DNMT3B1-7 variants were 66%, 71%, 17%, 51%, 76.2%, 50% and 61% in tumor tissue, respectively; while 16%, 8.4%, 3.38%, 3.38%, 11.8%, 13.5% and 5.08% in the corresponding normal tissue, which was different from the pattern of △DNMT3B1-7 expression in NSCLC （62%, 76%, 2.5%, 46%, 18%, 27% and 16% in tumor tissue, respectively; while 18%, 11%, 0%, 3.3%, 0%, 0% and 0% in normal lung tissue, respectively; P〈0.0001）. Expressions of △DNMT3B2, 3B4 and 3B7 were higher in the patients with negative estrogen receptor （ER） than those with positive estrogen receptor （P=0.035, P=0.0141 and P=0.0219, respectively）. △DNMT3B7 expression was higher for the patients with negative progestogen receptor （PR） compared to those with positive progestogen receptor （P=0.0379）. Expression ratio of △DNMT3B5 in stage Ⅲ tumors is lower than that in stage Ⅰ/Ⅱ ones （P= 0.041）. But we did not find any relation between the △DNMT3B variants and the patients＇ survival. Conclusion： The pattern of △DNMT3B variants in breast cancer is different from that in NSCLC. Expressions of △DNMT3B2, 3B4 and 3B7 are associated with estrogen receptors status. While △DNMT3B7 is associated with progestogen receptor. No relation between the △DNMT3B variants and the patients＇ survival were found.

Relieving the Impacts of Oral Contraceptives on Lipids Profile by Taking Pills in a Novel Scheme

Objective To explore whether the changes on lipids profile induced by oral contraceptives could be reduced through alternatively administering two oral contraceptives of different formulations (either predominant in progestogen or estrogen) Materials &. Methods A total of 59 women aged 25- 45 were divided into two treatment groups.The subjects in Group A received oral contraceptive A (Oc A: NET 0. 600 mg + EE 0. 035 mg) and B (OcB: LNG 0. 15mg + EEO. 03 mg) alternatively during 12 treatment cycles. Each contraceptive was administrated for three cycles consecutively with starting from OcA. The subjects in the B group received OcB only during 12 treatment cycles. Fasting blood were drawn before treatment, at the end of each trimester treatment and at the end of one cycle after stopping treatment respectively. The concentrations of lipids and apolipoproteins were measured.Results OcA increased the levels of triglyceride(TG) , total cholesterol (TC), high density lipoprotein-cholesterol(HDL-c) , and apolipoprotein AI (apo AI) with statistical significance, whereas OcB significantly decreased all parameters above. As compared with the control group, the overall mean of variation in the study group was much less than that of the control group.Conclusion It indicates that the impacts of oral contraceptives on lipids profile could be moderated by means of alternatively administering Ocs of two different formulations , with estrogen-dominant or progestogen-dominant.

Expression of BI-1 protein and its significance in breast cancer

Objective： To investigate the correlations of expression of Bax inhibitor-1 （BI-1） gene and the receptors of estrogen and progestogen in breast cancer and its significance. Methods： Immunohistochemical methods had been used to detect the expressions of BI-1 gene and receptors of estrogen and progestogen in breast cancer. Results： The positive rates of expressions of BI-1 gene, estrogen receptor （ER） and progestogen receptor （PR） in breast cancer were 77.08%, 60.42% and 54.17%, respectively. The positive rate of expression of BI-1 gene was higher in the group with negative expression of ER than the positive group, their positive rates were 76.92% and 52.27%, respectively; but there was no statistical difference between the two groups with positive and negative expressions of PR. The positive rate of expression of BI-1 gene was also higher in the group with positive lymph node metastasis than the non-lymph node metastasis group, and their positive rates were 64.58% and 36.36%, respectively. The difference was statistically significant （P 〈 0.05）. Conclusion： BI-1 gene, in combination with ER, has guiding significance for patients with breast cancer to choose individual chemotherapy and radiotherapy after operation and can become an important indicator for judging the prognosis of breast cancer.

Relationship between expression of ER, PR, Her-2, Ki-67 and neoadjuvant chemotherapy effect in breast cancer

Objective: The purpose of the study was to investigate the relationship between the expression of estrogen receptor(ER), progestogen receptor(PR), human epidermal growth factor receptor(Her-2), Ki-67 and the effect of neoadjuvant chemotherapy in breast cancer. Methods: The expression of ER, PR, Her-2 and Ki-67 in 45 breast cancers which received neoadjuvant chemotherapy was detected by immunohistochemistry. Results: The effective rates in ER negative and PR negative groups were higher than those in ER positive and PR positive groups(83.3% vs 59. 4%, 82.4% vs 60.6%). There was no significant difference of the effective rate between Her-2 overexpressed group and Her-2 non-overexpressed group(81.8% vs 64.1%), and the same thing happened between Ki-67 negative group and Ki-67 positive group(67.7% vs 63.2%). Conclusion: In the patients with breast cancer, ER, PR negative ones were more sensitive to neoadjuvant chemotherapy. These patients may get more benefits from chemotherapy. ER, PR could be feasible markers for predicting the effective rate of neoadjuvant chemotherapy.

Progestogen-Only Injectable Contraceptives: The Profile of the Acceptors, Side Effects and Discontinuation in a Low Resource Setting, Nigeria

Progestogen-only injectable contraceptive is a highly effective, long lasting and reversible agent of fertility control. The objective is to determine the profile of the acceptors, side effects and indication for discontinuation of progestogen-only injectable contraceptives at UCTH, Calabar. This was a retrospective study of the clients who used progestogen-only injectable contraceptives at the family planning unit between 1st January 2008 and 31st December 2014. A total of 1392 clients used the injectable progestogen-only contraceptive out of 5986 total contraceptive users giving the prevalence rate of 23.3% over the period. Of these, 60.4% of the clients accepted the depot medroxyprogesterone acetate, while 39.6% accepted the norethisterone enanthate. It was mostly utilized by multiparous women, clients with tertiary education and those in their third decade of life. Secondary amenorrhea was the commonest side effect in 47.7% of the clients. Over the study period, 243 (19.8%) discontinued the method and 48.1% discontinued due to secondary amenorrhea while 31.4% was due to desire to get pregnant. Progestogen-only injectable contraceptive was associated with multiple side-effects, with secondary amenorrhea being the most common, and menstrual irregularity was the main reason for discontinuation. Providing adequate information to clients about this method of contraception and its probable side effects, supportive counseling during initiation of contraception and re-enforcement during follow-up visit can go a long way in enhancing patient satisfaction and hence continuation of progestogen-only injectable contraceptive despite minor side effects.

Correlation between magnetic resonance diffusion-weighted imaging ADC value of endometrial stromal sarcoma and the malignant biological features

Objective:To study the correlation between magnetic resonance diffusion-weighted imaging ADC value of endometrial stromal sarcoma and the malignant biological features.Methods:A total of 34 patients with endometrial stromal sarcoma who received surgical resection in Hubei Provincial Hospital of Integrated Chinese & Western Medicine between May 2014 and August 2016 were selected as the malignant group of the research, and 58 patients with uterine fibroids who received surgical resection between August 2015 and October 2016 were selected as the control group of the research. Magnetic resonance diffusion-weighted imaging was done before operation to measure apparent diffusion coefficient (ADC value). The lesions were collected after operation to determine the expression of proliferation genes as well as estrogen and progestogen receptors.Results:Endometrial stromal sarcoma ADC value of malignant group was significantly lower than uterine fibroid ADC value of control group;CyclinD1, Rb, Sp1, Survivin, ER , ERβ, PRA and PRB protein expression in endometrial stromal sarcoma lesions of malignant group were significantly higher than those of control group while SULT1E1 protein expression was significantly lower than that of control group;CyclinD1, Rb, Sp1, Survivin, ER , ERβ, PRA and PRB protein expression in endometrial stromal sarcoma lesions of subgroup with low ADC value were significantly higher than those of subgroup with high ADC value while SULT1E1 protein expression was significantly lower than that of subgroup with high ADC value.Conclusion: Magnetic resonance diffusion weighted imaging ADC values can be used to evaluate the malignant biological behavior of endometrial stromal sarcoma.

雌、孕激素对女性听觉功能的影响

人类感知、认知功能的性别差异与雌、孕激素有关，青春期女性雌、孕激素大量分泌会导致中枢神经系统的二性形态，同样这一性别差异也会影响听觉系统。雌激素对于听觉起到积极的保护作用，而孕激素可以通过其他类固醇受体来对抗雌激素的兴奋作用，但是目前对于不同生理周期中听觉功能的改变存在诸多分歧，本文就此相关内容进行综述。

Research Progress on Human Endometrium Decidualization In vitro Cell Models

Decidualization is a special type of differentiation of endometrial stromal cells into secretory decidualized cells,which is closely related to the occurrence of menstruation and establishment of pregnancy.Decidualization abnormalities can cause female infertility and abortion,and the decidualization modelin vitro is an important tool for studying relevant mechanisms.This article summarizes severalin vitro decidualization models in recent research from three aspects,including the selection of model cells and culture systems,evaluation of decidualization markers,and induction schemes.These models can be appropriately selected and applied in specific endometrium-related disease models,such as endometriosis,recurrent pregnancy loss,and preeclampsia.