The Reproductive Transition: Effects on Viral Replication, Immune Activation, and Metabolism in Women with HIV infection

Purpose of Review To describe research advances in the menopausal transition (MT) and its effects on HIV replication, immune activation, and metabolic parameters in women living with HIV (WLWH). Recent Findings. Physiologic changes due to declines in ovarian reserve characterize the MT. Evidence suggests that estrogen depletion influences HIV replication and the latent reservoir. Changes in markers of immune activation, waist circumference, and neurocognition, independent of chronologic age, occur before the final menstrual period (FMP). HIV effects on gut microbial translocation and adipose tissue, as well as health disparities in WLWH may contribute. Improved biomarker sensitivity to predict FMP provides opportunities to study MT in WLWH. Summary Research is needed to determine the effects of MT and HIV on virologic and clinical outcomes, using accurate assessments to predict the FMP and menopausal stages. These findings could inform the timing of interventions to prevent early onset of adverse outcomes in WLWH.

Truncated WT1 Protein Isoform Expression Is Increased in MCF-7 Cells with Long-Term Estrogen Depletion

Background. The wt1 gene codes for a transcription factor that presents several protein isoforms with diverse biological properties, capable of positively and negatively regulating genes involved in proliferation, differentiation, and apoptosis. WT1 protein is overexpressed in more than 90% of breast cancer; however, its role during tumor progression is still unknown. Methodology. In this work, we analyzed the expression of WT1 isoforms in several breast cancer cells with different tumor marker statuses and an in vitro assay using MCF-7 cells cultured with long-term estrogen depletion (MCF-7 LTED cells) with the finality to mimic the process of switching from hormone-dependent to hormone-independent. Moreover, growth kinetics, sensitivity to tamoxifen, and relative expression analysis of ER and Her2/neu were performed. Results. Initially, the expression of 52-54 kDa protein isoform of WT1 in the breast cancer cell line ER (+) was detected by western blot and was absent in ER (-), and the 36-38 kDa protein isoform of WT1 was detected in all cell lines analyzed. The analysis of alternative splicing by RT-PCR shows that the 17AA (+)/KTS (-) isoform of WT1 was the most frequent in the four cell lines analyzed. In vitro, the MCF-7 cells in the estrogen depletion assay show an increase in the expression of the 52-54 kDa isoform of WT1 in the first 48 hours, and this was maintained until week 13, and later, this expression was decreased, and the 36-38 kDa isoform of WT1 did not show change during the first 48 hours but from week 1 showed an increase of expression, and this remained until week 27. Growth kinetic analysis showed that MCF-7 LTED cells presented a 1.4-fold decrease in cellular proliferation compared to MCF-7 cells cultured under normal conditions. In addition, MCF-7 LTED cells showed a decrease in sensitivity to the antiproliferative effect of tamoxifen ( p ≤ 0.05 ). Samples collected until week 57 analyzed by qRT-PCR showed an increase in the relative expression of the Her2/neu and ER. Conclusions. Modulation of protein isoforms showed differential expression of WT1 isoforms dependent on estrogen receptor. The absence of 52-54 kDa and the presence of the 36-38 kDa protein isoform of WT1 were detected in ER-negative breast cancer cell lines classified as advanced stage cells. Long-term estrogen depletion assay in MCF-7 cells increased the expression of the 36-38 kDa isoform and reduced the 52-54 kDa isoform, and these cells show an increase in the expression of tumor markers of ER and Her2/neu. MCF-7 LTED cells showed low proliferation and insensitivity to tamoxifen compared to MCF-7 cells in normal conditions. These results support the theory about the relationship of the 36-38 kDa isoform of WT1 and the absence of ER function in advanced breast cancer.

Effects of Radix Polygalae on Cognitive Decline and Depression in Estradiol Depletion Mouse Model of Menopause

Postmenopausal syndrome refers to symptoms caused by the gradual decrease in female hormones after mid-40 years. As a target organ of estrogen, decrease in estrogen causes various changes in brain function such as a decrease in choline acetyltransferase and brain-derived neurotrophic factor; thus, postmenopausal women experience cognitive decline and more depressive symptoms than age-matched men. Radix Polygalae has been used for memory boosting and as a mood stabilizer and its components have shown neuroprotective, antidepressant, and stress relief properties. In a mouse model of estrogen depletion induced by 4-vinylcyclohexene diepoxide, Radix Polygalae was orally administered for 3 weeks. In these animals, cognitive and depression-related behaviors and molecular changes related to these behaviors were measured in the prefrontal cortex and hippocampus. Radix Polygalae improved working memory and contextual memory and despair-related behaviors in 4-vinylcyclohexene diepoxide-treated mice without increasing serum estradiol levels in this model. In relation to these behaviors, choline acetyltransferase and brain-derived neurotrophic factor in the prefrontal cortex and hippocampus and bcl-2-associated athanogene expression increased in the hippocampus. These results implicate the possible benefit of Radix Polygalae in use as a supplement of estrogen to prevent conditions such as postmenopausal depression and cognitive decline.

Inflammatory Potential of Diet Is Associated with Biomarkers Levels of Inflammation and Cognitive Function among Postmenopausal Women

In postmenopausal women (PW), estrogen depletion may predispose to cognitive decline through an increased risk of chronic inflammation. Unhealthy diets also appear to have an impact on the cognitive health of these women. The aim of this study was to investigate the association between inflammatory potential of the diet, levels of inflammatory biomarkers, and cognitive function in PW. In a population of 222 PW, energy intake-adjusted Dietary Inflammatory Index (E-DII) was used to assess the dietary inflammatory potential. Cognitive function was estimated using the Polish version of Mini-Mental State Examination (MMSE), corrected by age and educational level. Selected biochemical inflammatory markers (C-reactive protein, CRP; interleukin-6, IL-6; and tumor necrosis factor alpha, TNF-α) were measured by ELISA tests. PW with an anti-inflammatory diet (first tercile) had significantly higher MMSE, while BMI, percentage fat mass and TNFα concentration were significantly lower compared to those with the most proinflammatory diets (third tercile). Women with cognitive impairment had significantly higher IL-6 concentrations (4.1 (0.8) pg/mL vs. 2.5 (0.2) pg/mL, p = 0.004), and were less educated (12.7 (0.7) years vs. 14.1 (0.2) years, p = 0.03) and less physically active compared to cognitively normal women. PW with the most proinflammatory diets had increased odds of cognitive impairment compared to those with the most anti-inflammatory diets, even after adjustment (OR = 11.10, 95% confidence level; 95%CI: 2.22; 55.56; p = 0.002). Each one-point increase in E-DII (as a continuous value) was also associated with 1.55-times greater odds of cognitive impairment (95%Cl: 1.19; 2.02 p = 0.003) in this population. Dietary inflammation may increase the risk of cognitive impairment in PW, but future studies should include a more sensitive battery of tests to assess cognitive function in this population. Implementation of an anti-inflammatory dietary pattern in PW may help prevent cognitive decline.

Effect of Adherence to Physical Exercise on Cardiometabolic Profile in Postmenopausal Women

Background: Menopause is associated with negative cardiovascular adaptations related to estrogen depletion, which could be counteracted by physical exercise (PhE). However, the impact of total adherence-rate (TA) to PhE and sedentary time (SedT) on cardiometabolic profile in this population has not been elucidated. Methods: For 13-weeks, 43 women (57.1 ± 4.7 years) participated in a 4-days-a-week moderate-intensity walking training. They underwent laboratory, anthropometric and echocardiographic assessment, before and after training (T0–T1). Spontaneous physical activity (PhA) was assessed with a portable multisensory device. The sample was divided according to TA to PhE program: <70% (n = 17) and ≥70% (n = 26). Results: TA ≥ 70% group experienced a significant T1 improvement of relative wall thickness (RWT), diastolic function, VO2max, cortisol, cortisol/dehydroandrostenedione-sulphate ratio and serum glucose. After adjusting for SedT and 10-min bouts of spontaneous moderate-to-vigorous PhA, TA ≥ 70% showed the most significant absolute change of RWT and diastolic function, body mass index, weight and cortisol. TA ≥ 70% was major predictor of RWT and cortisol improvement. Conclusions: In a group of untrained, postmenopausal women, a high TA to a 13-weeks aerobic PhE program confers a better improvement in cardiometabolic profile, regardless of SedT and PhA levels.

Letrozole Suppresses the Fusion of Osteoclast Precursors through Inhibition of p38-Mediated DC-STAMP Pathway

Letrozole is a reversible nonsteroidal aromatase inhibitor that is widely used in postmenopausal breast cancer patients. It is well established that letrozole decreases bone density owing to estrogen depletion; however, few studies have reported its direct effect on bone cells in vitro. Therefore, we investigated the effect of letrozole on bone metabolism, focusing on osteoclastogenesis. Letrozole did not affect the viability, proliferation, or migration of bone marrow-derived macrophages (BMMs); however, it reduced the multinucleation of immature osteoclasts and subsequent bone resorption in vitro. Overall, letrozole inhibited the expression of dendritic cell-specific transmembrane protein (DC-STAMP), tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K. Among them, the reduced expression of DC-STAMP was the most prominent. However, this downregulation of DC-STAMP expression following letrozole treatment was not related to the inhibition of major osteoclastogenesis pathways, such as the nuclear factor-κB (NF-κB), c-Fos, and nuclear factor of activated T cell c1 (NFATc1) pathways, but was attributed to the inhibition of p38, which is known to reside upstream of DC-STAMP expression. Notably, the anti-osteoclastogenic effect of letrozole was abolished following treatment with the p38 activator anisomycin. Contrary to our expectations, these results strongly suggest a previously unknown anti-osteoclastogenic activity of letrozole, mediated by the downregulation of the p38/DC-STAMP pathway.