Oestetrol stimulates proliferation and oestrogen receptor expression in breast cancer cell lines: comparison of four oestrogens.

OBJECTIVES: 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. METHODS: 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 (ERß) was determined by Western-Blot. RESULTS: 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 ERß was significantly upregulated by all oestrogens tested, without differences between the latter. CONCLUSIONS: 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.

Anti-Müllerian hormone levels in women with polycystic ovarian syndrome compared with normal women of reproductive age in China.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Serum anti-Müllerian hormone and insulin resistance in the main phenotypes of non-obese polycystic ovarian syndrome women in China.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Multi-agent Continuous Control with Generative Flow Networks.

Generative Flow Networks (GFlowNets) aim to generate diverse trajectories from a distribution in which the final states of the trajectories are proportional to the reward, serving as a powerful alternative to reinforcement learning for exploratory control tasks. However, the individual-flow matching constraint in GFlowNets limits their applications for multi-agent systems, especially continuous joint-control problems. In this paper, we propose a novel Multi-Agent generative Continuous Flow Networks (MACFN) method to enable multiple agents to perform cooperative exploration for various compositional continuous objects. Technically, MACFN trains decentralized individual-flow-based policies in a centralized global-flow-based matching fashion. During centralized training, MACFN introduces a continuous flow decomposition network to deduce the flow contributions of each agent in the presence of only global rewards. Then agents can deliver actions solely based on their assigned local flow in a decentralized way, forming a joint policy distribution proportional to the rewards. To guarantee the expressiveness of continuous flow decomposition, we theoretically derive a consistency condition on the decomposition network. Experimental results demonstrate that the proposed method yields results superior to the state-of-the-art counterparts and better exploration capability. Our code is available at https://github.com/isluoshuang/MACFN.

Interaction Pattern Disentangling for Multi-Agent Reinforcement Learning.

Deep cooperative multi-agent reinforcement learning has demonstrated its remarkable success over a wide spectrum of complex control tasks. However, recent advances in multi-agent learning mainly focus on value decomposition while leaving entity interactions still intertwined, which easily leads to over-fitting on noisy interactions between entities. In this work, we introduce a novel interactiOn Pattern disenTangling (OPT) method, to disentangle the entity interactions into interaction prototypes, each of which represents an underlying interaction pattern within a subgroup of the entities. OPT facilitates filtering the noisy interactions between irrelevant entities and thus significantly improves generalizability as well as interpretability. Specifically, OPT introduces a sparse disagreement mechanism to encourage sparsity and diversity among discovered interaction prototypes. Then the model selectively restructures these prototypes into a compact interaction pattern by an aggregator with learnable weights. To alleviate the training instability issue caused by partial observability, we propose to maximize the mutual information between the aggregation weights and the history behaviors of each agent. Experiments on single-task, multi-task and zero-shot benchmarks demonstrate that the proposed method yields results superior to the state-of-the-art counterparts. Our code is available at https://github.com/liushunyu/OPT.

The prevalence of metabolic syndrome in Chinese postmenopausal women and the optimum body composition indices to predict it.

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 > 1, P < 0.05), and the protective factor is high-density lipoprotein cholesterol (odds ratio = 0.114, P < 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 < 0.001). BMI and WC were highly correlated with BF (r > 0.900, P < 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) could be used to predict MetS. CONCLUSIONS: The prevalence of MetS in Chinese postmenopausal women is 33.7%. Body composition indices (WC > or = 80.75 cm, BF > or = 36.695%, sagittal abdominal diameter > or = 18.35 cm, or BMI > or = 24.835 kg/m) were discovered to predict MetS.

Association of common LH variant with hyperfunctional promoter in a Japanese infertile woman.

A common LH variant (V-LH) with Trp8Arg and Ile15Thr is often associated with ovarian dysfunction primarily in the Japanese population, and the LHB gene encoding V-LH is linked with a hyperfunctional promoter that could partly compensate for the somewhat weak biological effect of the V-LH in the Finnish and other several populations. We analyzed the promoter region in a Japanese infertile woman homozygous for the V-LH, to examine whether the hyperfunctional promoter is present or absent in the Japanese V-LH carriers with ovarian dysfunction. Direct sequencing was performed for a 661 bp promoter region from -8 to -668 bp of LHB, revealing homozygosity for eight nucleotide substitutions (-238A>G, -276G>A, -489C>A, -490T>A, -504T>A, -506T>C, -525T>G, and -552C>T) that are identical to those found in the hyperfunctional promoter. The results suggest that ovarian dysfunction frequently observed in the Japanese V-LH carriers would be due to some population-specific genetic and/or environmental factor(s) rather than to the lack of the hyperfunctional promoter and the resultant low biological effect of the V-LH. In addition, the tight linkage between the two missense substitutions in the coding region and the eight nucleotide substitutions in the promoter region of LHB appears to be common to various ethnic groups.