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The prevalence of breast cancer currently ranks first among Chinese women with malignant tumors, occurring during premenopausal childbearing age in more than 60% of patients. With the increasing age of women at childbirth, the wide application of assisted reproductive technology (ART) and the rejuvenation of tumor patients, the prevalence of breast cancer occurring during pregnancy (PrBC) is gradually increasing. There are many domestic and foreign expert consensus articles and guidelines on fertility preservation for children and patients of childbearing age with malignant tumors, but there is a lack of expert consensus or guidelines on fertility preservation for patients with PrBC. Considering the uniqueness of PrBC patients, there is an urgent need for a standardized suggestion regarding their fertility preservation. The Committee of Fertility Protection and Preservation of China Association for the Promotion of Health Science and Technology together with the Chinese Society of Gynecological Endocrinology affiliated with the International Society of Gynecological Endocrinology (CSGE-ISGE) organized relevant experts from different disciplines to formulate this consensus to guide fertility preservation of PrBC patients.

(1) To characterize the cytokine expression profiles of endometriosis related infertile women in comparison to fertile women with endometriosis; (2) to investigate the correlation of the cytokine levels from different tissues.100 stage IV endometriosis patients were recruited and grouped by infertility status ((1) In the infertile group, the concentrations of IL-10 within serum, PF and eutopic endometrium were all significantly higher (This is the first study comparing the levels of cytokines within four different tissues of endometriosis women with or without infertility. The study revealed that endometriosis-related infertile women possess significant differences in cytokine levels in comparison to fertile women with endometriosis. The levels of inflammatory factors from different tissues had certain positive correlations. Infertility may indicate the progress of the disease.

(1) To investigate anti-Mullerian-hormone (AMH) in adolescents with polycystic ovary syndrome (PCOS) compared to age-matched girls without PCOS; (2) to determine whether AMH is a valuable marker for diagnosing PCOS and to explore the best cutoff value in adolescents; (3) using a multivariate predictive model for the diagnosis of PCOS.Ninety girls (aged 10-20 years) recruited during two years for the PCOS-group ((A) AMH was significantly higher in PCOS patients than in controls (10.21 ± 5.85 ng/ml vs. 4.31 ± 2.84 ng/ml,AMH may be a useful biomarker for the diagnosis of PCOS in Chinese adolescent girls. A cutoff value of 6.32 ng/mL best discriminated between PCOS patients and controls. Besides AMH a multivariate predictive model should include TT.

To evaluate for the first time whether Zi Gui Nv Zhen® capsules (ZGNZC), until now used in traditional Chinese medicine (TCM) for menopausal complaints, can increase the fertility of Chinese women ...

To assess possible risk factors for female sexual dysfunction (FSD), aiming especially at smoking in China.Female Sexual Function Index (FSFI) for assessing FSD; 621 women (24-75 years) divided into 'group FSD' (FSFI≤ 26.55) and 'group No FSD' (FSFI26.55). Univariate and multivariate analysis to detect potential risk factors for FSD.Active smoking was the strongest risk factor after multiple adjustments (OR= 6.226, 95%CI = 1.561 ∼ 24.822), but passive smoking also was significantly associated with a risk of FSD (OR = 1.887, 95%CI = 1.092 ∼ 3.260) (The risk of FSD was closely related to depletion of ovarian function. Active smokers had the highest risk, but passive smoking also had a significant relationship to FSD. Although female smokers are rare in China, 'husband smoking' is frequent. Thus, our results should have significant healthcare consequences.

To investigate the correlation between abdominal adipose tissue and lumbar bone mineral density (BMD) in different menopausal periods of Chinese women.230 women were included in this cross-sectional study. Subjects were divided into a perimenopausal and postmenopausal group. Lumbar BMD was measured by QCT to assess total adipose tissue (TAT), visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). The concomitant variables age, body mass index (BMI), and endocrine hormones were also considered. Multiple linear regression was used to assess the relationship between abdominal adipose tissue and BMD.In the perimenopausal group, Spearman correlation analysis showed that there was no significant association among TAT, SAT, VAT, and BMD (allHigh VAT volume is associated with low lumbar BMD in both perimenopausal and postmenopausal women. TAT and SAT have no significant correlation with lumbar trabecular BMD.

The prevalence and intensity of menopausal symptoms differ depending on ethnicity, culture, and country. Epidemiological data from China are scarce.To compare the prevalence and severity of menopausal symptoms in peri- and postmenopausal Chinese women.This was a prospective two year cohort study that included all eligible women from 31 Chinese provinces attending our 'Menopause Clinic', the first official specialized center in China. Structured questionnaires containing seven domains with 41 items in total were used to assess the following menopausal symptoms using descriptive analysis: negative mood, cognitive symptoms, sleep disorder, vasomotor symptoms (VMS), urogenital symptoms, autonomic nervous disorder, and limb pain/paresthesia.A total of 4063 women with a mean age of 50.53 ± 6.57 (Urogenital symptoms among midlife Chinese women are common, frequently also in combination with sexual dysfunction, although many do not often complain about these in the first place. Postmenopausal women presented more prevalent and severe menopausal symptoms. In contrast to Western countries, VMS are rare among our population. A multidisciplinary approach and use of hormonal and non-hormonal therapies should be considered for these women.

Purpose Until now, it is not clear how much total ovarian tissue can be removed without affecting ovarian functions. Aim to investigate impact of stepwise removed ovarian tissue on endocrine hormone levels reflecting ovarian function, follicle morphology and weight in rats. Methods The study was performed with six groups of animals, each consisting of six ten-week-old Sprague-Dawley rats. A blood test was performed on the day of surgery (baseline) and fortnightly thereafter to assess serum hormones reflecting ovarian function: estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), anti-Müllerian hormone (AMH), inhibin B (INHB); weight was also assessed. The ovaries obtained from surgical resection and from the rats sacrificed 12 weeks after surgery were stained with hematoxylin-eosin. Surgeries in the groups; [%] of remaining total ovarian tissue: Group 1, non-ovariectomized [100% tissue]. Group 2, half of left ovary excised [75% tissue]. Group 3, left ovary excised [50% tissue]. Group 4, left ovary + half of right ovary excised [25% tissue]. Group 5, left ovary + three quarters of right ovary excised [12.5% tissue]. Group 6, bilateral ovariectomy [0% tissue]. Results During the 12 weeks, group 4, 5 and 6 had higher FSH and lower AMH and INHB values compared to the control (group 1) ( p 0.05). All ovarian function parameters completely stopped in group 5, i.e. the same as the bilateral ovariectomized rats (group 6). Weight significantly increased in group 6 ( p

This study aimed to assess the effect on the cardiovascular independent risk factor Lipoprotein(a) [Lp(a)] in overweight or obese polycystic ovary syndrome (PCOS) patients with ethinyl-estradiol/drospirenone (EE/DRSP) alone or plus orlistat.In this randomized controlled prospective study, 66 PCOS patients with overweight or obesity were matched according to age and BMI. All participants were randomly divided into two groups to receive EE/DRSP plus Orlistat (Lp(a) and CRP were significantly decreased at 3 months only in the EE/DRSP plus Orlistat group. There were significant reductions in LDL-C, weight, BMI, waist circumference (WC), body fat percentage (BFP), FT in both groups compared to baseline. However, these reductions were significantly greater in EE/DRSP plus Orlistat group. The levels of HDL-C, TG, and SHBG significantly increased, while TT and LH significantly decreased in both groups over time. TC, FINS, FPG were not significantly changed in both groups after the intervention.This is the first study found that EE/DRSP plus Orlistat could significantly decrease Lp(a) in overweight or obese PCOS patients. This result can be assessed as particularly important, because Lp(a) is well-known as an independent risk factor predicting an increased risk of cardiovascular diseases (CVDs).

Objectives A few observational studies have suggested that progesterone and dydrogesterone may have a lower risk of breast cancer than other progestogens. In our earlier xenograft animal experiments, progesterone did not stimulate breast tumors. The aim of this study was to test dydrogesterone for the first time. The study also evaluated the effects of PGRMC1 on proliferation with progestogens. Methods (1) In-vitro study. The proliferative effects of dydrogesterone and of progesterone were assessed in vitro using T47D cells transfected with PGRMC1 or empty vector in the presence or absence of estradiol. Additionally, to find the strongest proliferator for inclusion as a comparator in the xenograft animal study, norethisterone, levonorgestrel, desogestrel, dienogest, drospirenone, nomegestrol, and cyproterone acetate were tested. Methods (2) Xenograft main study. PGRMC1-transfected or empty-vector T47D and MCF7 xenotransplants were each treated with four different hormonal preparations: E2+placebo; E2+dydrogesterone; E2+progesterone; E2+norethisterone. A total of 112 castrated mice were randomly allocated to the 16 groups. This was thus a prospective, randomized, blinded, placebo-controlled four-arm study (45–50 days) with the two T47D and two MCF7 xenografts. Tumor volumes were monitored twice weekly. Results (1) In-vitro study. The strongest proliferation was with norethisterone, but only with PGRMC1-transfected cells. There was significant proliferation with dydrogesterone, but not with progesterone in the absence of estradiol. However, no increase in proliferation was achieved by adding dydrogesterone to estradiol compared with the proliferation induced with estradiol alone, in contrast to norethisterone. Results (2) Xenograft main study. There was significantly faster tumor growth with norethisterone + E2 than with E2+placebo in T47D and MCF7 PGRMC1 xenografts, but not with dydrogesterone + E2 or progesterone + E2. There was less tumor growth in empty-vector xenografts, without between-group differences. Conclusion PGRMC1 increases the breast-cell proliferation effects of certain progestogens, including dydrogesterone, in contrast to progesterone, but not during estradiol-induced proliferation, either in vitro or in a xenograft animal model, in contrast to norethisterone. Thus the proliferative potency of dydrogesterone may be similar to that of progesterone. Clinical studies in women overexpressing PGRMC1 are recommended.

Objective To investigate temporary or long-term changes of AMH after laparoscopic endometrioma cystectomy and its dependency on characteristics of endometriomas. Methods One hundred and seventy-one women, open-labeled prospective study; five groups divided according age ≤/> 35, uni-/bilateral, cyst ≤/> 7 cm, coagulation/suture surgery, stage III/IV; between- and within-group analyses after 1, 3, 6, and 12 months. Results After 12 months, compared to pretreament, AMH decreased significantly for patients with bilateral cysts, cyst size >7 cm and endometriosis stage IV. In the between-group analysis all comparisons were significant, with exception of the surgery type. However, this was different performing the multiple linear regression analysis suggesting lower postoperative decrease using suturing technique. This analysis also showed higher age at pretreatment and bilateral cysts as risk factor for AMH decline. Conclusions Effects of endometrioma cystectomy on AMH are dependent on characteristics of the endometrioma, showing long-term a decrease in patients with larger, bilateral cysts and in stage IV endometriosis, but only short-time decrease in smaller, unilateral cysts and stage III which sometimes also can fully recover in AMH production within one year. In our study suture compared to coagulation surgery was protective, i.e. may lead to lower postoperative AMH decline.

The aim of this study was to investigate early clinical features and risk factors for cesarean scar pregnancy (CSP). Study group of 206 CSP patients out of 6853 women with early pregnancies, diagnosed from 2014 to 2016 was compared with a randomly selected control group of 412 patients. Early clinical features for CSP were vaginal bleeding (OR: 9.65; 95% CI: 5.67-16.41), lower abdominal pain (OR: 3.8; 95% CI: 1.52-9.54) and increased white blood cells (OR: 1.30; 95% CI: 1.12-1.50). Important risk factors for CSP were artificial abortion within the last pregnancy (OR: 4.13; 95% CI: 2.23-7.66), 0 ∼ 1 year and 2 ∼ 3 year interval between present and last pregnancy (OR: 2.27; 95% CI: 1.11-4.67 and OR: 2.15; 95% CI: 1.15-4.03). Pregnancy problems are important issues within the scope of 'Gynecological Endocrinology'. Vaginal bleeding and lower abdominal pain, although unspecific, could be early clinical symptoms of CSP, especially if main risk factors exist such as abortion within the last pregnancy and short interval to the last pregnancy. Knowing this can help for prevention and early diagnosis CSP which can reduce life-threatening complications such as massive hemorrhage and can avoid hysterectomy. Consequence also must be to avoid unwanted pregnancies by using effective contraception, especially in risk patients.

In order to promote the standard application of ovarian tissue cryopreservation in China, and to provide effective scientific medical services of fertility preservation for patients, the First Chinese Guideline of Ovarian Tissue Cryopreservation and Transplantation is established according to the agreements between gynecologists, embryologists, oncologists, pediatricians, breast oncologists, hematologists, and experts on Traditional Chinese Medicine (TCM), based on already successful treated cases within Beijing Obstetrics and Gynecology Hospital, Capital Medical University, China, and based on already existing international guidelines on fertility preservation including important publications in this field. The guideline includes selection criteria, evaluation, and indications; SOPs of ovarian tissue removal, transportation, preparation, freezing, and thawing; approaches of ovarian tissue transplantation and follow-up; practical recommendations for ovarian tissue cryopreservation and transplantation including recommendations of the diseases where this method could be available, and treatment of menopausal symptoms during the peri-transplantation period (time between cryopreservation and retransplantation). The aim of this guideline was to be scientific, practical, and operable.摘要： 为提高中国卵巢组织冻存的标准化应用, 以及为患者提供有效科学的生育力保护医疗服务, 根据首都医科大学附属北京妇产医院成功案例, 并汇总现有的生育力保护领域的国际指南和重要出版物, 通过妇产科、生殖科、肿瘤科、儿科、乳腺科、血液科、中医科等专家的充分讨论, 制定首部中国卵巢组织冻存移植指南。本指南包括筛选标准、评估指征；卵巢组织取材、转运、复苏、卵巢组织移植方法和随访的标准化操作流程；卵巢组织冻存移植的实践推荐, 包括此技术的适用疾病推荐, 以及移植前后更年期症状的治疗。本指南聚焦于 科学性、实用性以及可操作性。.

To evaluate the effect of Diane-35, alone or in combination with orlistat or metformin, on androgen and body fat percentage parameters in Chinese overweight and obese polycystic ovary syndrome (PCOS) patients with insulin resistance. A total of 240 PCOS women were randomly allocated to receive Diane-35 alone (D group), Diane-35 plus orlistat (DO group), Diane-35 plus metformin (DM group), or Diane-35 plus orlistat plus metformin (DOM group). Serum TT, DHEA-S, androstenedione, SHBG, FT, FAI, body fat, and body fat percentage were assessed at baseline and after 12 weeks of treatment. Significant changes in serum TT, SHBG, and FAI were observed in all treatment groups compared with baseline. DHEA-S and androstenedione significantly decreased in the DO, DM, and DOM groups after treatment. FT only significantly decreased in the DOM group. Body fat and body fat percentage significantly decreased in the DO and DOM groups. Compared with the D group, DHEA-S significantly decreased in the DO, DM, and DOM groups (F = 4.081, p = 0.008); SHBG significantly increased in the DOM group (F = 3.019, p = 0.031); and FAI significantly decreased in the DO group (χ2 = 12.578, p = 0.006). There were significant differences between groups in body fat percentage (χ2 = 23.590, p

Herbal extracts used for the alleviation of postmenopausal symptoms might have a lower risk of breast cancer development than hormone therapy. Serelys® is a product composed of purified pollen cytoplasm extracts. Recent experimental data revealed that estrogens might trigger a further proliferative effect on breast cancer cells via the progesterone receptor membrane component-1 (PGRMC1) in addition to the proliferative effect via intracellularly located receptors. MCF-7 and T47D cells were stably transfected with PGRMC1. Different concentrations of the extract alone and in combination with fixed concentrations of estradiol or a growth factor mixture were tested. Proliferation of treated cells was determined by the 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium bromide (MTT)-test and apoptosis was determined using a Cell Death Detection ELISA kit (CDD). Serelys® was neutral in the cell lines transfected or not transfected with PGRMC1. It was also neutral in combination with estradiol or growth factors in terms of cell proliferation and cell apoptosis. Thus in contrast to hormone therapy Serelys® appears to trigger no further breast cancer risk when applied in the post menopause to women, who do or do not overexpress PGRMC1. Overall Serelys® may be an effective alternative for alleviating postmenopausal symptoms without increasing breast cancer risk.

The aim of this study was to evaluate the effect of orlistat or metformin combined with Diane-35 on anthropometric, hormonal and metabolic parameters in overweight and obese polycystic ovary syndrome (PCOS) patients with insulin resistance (fasting insulin 10 mIU/L). A total of 240 PCOS women were randomly allocated to orlistat plus Diane-35(OD group), metformin plus Diane-35(MD group), orlistat plus metformin plus Diane-35(OMD group) or Diane-35 (D group). Body weight, BMI, waist and hip circumference, blood pressure, endocrine profile, lipid profile and insulin resistance were assessed at baseline and after 3 months. Significant reductions in waist and hip circumference, serum LH, total testosterone and uric acid were observed in all groups compared with baseline. TG and TC significantly decreased in the OD group. Homeostasis model assessment insulin resistance (HOMA-IR) index was reduced in the OD (p = .015), MD (p = .001) and OMD (p = .004) groups. Body weight, BMI, systolic BP and HDL-C significantly changed in the OD and OMD group compared with the D group (p .05). Side effects were less with orlistat than metformin. This study demonstrated that orlistat is more effective in reducing weight and lipid profile than metformin. Besides, orlistat has mild side-effects and is better tolerated compared with metformin.

During menopausal hormone therapy (MHT) a possible increase in breast cancer risk is thought to depend mainly on the progestogen component. In vitro studies have shown that the progesterone receptor membrane component 1 (PGRMC1) is important for tumor proliferation induced by progestogens. The primary aim of this study was to compare for the first time the natural progestogen, progesterone (P), with a synthetic progestogen, norethisterone (NET), using a xenograft model.MCF7 cells, transfected with PGRMC1 plasmid or empty vector, were injected into nude mice and estradiol (E2) pellets were implanted. After 12days, NET or P or placebo pellets were implanted. Tumor volumes in all groups (6 mice/group) were monitored for 6-7 weeks. Immunohistochemical expression of PGRMC1 and KI-67 was assessed. These experiments were repeated using T47D cells.Compared with the control condition, E2 and sequential E2/NET combination increased xenograft tumor growth with MCF7 and T47D cells that transgenically expressed PGRMC1 (p0.01); progesterone did not increase growth. Breast cancer cells transfected with empty vectors did not respond to either progestogen. Comparing KI-67 and PGRMC1 expression, the Pearson correlation was r=0.848, p=0.002.E2 plus NET increases tumor growth in human breast cancer cells overexpressing PGRMC1, but there is no change with progesterone. To our knowledge, this is the first comparison of both progestogens in vivo using nude mice, which are frequently used in xenograft models. Clinical trials are needed to determine whether women with overexpression of PGRMC1 are at increased risk of breast cancer if NET instead of progesterone is used in MHT.

Progesterone receptor membrane component 1 (PGRMC1) is mediating strong breast cancer cell proliferation induced by certain synthetic progestogens which we have shown within already published in vi...

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin (R). This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin (R) in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin (R), an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin (R) may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

There are still open questions about ovulation induction in clomiphene citrate-(CC)-resistant infertile women. Especially little is known about efficacy and safety of letrozole (LTZ) combined with low-dose highly purified human menopausal gonadotropin (Hp-HMG) in women with polycystic ovary syndrome (PCOS).Prospective, single-arm single-center trial in 200 infertile PCOS patients refractory for at least three CC-treatment cycles. Women with hyperandrogenism took Diane-35 for at least 3 months. All patients got LTZ on day 3 for 5 d in combination with Hp-HMG, starting with 75 IU from cycle day 7 and maintained for up to 3 d. The maximum dose was 150 IU. Primary end-points were ongoing and clinical pregnancy rate, secondary end-points mono-follicular development, ovulation rate, OHSS, multiple pregnancy and early pregnancy loss. Major safety end-point was the incidence of adverse events.Within 395 cycles the ongoing pregnancy rate was 28.24%, for cycles 35.23%, for patients 68%. The rate of ovulation per cycle was 97.7%, percentage of mono-follicular development 70.9%. No severe OHSS, multiple pregnancy, local or systemic side effects were seen.LTZ combined with low-dose Hp-HMG is an effective and safe choice for reducing hyperstimulation and increasing pregnancy rate in CC-resistant women with PCOS.

Ovarian tissue cryopreservation is one of the most important methods to protect female fertility, but we just recently established the first central laboratory in China, now building a network with other hospitals. The aim was to estimate the thawed ovarian tissue viability and to explore the feasibility of short-distance transportation. Fifteen samples were obtained from each of 11 patients, i.e. in total 165 samples. One fresh sample was used for follicle counts, 14 punches were cryopreserved, thawed, and randomly divided into seven groups depending on the time after thawing: 0, 20, 40, 60, 80, 100, 120 min. Follicle counts, steroid hormones, and lactate levels were assessed. No significant differences for the three parameters of tissue viability comparing the seven groups were seen. The time can last up to two hours for the delivery of tissue samples from the laboratory to the surgery room. To our knowledge, this question has been tested for the first time systematically within a prospective randomized comparative study.

The aim of this study was to investigate the clinical, endocrinic and metabolic indicators in polycystic ovary syndrome (PCOS) with different Rotterdam criteria (RC)-based subtypes, thus to guide the treatments. Six hundred and forty-seven PCOS cases were divided into four groups, with 60 cases set as the control group, the clinical and endocrinic indicators of different subtypes were evaluated. Group A was the most common and the most serious (63.2%), while group B was the least (9%). The clinical signs, as well as the endocrinic and metabolic characteristics, of the two groups were similar, but group A exhibited higher androgen level and hirsutism score. The phenotypes of group C (15.6%) and group D (12.9%) were mild, but compared with the control group, luteinizing hormone (LH) and LH/follicle stimulating hormone (FSH) were significantly increased. Insulin resistance in these four subtypes were positively correlated with apolipoprotein B (ApoB)/apolipoprotein A1 (ApoA1), while only positively correlated with serum total testosterone, and negatively correlated with LH/FSH in group A. RC-PCOS typing could reflect the basic characteristics of the disease. Hyperandrogenism was the main basis for distinguishing PCOS, although the non-hyperandrogenism group could represent a relatively mild phenotype of PCOS, there might exist different pathogenic pathways.

The aim of this study was to compare the effect of Diane-35 versus Diane-35 + metformin on metabolic parameters in Chinese PCOS patients.Patients getting individualized life-style modification were treated with Diane-35. Metformin was added according to its indication. Within a 3-month prospective study, metabolic parameters were assessed.Eighty-three patients were recruited, 45 using Diane-35 and 38 Diane-35 plus metformin. Using Diane-35, triglycerides (TG) (p 0.05) and tendencially (p 0.1) total cholesterol (TC) increased, but significant positive effects on BMI, high-density lipoprotein cholesterol (HDL-C), and HDL-C/TC ratio were observed. Other lipids and the parameters for glucose metabolism remained unchanged. In the combination group, no negative effect on TG and TC was seen, other lipid fractions improved, as well as BMI, % body fat, and all parameters for glucose metabolism like fasting plasma glucose (FPG), fasting insulin, HOMA-insulin-resistance index, and insulin sensitivity index (ISI), whereby the beneficial effect of metformin got significance compared with Diane-35 for BMI, FPG, and ISI.With the exception of increasing triglycerides, Diane-35 had no relevant negative effects in the metabolic system. It does not negatively impact the beneficial effects of metformin in lipids and glucose metabolism. Diane-35 plus metformin is effective in improving the metabolic profile of Chinese PCOS patients.

Doctors and patients fear the risk of breast cancer when using hormone replacement therapy (HRT). This review focuses on the choice of progestogen for HRT in menopausal. The Women’s Health Initiative (WHI) has been the only large double-blind placebo-controlled study testing the risk of breast cancer (BC) using HRT. No increased risk using estrogen (E)-only was seen, there was a significant decrease in mortality due to BC after the use of HRT which persisted during the recent 18-year follow-up of the WHI. In contrast in the combined arm the risk increased. In about 20 observational studies using mostly medroxyprogesterone acetate (MPA) or estradiol-norethisterone acetate (NETA) an increased BC-risk was observed comparable with the WHI. Only for natural progestogen, progesterone and for dydrogesterone (retro-isomer of progesterone) was no increased risk seen for up to 5–8 years, when compared directly with other progestogens, but for longer treatment an increased risk cannot be excluded. In contrast, the mortality due to BC after use of E-only and combined HRT decreased in about a dozen observational studies, and was very recently confirmed in a Finnish study evaluating 490,000 women using estradiol (E2) plus different progestogens. There have been already more than 70 studies evaluating the risk of BC during HRT, and still there are many open questions. Therefore, this review covers our own and other experimental research which could answer important questions. Experimental research has demonstrated that certain synthetic progestogens, but not progesterone and to some extent also not dydrogesterone, can accelerate the proliferation of breast cancer cells in vitro and in animal studies via special cell membrane components which we recently also detected in patients with BC, and we found differences comparing all available synthetic progestogens. Derived from these mechanisms future research may provide screening for patients at risk and predict the prognosis of possible BC.

Depending on the type, duration and intensity of cigarette smoking, the efficacy of endogenous and exogenous estrogen can be reduced or completely cancelled. Not only does smoking diminish the beneficial effects of estrogen on hot flushes and urogenital symptoms and its positive effects on lipid metabolism, but smoking also can reduce estrogen's ability to prevent osteoporosis and perhaps also cardiovascular diseases. This is mainly caused by dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels, and has been demonstrated so far only with oral estrogen applications. Compensation for the failure of therapeutic action should not be made by increasing the dose in smokers since this might result in the production of potentially mutagenic estrogen metabolites associated with a higher risk of breast cancer. Since the favorable effects of estrogens seem to be not lost in smokers when estrogens are applied transdermally, this route should be preferred in smokers. The most important conclusion from the data presented is that the effects of smoking are very complex and dependent on a multiplicity of factors, so that different types of clinically relevant negative effects must be expected. Women who continue to smoke despite all warnings should be informed that smoking, in addition to all its other negative effects, can also jeopardize the success of hormone replacement therapy.

Objective was to evaluate anti-Müllerian-hormone (AMH) and parameters for insulin resistance (IR) in the main phenotypes of polycystic ovarian syndrome (PCOS), and to investigate their correlation for the first time in non-obese Chinese women.Within this prospective study, 160 PCOS cases and 40 healthy women, matched by age and BMI, were included. In four groups (n = 40) according to the four phenotypes of PCOS by definition of the National Institute of Health (2012), AMH, ovarian volume and number of follicles 2-9 mm were assessed as well as insulin resistance indexes (Homeostatic Model Assessment) (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI).AMH levels were higher in PCOS than in controls, with differences comparing the phenotypes, highest in the group with all three criteria for PCOS. However, for HOMA-IR and QUICKI and correlation to AMH no significant differences were found.AMH is a useful parameter to assess in the different phenotypes the severity of PCOS, and to compare with healthy women, for the first time demonstrated in Chinese patients. In contrast, the parameters for IR and their relation to AMH did not show clear differences comparing the four phenotypes, and need further investigation.

Aim was to evaluate anti-Müllerian-hormone (AMH) in women with polycystic ovary syndrome (PCOS) comparing with normo-ovulatory women, and to assess for the first time AMH levels across reproductive lifespan in Chinese women.Within the prospective cross-sectional study in PCOS cases and in normal subjects, AMH and other hormone levels were measured in early follicular phase in five age groups. Additionally ovarian ultrasound parameters were assessed.A total of 437 PCOS patients and 150 normo-ovulatory women matched by age were included. AMH levels were 2- to 3-fold higher in PCOS cases. In both groups AMH decreased with age in a non-linear pattern. In normo-ovulatory women AMH levels were relatively constant from 18 to 25 years and then declined with age. In contrast, AMH in PCOS cases declined with an increasing rate from 18 to 45 years, narrowing the difference in older women.AMH may be a useful parameter to assess the severity and prognosis of PCOS since certain differences exist to normo-ovulatory women. Further studies may improve the understanding of the relationship between AMH levels and age, providing more scientific basis for fertility counselling for both healthy women and PCOS cases.

Aim was to evaluate endocrine, metabolic and thyroid parameters which could help to explore the relationship between thyroid function and metabolic changes in Chinese polycystic ovary syndrome (PCOS) patients.Within a prospective study in PCOS patients compared with healthy women, thyroid parameters were assessed, as well as changes of endocrine, metabolic and clinical characteristics.144 PCOS patients and 48 normo-ovulatory women matched by age as controls were included. There were significant increases of thyroid-stimulating hormone (TSH), total triiodothyronine (TT3) and total thyroxine (TT4) in the PCOS patients. Body mass index (BMI), waist and hip ratio (WHR), luteinizing hormone (LH), LH/follicle-stimulating hormone (FSH) and total testosterone (T) were significantly higher in PCOS compared with the controls. Total cholesterol (CHO), triglycerides (TG) and apolipoprotein B (ApoB) levels in PCOS were higher, whereas high-density lipoprotein (HDL) and apolipoprotein A (ApoA) were lower compared with the controls. Insulin and homeostatic model assessment of insulin resistance (HOMA-IR) were significantly higher in patients with PCOS.Our study confirms the well-known negative metabolic changes in PCOS patients. The small increases of TSH, TT3 and TT4 level may be related with these metabolic changes in PCOS patients. Further studies may improve the understanding of the relationship between thyroid function and metabolic changes.

Dienogest (DNG) is a 19-nortestosterone derivative (a C-19 progestogen) with a cyanomethyl instead of an ethinyl group at the C-17 position, which may make the compound elicit fewer hepatic effects than other C-19 nortestosterone derivatives. Its similarity to norethisterone is reflected in its high endometrial efficacy, which could explain the high stability of the menstrual cycle women achieve when they use DNG in combination with ethinyl estradiol (EE) or with estradiol valerate (E2V). Its strong endometrial efficacy underlies the use of DNG (on its own) to treat endometriosis, and gives it antiproliferative and anti-inflammatory effects in the treatment of endometriotic lesions. Properties derived from its C-19 derivative structure include its short plasma half-life, of about 10h (which means the drug is not accumulated), and its high oral bioavailability, of more than 90%. However, DNG also has some of the properties of typical of progesterone derivatives, including a lack of effect on the metabolic and cardiovascular systems, and considerable antiandrogenic activity, the latter increased by its lack of affinity to the sex-hormone binding globulin (SHBG), in contrast to other C-19 progestogens. DNG has no glucocorticoid and no antimineralocorticoid activity. It also has no antiestrogenic activity, which suggests that it should not antagonize estradiol's beneficial effects. This is important for its use in the treatment of endometriosis, because, due to DNG's low gonadotropic activity, E2 levels are not decreased to zero, in contrast to treatments with gonadotropin-releasing hormone (GnRH) analogues. This maintenance beneficial E2 effects is of particular importance for the general tolerability of the first contraceptive pill to use E2V instead of EE, although clinical endpoint studies are still ongoing. These studies are expected, on the basis of its pharmacology, to demonstrate the cardiovascular safety of the new pill.

Nomegestrol acetate (NOMAC) is a 19-norprogesterone derivative with high biological activity at the progesterone receptor, a weak anti-androgenic effect, but with no binding to estrogen, glucocorticoid or mineralocorticoid receptors. At dosages of 1.5 mg/day or more, NOMAC effectively suppresses gonadotropic activity and ovulation in women of reproductive age. Hemostasis, lipids and carbohydrate metabolism remain largely unchanged. In normal and cancerous human breast cells, NOMAC has shown favorable effects on estrogen metabolism. Like natural progesterone (but in contrast to some other synthetic progestogens), it does not appear stimulate the proliferation of cancerous breast cells. While there has been some experience of the use of NOMAC in combination with estrogens as a hormone replacement therapy, most of the data on the compound are reported in the context of its inclusion as a component of a new contraceptive pill comprising 2.5 mg NOMAC combined with 1.5 mg estradiol. Because of its strong endometrial efficacy, and due to its high antigonadotropic activity and long elimination half-life (about 50 h), the contraceptive efficacy of the new pill is maintained even when dosages are missed. Furthermore, for the first time with a monophasic 24/4 regimen containing estradiol, cyclical stability can be achieved comparable with that obtained using pills containing ethinyl estradiol and progestogens like levonorgestrel or drospirenone. The addition of NOMAC to estradiol means that the beneficial effects of estrogen are not lost, which is of especial importance in relation to the cardiovascular system. On the basis both of its pharmacology and of studies performed during the development of the NOMAC/estradiol pill, involving some 4000 women in total, good long-term tolerability can be expected for NOMAC, although its safety profile is still to be fully ascertained, as the clinical endpoint studies are yet to be completed.

Evidence is accumulating that progestogens may play a crucial role in the development of breast cancer under contraception and hormone therapy in reproductive and menopausal women. Progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer may be important in tumorigenesis and thus may increase breast cancer risk. The aim of this project was to investigate the influence of progesterone and nine synthetic progestins on MCF-7 breast cancer cells overexpressing PGRMC1.MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12). To test the effects of progestogerone (P) and the synthetic progestins chlormadinone acetate (CMA), desogestrel (DSG), drospirenone (DRSP), dydrogesterone (DYD), levonorgestrel (LNG), medroxyprogesterone acetate (MPA), nomegestrol (NOM) and norethisterone (NET) on cell proliferation, MCF-7 and WT-12 cells were stimulated with different concentrations (0.01-1 µmol/l).In MCF-7 cells, DRSP, DSG, DYD, LNG and NET increased the proliferation at 1 µmol/l, the effect being highest for NET with about 20%. In WT-12 cells, the same progestins, but additionally MPA, showed a significant increase, which was much higher (30-245%) than in MCF-7 cells. Here again, NET showed the highest proliferative effect. No effect was found for CMA, NOM and P.Some synthetic progestins trigger a proliferative response of PGRMC1-overexpressed MCF-7 cancer cells. The effect of progestogens on breast cancer tumorigenesis may clearly depend on the specific pharmacology of the various synthetic progestins.

Objective Breast cancer risk is still an important topic regarding hormone therapy as well as oral contraception. Evidence that progestogens may play a crucial role is accumulating. Progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer may be important in tumorigenesis and thus may increase breast cancer risk. The aim of this project was to investigate the influence of different estradiol (E2) concentrations and the addition of two progestogens on MCF-7 breast cancer cells overexpressing PGRMC1. Methods MCF-7 cells were stably transfected with PGRMC1 expression plasmid (MCF-7/PGRMC1-3HA [WT-12]). To test the effects of E2 and progestogens on cell proliferation, MCF-7 and WT-12 cells were stimulated with different concentrations of E2 (10 and 10 M) alone and in combination with progesterone and medroxyprogesterone acetate (each 10 M). Results E2 elicited a concentration-dependent proliferative effect on both cell lines, which was much more pronounced in WT-12 cells (50% vs 200%). This effect could be completely abrogated by the addition of the E2 antagonist fulvestrant. Addition of progesterone had no influence on the E2-induced effect, whereas medroxy-progesterone acetate enhanced the E2-induced effect at a low E2 concentration, which was, again, more pronounced in the WT-12 cells. The figures were between 20% and 40% in MCF-7 and between 60% and 250% in WT-12 cells. Conclusions Overexpression of PGRMC1 sensitizes the proliferative response of the MCF-7 breast cancer cell line to estradiol. The effect of progestogens on breast cancer tumorigenesis may depend on the specific progestogen used for hormone therapy or oral contraception.

Objective: The aim of this study was to determine the prevalence of metabolic syndrome (MetS) in Chinese postmenopausal women and explore the optimum body composition indices to predict MetS. Methods: Participants were independent, community-dwelling women. Recruitment occurred through advertisements in newspapers and flyers posted in the local community. A total of 181 postmenopausal women were recruited. Their parameters were measured, including body height, weight, waist circumference (WC), hip circumference, sagittal abdominal diameter, blood pressure, follicle-stimulating hormone, luteinizing hormone, estradiol, triglyceride, high-density lipoprotein cholesterol, fasting plasma glucose, and body fat (BF; %). Logistic regression analyses were applied for correlation between stated variables. Optimization of body composition indices to predict MetS in postmenopausal women was analyzed with the area under the curve of the receiver. Results: The prevalence of MetS in postmenopausal women was 33.7%. The risk factors of MetS in postmenopausal women were age, family history of metabolic disorders (obesity, hypertension, hyperlipemia, and diabetes mellitus), body composition indices (body mass index [BMI], WC, waist-to-hip ratio, sagittal abdominal diameter, and BF), and metabolic indices (systolic and diastolic blood pressure, fasting plasma glucose, and triglyceride; odds ratio 9 1, P G 0.05), and the protective factor is high-density lipoprotein cholesterol (odds ratio = 0.114, P G 0.05). All body composition indices in our study had a positive correlation with number of MetS factors. The body composition indices in our study showed a positive correlation with each other (P G 0.001). BMI and WC were highly correlated with BF (r 9 0.900, P G 0.001). Through receiver operating characteristic curve analysis, it was determined that body composition indices (WC, 80.75 cm; BF, 36.695%; sagittal abdominal diameter, 18.35 cm; or BMI, 24.835 kg/m 2 ) could be used to predict MetS. Conclusions: The prevalence of MetS in Chinese postmenopausal women is 33.7%. Body composition indices (WC Q80.75 cm, BF Q36.695%, sagittal abdominal diameter Q18.35 cm, or BMI Q24.835 kg/m 2 ) were discovered

Objective: To determine whether or not there is an increased level of serum C-reactive protein (CRP), of peripheral white cell count and of associated factors in Chinese patients with polycystic ovary syndrome (PCOS). Subjects and Methods: Seventy-four patients with PCOS were recruited for the study. The control group consisted of 51 normal healthy women of a similar age and body mass index (BMI). The basic physical parameters, white cell count, CRP, sex hormone and fasting insulin were measured. The glycolipid metabolic index and the insulin sensitivity index were calculated. Results: The serum CRP level (2.13 vs. 0.86 mg/l, p < 0.001) and total leukocyte count (7.50 ± 1.83 vs. 6.55 ± 1.66 × 109/l, p < 0.01) were significantly higher in PCOS patients than in normal healthy women. Even PCOS patients with normal BMI had an increase in CRP and leukocyte count. The serum CRP level of PCOS patients was positively correlated with BMI (R = 0.57, p < 0.001) and triglycerides (R = 0.47, p < 0.001) and negatively correlated with the insulin sensitivity index (R = –0.60, p < 0.001). Conclusion: The data showed that chronic nonspecific inflammation exists among Chinese patients with PCOS and that this kind of inflammation was related to insulin resistance, BMI, and triglycerides.

Objective To investigate changes in levels of lipids and lipoproteins in Chinese women during perimenopause and postmenopause as primary study endpoints, for the first time including lipoprotein(a). Methods The retrospective study was performed in 1015 women without hormone therapy aged 34-76 years from 20 provinces of China who visited the Beijing Obstetrics & Gynecology hospital. Menopausal status was defined by the criteria of the 2011 Stages of Reproductive Aging Workshop. Results Levels of total cholesterol, triglycerides and low density lipoprotein (LDL) cholesterol increased and that of high density lipoprotein (HDL) cholesterol decreased in the postmenopausal compared to the perimenopausal group. In the women with body mass index (BMI) ≥ 25 kg/m(2), total cholesterol and LDL cholesterol increased, HDL cholesterol decreased and changes in triglyceride levels were not significant. In the women with BMI

Our and other studies have pointed on an important role of progesterone receptor membrane component 1 (PGRMC1) in development of breast cancer, especially in hormone therapy. To investigate if PGRMC1 could be used to predict the risk for getting breast cancer, we assessed in tissues of patients with primary invasive breast cancer, if the expression of PGRMC1 may be associated with the expression of estrogen receptor alpha (ERα), progesterone receptor (PR), and ki67.Samples from 109 patients with breast cancer between the years 2008 and 2014 were obtained with the patients' consent. Each sample was evaluated for the ERα, PR, Ki67, and PGRMC1 expression by immunohistochemistry using serial sections from the ame paraffin block comparing malignant tissue to benign tissue.Expression of PGRMC1 is increased in tumor area compared with non-cancerous tissue and positively correlates with ERα expression (OR = 1.42 95%CI 1.06-1.91, p = 0.02). No association was obtained between expression of PGRMC1 and PR or Ki67.It can be suggested that women with breast epithelium highly expressing PGRMC1 and in interaction with ERα may have an increased risk to develop breast cancer, especially when treated with hormone therapy.

Dienogest (DNG) is already used in hormone therapy, since recently being also the progestogenic component of the first estradiol based contraceptive pill. Data on breast cancer risk are currently not available. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in tissues of breast cancer patients and has already been proposed as a predictor for breast cancer risk.MCF-7 cells overexpressing PGRMC1 were stimulated with DNG, medroxyprogesterone acetate (MPA), norethisterone (NET) and progesterone (P) as well as sequentially and continuously combined with estradiol (E2).DNG and MPA alone elicited a significant proliferation at 10⁻⁶ and 10⁻⁵ M. NET increased cell proliferation at all concentrations tested whereas P showed no effect. E2 alone elicited a significant increase at 10⁻¹⁰ M, no effect was seen at 10⁻¹² M. Addition of the progestins (10⁻⁶ M) to E2 at 10⁻¹⁰ M had, compared to E2 only, no additional proliferating effect. However, at the low E2 concentration, DNG, MPA and NET significantly increased the E2-stimulated cell proliferation.DNG increased proliferation alone and in combination with low E2 concentrations. Thus a progestogen-derived breast cancer risk in the presence of low E2 concentrations cannot be excluded at least in women overexpressing PGRMC1.

Oestetrol (15-alpha-hydroxyoestriol, E₄) is an endogenous oestradiol metabolite mainly produced at high concentrations in the fetal liver. In earlier studies E₄ was investigated for its use as marker for pregnancies at risk, especially with vascular problems. Some current investigations suggest that the use of E4 in hormone therapy or contraception may have advantages in terms of breast cancer risk when compared to other oestrogens.Proliferation of two oestrogen receptor-positive breast cancer cell lines (ZR 75-1 and HCC 1500) was investigated after incubation with oestrone (E₁), oestradiol (E₂), oestriol (E₃), and oestetrol (E₄). Receptor expression of oestrogen receptor-alpha (ERα) and -beta (ERβ) was determined by Western-Blot.All four oestrogens elicited a significant proliferative stimulation at concentrations of 10(-10) und 10(-9) M as compared to controls. Oestrone displayed a significantly weaker effect than E₂. Oestetrol was significantly less effective than E₂ at the lower concentration. Expression of ERα and ERβ was significantly upregulated by all oestrogens tested, without differences between the latter.Our results indicate a slightly lower proliferative effect of E₄, but only at low concentrations. However, no difference was found regarding receptor expression. Breast cancer risk associated with use of oestetrol should be tested in clinical trials.

Recently the first monophasic contraceptive pill containing estradiol has been developed which is thought to be a milestone in contraception. Nomegestrol acetate (NOM) is the progestogenic component. Progesterone receptor membrane component 1 (PGRMC1) is highly expressed in the tissue of breast cancer patients, and can predict a progestogen dependent risk of breast cancer.MCF-7 cells were transfected with PGRMC1 expression plasmid, and were stimulated with estradiol (E2, 10(-12) and 10(-10) M). NOM, progesterone (P), medroxyprogesterone acetate (MPA) and norethisterone (NET) (each 10(-7) M) were added sequentially or continuously.E2 at 10(-10) M elicited a significant increase of cell proliferation from 150 to 200%. No effect was seen at 10(-12) M. Addition of the progestogens to E2 at 10(-10) M had no significant effect. However, at an E2 10(-12) M, NET significantly stimulated cell proliferation more pronounced in the continuous combined model. No effect was seen for NOM, P and MPA. The E2/NET combined effect could be abrogated by the addition of an estrogen receptor (ER) antagonist.Since NOM did not increase proliferation it may be concluded that it will be neutral in terms of breast cancer risk when combined with E2 at least in women overexpressing PGRMC1.

To assess the benefits and risks during hormone replacement therapy (HRT) in postmenopausal women, the only placebo-controlled study testing clinical endpoints with high statistical power has been the Women's Health Initiative (WHI). Although this trial, conducted mainly in older high-risk women, might not reflect the practical conditions for the normal use of HRT, the WHI for the first time provides the main risks in relative as well as in absolute numbers, which are venous thromboembolism and breast cancer, and in older women also myocardial infarction and stroke. Proven benefits such as treatment of climacteric symptoms, reduction of osteoporotic fractures and decrease of colon cancer risk seem to be only important for younger women, because only with early start of HRT cardiovascular risks can be reduced. Reduction of cardiovascular risks can be achieved using transdermal HRT, which, however, was not tested in a placebo-controlled study design similar to that in the WHI. This review focuses on the results of the WHI, comparing different age groups, and in general especially on the main fear of women, risk of breast cancer, which has been defined as a special project between two universities, a close collaboration of a German and Chinese research group.