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Bone is a multi-skilled tissue, protecting major organs, regulating calcium phosphate balance and producing hormones. Its development during childhood determines height and stature as well as resistance against fracture in advanced age. Estrogens are key regulators of bone turnover in both females and males. These hormones play a major role in longitudinal and width growth throughout puberty as well as in the regulation of bone turnover. In women, estrogen deficiency is one of the major causes of postmenopausal osteoporosis. In this review, we will summarize the main clinical and experimental studies reporting the effects of estrogens not only in females but also in males, during different life stages. Effects of estrogens on bone involve either Estrogen Receptor (ER)α or ERβ depending on the type of bone (femur, vertebrae, tibia, mandible), the compartment (trabecular or cortical), cell types involved (osteoclasts, osteoblasts and osteocytes) and sex. Finally, we will discuss new ongoing strategies to increase the benefit/risk ratio of the hormonal treatment of menopause.

Hepatocyte estrogen receptor α (ERα) was recently recognized as a relevant molecular target for nonalcoholic fatty liver disease (NAFLD) prevention. The present study defined to what extent hepatocyte ERα could be involved in preserving metabolic homeostasis in response to a full (17β‐estradiol [E2]) or selective (selective estrogen receptor modulator [SERM]) activation. Ovariectomized mice harboring a hepatocyte‐specific ERα deletion (LERKO mice) and their wild‐type (WT) littermates were fed a high‐fat diet (HFD) and concomitantly treated with E2, tamoxifen (TAM; the most used SERM), or vehicle. As expected, both E2 and TAM prevented all HFD‐induced metabolic disorders in WT mice, and their protective effects against steatosis were abolished in LERKO mice. However, while E2 still prevented obesity and glucose intolerance in LERKO mice, hepatocyte ERα deletion also abrogated TAM‐mediated control of food intake as well as its beneficial actions on adiposity, insulin sensitivity, and glucose homeostasis, suggesting a whole‐body protective role for liver‐derived circulating factors. Moreover, unlike E2, TAM induced a rise in plasma concentration of the anorectic hepatokine growth differentiation factor 15 (Gdf15) through a transcriptional mechanism dependent on hepatocyte ERα activation. Accordingly, ERα was associated with specific binding sites in the Gdf15 regulatory region in hepatocytes from TAM‐treated mice but not under E2 treatment due to specific epigenetic modifications. Finally, all the protective effects of TAM were abolished in HFD‐fed GDF15‐knockout mice. Conclusion: We identified the selective modulation of hepatocyte ERα as a pharmacologic strategy to induce sufficient anorectic hepatokine Gdf15 to prevent experimental obesity, type 2 diabetes, and NAFLD.

Tooth inhalation remains a rare incident but it may occur during dental care, especially in children. We report here the case of a four-year-old boy with Down syndrome who came to the hospital after a dental trauma. During the extraction procedure, he aspired his maxillary incisor without presenting any signs of respiratory distress and was discharged by the surgical team, who thought that he had swallowed the tooth. Three weeks later, he was admitted to the emergency service because of a pulmonary infection. Two endoscopy interventions under general anesthesia were necessary to recover the foreign body inside the left lung. Because of the multiple symptoms associated with the trisomy 21 syndrome (general hypotonia, impaired immunity, etc.), practitioners should be very mindful of aspiration risks and complications during dental care. The systematic prescription of lung radiography would prevent the onset of pulmonary infections and enable an earlier intervention.

Endometriosis is a frequent and chronic inflammatory disease with impacts on reproduction, health and quality of life. This disorder is highly estrogen-dependent and the purpose of hormonal treatments is to decrease the endogenous ovarian production of estrogens. High estrogen production is a consistently observed endocrine feature of endometriosis. mRNA and protein levels of estrogen receptors (ER) are different between a normal healthy endometrium and ectopic/eutopic endometrial lesions: endometriotic stromal cells express extraordinarily higher ERβ and significantly lower ERα levels compared with endometrial stromal cells. Aberrant epigenetic regulation such as DNA methylation in endometriotic cells is associated with the pathogenesis and development of endometriosis. Although there is a large body of data regarding ERs in endometriosis, our understanding of the roles of ERα and ERβ in the pathogenesis of endometriosis remains incomplete. The goal of this review is to provide an overview of the links between endometriosis, ERs and the recent advances of treatment strategies based on ERs modulation. We will also attempt to summarize the current understanding of the molecular and cellular mechanisms of action of ERs and how this could pave the way to new therapeutic strategies.

In women, oral menopausal hormonal therapy (MHT) is associated with adverse effects including an increased incidence of thromboembolic events, classically attributed to an increase in several liver-derived coagulation factors due to hepatic first pass. While platelets are central players in thrombus constitution, their implication in women treated with estrogens remains incompletely characterized. Platelets and their medullar progenitors, megakaryocytes, express estrogen receptors (ER) that may explain, at least in part, a sensitivity to hormonal changes. The purpose of this review is to summarize our current knowledge of estrogen actions on platelets and megakaryocytes in mice following in vivo administration and in women using MHT.

Estetrol (E 4 ) is a natural estrogen with a long half‐life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor α (ERα) ligand‐binding domain bound to 17β‐estradiol (E 2 ) and E 4 are very similar, as well as their capacity to activate the two activation functions AF‐1 and AF‐2 and to recruit the coactivator SRC3. In vivo administration of high doses of E 4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERα actions. However, E 4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane‐initiated steroid signaling (MISS). Furthermore, E 4 antagonized E 2 MISS‐dependent effects in endothelium but also in MCF‐7 breast cancer cell line. This profile of ERα activation by E 4 , uncoupling nuclear and membrane activation, characterizes E 4 as a selective ER modulator which could have medical applications that should now be considered further. Synopsis Estetrol (E 4 ) is shown to be a less potent estrogen than E 2 but with the features of a natural Selective ER Modulator suggesting its application as a safe oral contraceptive or for the hormonal treatment of menopause. The nuclear transcriptional activity of ERα in the mouse uterus leading to the proliferation of the endometrial epithelium is modulated by E 4 . The prevention of atheroma, another process recognized to be nuclear ERα‐dependent, is promoted by E 4 in hypercholesterolemic mice. At variance with E 2 , neither acceleration of endothelial healing nor activation of endothelial NO synthase, two ERα membrane‐dependent effects, are affected by E 4 . The ERα membrane‐dependent effects of E 2 are antagonized by E 4 , not only in the endothelium, but also in MCF‐7 breast cancer cells. E 4 acts as a natural Selective Estrogen Receptor Modulator (SERM) uncoupling nuclear and membrane activation, and its medical potential should now be fully explored. Graphical Abstract Estetrol (E 4 ) is shown to be a less potent estrogen than E 2 but with the features of a natural Selective ER Modulator suggesting its application as a safe oral contraceptive or for the hormonal treatment of menopause.

Postmenopausal hormone replacement therapy (HRT) with estrogen plus progestogens is the first line therapy to treat menopausal symptoms. The progestogen is added to estrogen to reduce or eliminate the excess risk of endometrial cancer due to the unopposed effect of estrogen. Whereas progestin clearly opposes the proliferative and deleterious long-term actions of estrogen on the endometrium, the interference of progestin on the other estrogen action remains unclear. We previously reported that chronic subcutaneous 17α-estradiol (E2) in mice decreases platelet responsiveness, prolongs the tail-bleeding time and protects against acute thromboembolism. Here, we report the tissue-specific interference of progesterone (P4) on the action of E2 in ovariectomized mice. We first confirm that, in our experimental conditions, P4 attenuates the proliferative action of E2 on the uterus and the effects of E2 on vagina weight and lubrication. We then studied the effect of E2 combined with P4 on hemostasis and thrombosis in vivo in mice and found that P4 did not interfere with the main actions of E2 on platelets, bleeding time and arterial and venous thrombosis. Thus, whereas activation of progesterone receptor interferes with the action of E2 on its classic sex targets, P4 appears to have minimal effect on the hemostasis and thrombosis actions of E2, supporting the prominent role of estrogens and the accessory role of natural progestin on the extra-reproductive cells and tissues involved in thrombosis.

Objective: The aim of this study was to evaluate the attitude of parents towards the oral health of their children before oral rehabilitation under general anesthesia (GA).Study design: Children receiving dental treatment under GA between November 2013 and July 2014 in the Pediatric Dentistry Department (University Hospital Center, Toulouse, France) were enrolled in an oral health preventive program. An anonymous questionnaire was self-administered by the parents during the pre-operative session. Results: The sample comprised 67 children with a mean age of 4.8 years. 48 % of the parents had difficulties in maintaining the oral hygiene of their child. Two thirds of them reported a lack of cooperation. An adult cleaned the child's teeth in 43% of the cases. 14% of the study population brushed their teeth twice a day or more. In addition, half of the parents reported that they modified food consumption or teeth cleaning habits of their children since the initial consultation. Conclusions: This study suggests a low compliance of parents and children with the recommendations on oral hygiene and food consumption given at the initial visit and demonstrates the feasibility of a preventive program in this population.

Purpose The oral care of a child with autism spectrum disorders (ASD) is a challenge, not only for dentists, but also for parents. The objective of this study was to evaluate the difficulties encountered by parents in maintaining oral hygiene in autistic children and the solutions they found to facilitate this daily act. Methods A questionnaire with closed and open questions about characteristics of the child and oral health at home, conducted via Google Form, was sent to French families through 301 associations of parents with autistic children. For the quantitative analysis, logistic regression was used. The open answers were analysed by theme. Results This study included 756 offspring aged 14.4 (± 8.1) years. Girls were 1.7 (95% CI: 1.1–2.8) times more likely to have toothbrushing difficulty than boys. Nonverbal patients (OR:3.2; 95% CI: 2.2–4.9), autistic patients (OR:2.8; 95% CI: 1.4–5.2), patients using pictograms (OR:1.6; 95% CI: 1.1–2.4), and younger children (OR:0.9; 95% CI: 0.9–0.9) were significantly more likely to encounter difficulties in tolerating toothbrushing. The qualitative analysis showed that parents used three main ways to facilitate toothbrushing: planning, modelling and making it enjoyable. Seventy-nine percent of parents did not feel sufficiently informed about the different oral hygiene prevention tools and techniques for their ASD children and would like to be educated in the daily management of oral hygiene. Conclusion The role of parents remains essential and professionals should work in collaboration with them.