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The age-related reproductive disorders are the main concerns in old birds. It was suggested that a drop in egg production and reproductive performance, towards the end of their laying period was caused partly by a decrease in the baseline concentration of plasma LH. Urtica dioica (nettle) is a plant with natural aromatase inhibitors. Steroid hormone levels are regulated by inhibition of the aromatase enzyme. Few studies have examined the effect of nettle on the egg production in adult hens. The aim of this study was to investigate the effects of diet supplemented with nettle powder (NP) in aged quails. One hundred and forty-52-week-old Japanese quails were randomly assigned to four treatments consisting of seven replicates (n = 5; four females and one male) and fed with diets containing NP at 0% (control group), 0.5, 1.0, and 1.5% (treatment groups). At 62 week of age, our results indicated the NP improved egg production, feed conversion ratio, eggshell thickness and Haugh unit (p

Postmenopausal women are at an increased risk for intervertebral disc degeneration, possibly due to the decrease in oestrogen levels. Low-magnitude, high-frequency vibration (LMHFV) is applied as a therapeutic approach for postmenopausal osteoporosis; however, less is known regarding possible effects on the intervertebral disc (IVD) and whether these may be oestrogen-dependent. The present study investigated the effect of 17β-oestradiol (E2) and LMHFV in an IVD organ culture model. Bovine IVDs (n = 6 IVDs/group) were treated with either (i) E2, (ii) LMHFV or (iii) the combination of E2 + LMHFV for 2 or 14 days. Minor changes in gene expression, cellularity and matrix metabolism were observed after E2 treatment, except for a significant increase in matrix metalloproteinase (MMP)-3 and interleukin (IL)-6 production. Interestingly, LMHFV alone induced cell loss and increased IL-6 production compared to the control. The combination of E2 + LMHFV induced a protective effect against cell loss and decreased IL-6 production compared to the LMHFV group. This indicates possible benefits of oestrogen therapy for the IVDs of postmenopausal women undergoing LMHFV exercises.

Contains fulltext : 248669.pdf (Publisher’s version ) (Open Access) AIMS: To determine the effects of oestrogen or oestrogen deprivation on vaginal wound healing. Impaired wound healing following prolapse surgery may increase the risk of recurrent prolapse in the future. Vaginal oestrogen therapy may improve wound healing, hereby possibly improving surgical outcomes. METHODS: A systematic search of OVID MEDLINE, OVID Embase, and Web of Science was conducted up to January 28, 2020. We included original studies comparing wound healing-related outcomes of oestrogen exposed subjects (female animals and women) to hypo-oestrogenic subjects after vaginal surgery. Data on wound healing-related outcome measures were extracted. For each individual comparison, the standardised mean difference (Hedges' g; SMD) and 95% confidence interval (CI) were calculated. RESULTS: Of the 1474 studies reviewed, 14 studies were included for review, and 11 provided data for meta-analysis. Oestrogen improves neovascularisation (SMD: 1.13, 95% CI: 0.67-1.60), microscopic wound closure (SMD: 0.98, 95% CI: 0.66-1.29), collagen synthesis (SMD: 1.08, 95% CI: 0.42-1.74), and tissue strength (SMD: 1.26, 95% CI: 0.53-1.99) in animals. Oestrogen increases granulation (SMD: 1.67, 95% CI: 0.54-2.79) and accelerates macroscopic wound closure (SMD: 1.82, 95% CI: 1.22-2.42) in women and animals. Oestrogen decreases the inflammatory response (SMD: -0.58, 95% CI: -1.14 to -0.02) in women and animals and reduces levels of transforming growth factor (TGF)-β1 (SMD: -1.68, 95% CI: -2.52 to -0.83) in animals. All results were statistically significant. CONCLUSIONS: Oestrogen therapy has a positive effect on vaginal wound healing. Future studies should determine whether oestrogen therapy has the potential to improve surgical outcomes.

AimsDeciphering the genetic relationships between major depressive disorder (MDD) and osteoarthritis (OA) may facilitate an understanding of their biological mechanisms, as well as inform more effective treatment regimens. We aim to investigate the mechanisms underlying relationships between MDD and OA in the context of common genetic variations.MethodsLinkage disequilibrium score regression was used to test the genetic correlation between MDD and OA. Polygenic analysis was performed to estimate shared genetic variations between the two diseases. Two-sample bidirectional Mendelian randomization analysis was used to investigate causal relationships between MDD and OA. Genomic loci shared between MDD and OA were identified using cross-trait meta-analysis. Fine-mapping of transcriptome-wide associations was used to prioritize putatively causal genes for the two diseases.ResultsMDD has a significant genetic correlation with OA (rg= 0.29) and the two diseases share a considerable proportion of causal variants. Mendelian randomization analysis indicates that genetic liability to MDD has a causal effect on OA (bxy= 0.24) and genetic liability to OA conferred a causal effect on MDD (bxy= 0.20). Cross-trait meta-analyses identified 29 shared genomic loci between MDD and OA. Together with fine-mapping of transcriptome-wide association signals, our results suggest that Estrogen Receptor 1 ( ESR1), SRY-Box Transcription Factor 5 ( SOX5), and Glutathione Peroxidase 1 ( GPX1) may have therapeutic implications for both MDD and OA.ConclusionThe study reveals substantial shared genetic liability between MDD and OA, which may confer risk for one another. Our findings provide a novel insight into phenotypic relationships between MDD and OA. Cite this article: Bone Joint Res 2022;11(1):12–22.

Flexible Planung des Menstruationszyklus ist nur einer der Gründe warum Frauen zu oralen Kontrazeptiva als ihr Mittel der Wahl bei der Verhütung greifen. Die Bestandteile der Anti-Baby-Pille – eine Östrogen- und eine Gestagenkomponente – haben unterschiedliche Wirkungen, was zur einer individuellen Anwendung führt und weshalb sie weltweit Verwendung findet. Doch ihre Einnahme hat nicht nur positive, sondern kann auch ungewollte Effekte hervorrufen. Diese Nebenwirkungen können in Europa bei der European Medicines Agency gemeldet werden, wo sie in die Datenbank für dementsprechende Meldungen eingepflegt werden. Diese wird laufend aktualisiert und ist öffentlich zugänglich. Für diese Arbeit wurden vier Wirkstoffkombinationen ausgesucht, die alle aus der gleichen Östrogenkomponente, aber jeweils aus einem anderen Progestagen bestehen. Die zugehörigen Daten der letzten zwanzig Jahre wurden von der Datenbank heruntergeladen und mit Hilfe eines Datenfilter-Codes in Python so bearbeitet, dass sie zum Schluss visualisiert werden konnten. Flexible menstrual cycle planning is just one of the reasons why women turn to oral contraceptives as their contraceptive of choice. The components of the contraceptive pill - an estrogen component and a progestin component - have different effects, which leads to individual application, which is why it is used worldwide. But taking them has not only positive properties, but can also cause unwanted effects. In Europe, these adverse reactions can be reported to the European Medicines Agency, where they are entered into the database for corresponding reports. This is continuously updated and is publicly accessible. Four drug combinations were selected for this work, all consisting of the same oestrogen component, but each consisting of a different progestins. The related data for the last twenty years was downloaded from the database and processed using a data filter code in Python so that it could be visualized at the end.

Post-menopausal osteoporosis is a chronic age-related illness marked by a decrease of bone density and quality, as well as a higher risk of fragility fractures. Fragility fractures are recognized to have a major impact on individuals and society both personal and financially. In recent years, it has been a hidden epidemic impacting over 200 million people globally. It is claimed that one osteoporosis fracture happens every three seconds throughout the world. The termination of ovarian hormone production, which causes rapid bone loss, puts postmenopausal women at greater risk of developing osteoporosis. The gradual changes in structure, quality and density of the bones lead to the fracture and a rise in morbidity and death among menopausal women. Interventions that enhance a woman’s well-being and quality of life by reducing the intensity and frequency of post-menopausal osteoporosis. Hormone therapy is helpful in managing menopausal symptoms; nevertheless, it has been linked to a number of potentially significant side effects, including the development of ovarian and breast cancer. As a result, there has been an increase in demand for alternative treatment options. Plant species with potential antiosteoporosis characteristics are highlighted and further discussed in order to aid future medication development for treating this illness. Many plants and there components have been demonstrated to have antiosteoporosis action based on a vast number of chemical and pharmacological studies. Plant-derived molecules have lately piqued the curiosity of researchers working on novel medicinal agents. As a result, therapeutic interventions that can delay reduce or prevent bone loss in ageing people, especially postmenopausal women, are essential to a person’s well-being and quality of life. The plants included in this review are those that have been frequently used in traditional medicine and have shown clinical efficacy in the management of post-menopausal osteoporosis. While numerous plants can prevent and treat osteoporosis, only a fraction of plants have been discussed, including their origin, active components, and pharmacological activity, we evaluated the challenges and methods utilized in the therapy of postmenopausal osteoporosis during the COVID-19 pandemic.

Background Migraine is a common neurological disease with extremely debilitating, but fully reversible symptoms. Women suffer from migraine more often than men. It was assumed that fluctuation of oestrogen level during menstrual cycle is one of many factors responsible for more frequent migraine attacks. The second-to-fourth digit ratio (2D:4D) is considered as an indicator of prenatal sex steroids. Balance of prenatal androgens (testosterone) and oestrogen has been studied in numerous diseases that are affected by hormones. However, the relationship between migraine and the sex steroids balance in prenatal development is still unexplained. The aim of this paper is to provide an evidence of relationship between prenatal oestrogen and testosterone exposure following 2D:4D digit ratio, and migraine prevalence in adults. Methods We examined a group of 151 adults (33 males, 118 females) with migraine and a control group of 111 adults (45 males, 66 females). 2D:4D digit ratio of both hands was measured using sliding Vernier calliper. Results Significant differences were found in the right hand. Female migraineurs had lower value of 2D:4D ratio than the control group and the right 2D:4D was lower than left 2D:4D (Δ2D:4D), suggesting prenatal testosterone dominance. The opposite relationship was observed in males. Male migraineurs had higher value of 2D:4D ratio and Δ2D:4D was greater than the control group, suggesting prenatal oestrogen dominance. Conclusions Our results suggest that depending on sex, different proportion of prenatal sex steroids might be a risk factor of migraine in adults. Women with migraine were presumably exposed in prenatal life to higher testosterone levels relative to oestrogen, while men with migraine were probably exposed in prenatal life to higher levels of oestrogen relative to testosterone.

Lycopodium clavatum sporopollenin exine capsules (SpECs) are known to both adsorb and absorb chemicals. The aim of the present work was to determine whether oestradiol (E2) is ‘bioavailable’ to bioindicator species, either pre-adsorbed to, or in the presence of, SpECs. SpEC uptake was confirmed for Daphnia magna and Dreissena bugensis. E2 levels varied among treatments for Caenorhabditis elegans though there was no relationship to SpEC load. E2 was not detected in D. bugensis tissues. Expression changes of general stress and E2-specific genes were measured. For C. elegans, NHR-14 expression suggested that SpECs modulate E2 impacts, but not general health responses. For D. magna, SpECs alone and with E2 changed Vtg1 and general stress responses. For D. bugensis, SpECS were taken up but no E2 or change in gene expression was detected after exposure to E2 and/or SpECs. The present study is the first to investigate SpECs and bound chemical dynamics.

Objectives: Composite resins are the most preferred filling material because of their excellent aesthetic qualities. However, a filling material should also be biocompatible as well as aesthetic. The aim of this study was to determine the serum and saliva bisphenol-A (BPA) levels and to examine the effects of serum BPA on reproductive hormone levels after healthy men were treated with composite fillings. Methods: Eighteen healthy males each received 2 composite restorations. Saliva and blood samples of subjects were collected before resin application and 1 day and 1, 3, and 5 weeks after the resin was applied. BPA amounts in samples were detected using high-performance liquid chromatography (HPLC). Serum gonadotropins, testosterone, sex hormone binding globulin, free androgen index, and oestrogen levels were measured with radioimmunological assay kits. Statistical analysis of data was made using Friedman, Wilcoxon signed ranks and Mann-Whitney U tests (α = 0.05). Results: The amount of BPA released from composite resins over time was not significantly elevated in either saliva or serum (P > 0.5). In addition, serum BPA levels were significantly higher than saliva BPA levels for both composites (P < .05), but saliva and serum BPA levels were not statistically different when comparing the 2 composites (P > .05). Conclusions: BPA from composite resins used in this study did not significantly alter serum hormone levels.

Background: Failure of immunologic homeostasis and resultant hepatocyte destruction in autoimmune hepatitis (AIH) is likely the result of environmental triggers within a permissive genetic architecture. Aims: We aimed to identify risk factors associated with AIH in a well-phenotyped AIH cohort. Methods: We prospectively collected environmental questionnaires from 358 AIH cases and 563 healthy controls. Response frequencies were compared using logistic regression, adjusting for age at recruitment, sex and education. Results: AIH cases were more likely to ever have a urinary tract infection (UTI) (53.6% vs 33.9%, P < .001) and recurrent UTI (more than 1 per year) (23.5% vs 15.9%, P = .002) compared to controls. Female cases more frequently had ever used oral contraceptives (83.0% vs 73.7%, P = .006), fewer pregnancies (median = 1 vs 3, P < .001) and less often used hormone replacement therapy compared to controls (28.5% vs 60.1%, P < .001). Current smoking was more prevalent in cases (18.9% vs 7.4%, P = .022), yet no difference according to historical smoking behaviours was observed. Finally, cases were less likely to have history of mumps (32.4% vs 53.1%, P = .011) and rheumatic fever (1.1% vs 4.4%, P = .028), but reported higher vaccination frequency to chicken pox (38% vs 28.1%), measles (66.5% vs 39.3%), mumps (58.7% vs 34.6%), rubella (55.3% vs 32.7%), pertussis (59.8% vs 40.1%) and pneumococcus (47.2% VS 39.4%) (P < .002). Conclusions: Environmental factors are important in AIH pathogenesis. Replication of these findings and prospective examination may provide new insight into AIH onset and outcomes.

In this study, we aimed to explore the molecular mechanisms underlying the development of osteoporosis in post‐menopausal females. Real‐time PCR was conducted to measure the expression of potential lncRNAs involved in the osteoporosis of post‐menopausal females. In addition, Western blot and IHC assays were used to study the possible correlation among HOTAIR, miR‐138 and TIMP1, while a computational analysis was carried out to predict the ‘seed sequence’ responsible for the binding between miR‐138 and HOTAIR/TIMP1. Furthermore, luciferase reporter assays were conducted to validate the negative regulatory relationship between miR‐138 and TIMP1/HOTAIR. To evaluate the effect of oestrogen on the function of HOATIR and its downstream effectors, luciferase activity was measured in cells cotransfected with different vectors or treated with different doses of oestrogen. The results of the luciferase assay were further validated by real‐time PCR, Western blot, MTT assay and flow cytometry. Among the candidate lncRNAs, HOTAIR was the only lncRNA down‐regulated in post‐menopausal females. HOTAIR bound to miR‐138 and negatively regulated its expression. Meanwhile, miR‐138 could also bind to TIMP1 mRNA and reduce its expression. Furthermore, a dose‐dependent up‐regulation of HOTAIR was observed in cells treated with oestrogen, and the elevated HOTAIR increased the level of TIMP1 by targeting miR‐138. In addition, oestrogen promoted cell viability and suppressed cell apoptosis, and effects of oestrogen were blocked by the silencing of HOTAIR. Therefore, it can be concluded that oestrogen deficiency could induce the apoptosis of osteoblasts and lead to osteoporosis in post‐menopausal females via modulation of the HOTAIR/miR‐138/TIMP1 signalling axis.

Dramatic physiological changes of women body due to pregnancy may elicit temporomandibular joint disorders (TMD). Furthermore, decrease immunity and stresses of pregnancy contribute to provoke TMD. To limit and prevent TMD, small lifestyle changes can be employed during pregnancy to insure warding off joint affection. Similarly, treatment options are available and one of the basic and apparent options is the use of bite plates. Because of the prevalence and importance of TMD in pregnant women, this literature review suggests adding education on TMD and its prevention to any antenatal program. There is a real demand for more studies on incidence of TMD during pregnancy and prognosis after that.

Dramatic physiological changes of women body due to pregnancy may elicit temporomandibular joint disorders (TMD). Furthermore, decrease immunity and stresses of pregnancy contribute to provoke TMD. To limit and prevent TMD, small lifestyle changes can be employed during pregnancy to insure warding off joint affection. Similarly, treatment options are available and one of the basic and apparent options is the use of bite plates. Because of the prevalence and importance of TMD in pregnant women, this literature review suggests adding education on TMD and its prevention to any antenatal program. There is a real demand for more studies on incidence of TMD during pregnancy and prognosis after that.

Background: Mastalgia or breast pain common benign breast disorder in women in her reproductive life. Mastalgia estimate prevalence 41–71%. It affects to overall quality of life and associated with anxiety, stress, and other psychological factors. Objective: The purpose of the study was to conduct a review of alternative therapy in the management of mastalgia. Method: A review was conducted using search terms cyclical mastalgia (CM), yoga therapy, breast treatment, primrose oil, oestrogen, progesterone and all the probable term in national and international data repositories such as PubMed, Scopus, science direct, google scholar, web of science in English language. Result: The review of alternative therapies in the management of CM suggests that most of the studies used primrose oil, vitamins, and physical activity. There are very few studies conducted in relation to yoga and cyclical mastalgia. Further, most of the studies explored effect of alternative therapies on psychological outcomes. None of the studies investigated efficacy of these therapies on hormonal changes. Conclusion: Evidence suggests that biochemical clinical trial is effective with side effect, primrose oil and seeds treatment is less effective. One evidence-based study with integrated yoga therapy should be considered in the management of cyclical mastalgia. More high-quality trial with yogic approach needed to first line management of patients presenting with CM.

Background: Doppler of uterine and sub-endometrial arteries might be beneficial for the prediction of pregnancy success. None or few studies evaluated them when using oral ovulation induction. Methods: This study is a randomized prospective study. We recruited infertile couples with PCOS or unexplained subfertility from the infertility unit at Al-Moosa Specialist Hospital in eastern province in the Kingdom of Saudi Arabia. We randomize cycles to use clomiphene or letrozole. We study the uterine arteries doppler indices difference between the hCG trigger day and the mid-luteal phase day with positive and negative pregnancy test groups. Results: In the negative pregnancy test group, there was no sufficient evidence suggesting a difference for sub endometrial artery PI and RI between the trigger day and mid-luteal phase day with a p-value of 0.95 and 0.765, respectively. For the uterine artery PI and RI, there was evidence suggesting a difference between the trigger day and the mid-luteal phase day with a p-value of .003 for both of them. In the positive pregnancy test group, there was evidence to suggest a difference between the trigger day and the mid-luteal phase day for the sub endometrial artery RI with a p-value of 0.035. However, there was no sufficient evidence to suggest that there was a difference for PI of the sub endometrial artery and the uterine artery PI and RI between the day of the trigger and mid-luteal phase day with a p-value of 0.137, 0.533 and 0.687 respectively. Conclusions: When uterine artery PI and RI decrease, we can predict failed ovulation treatment. In comparison, we can predict a successful pregnancy with increasing sub-endometrial artery RI.

Endometriosis is a benign gynaecological disease appearing with pelvic pain, rising dysmenorrhoea and infertility seriously impacting on 10% of reproductive‐age females. This research attempts to demonstrate the function and molecular mechanism of RhoA/ROCK pathway on epithelial‐mesenchymal transition (EMT) and proliferation in endometriosis. The expression of Rho family was abnormally changed in endometriotic lesions; in particular, RhoA and ROCK1/2 were significantly elevated. Overexpression of RhoA in human eutopic endometrial epithelial cells (eutopic EECs) enhanced the cell mobility, epithelial‐mesenchymal transition (EMT) and proliferation, and RhoA knockdown exhibited the opposite function. Oestrogen up‐regulated the RhoA activity and expression of RhoA and ROCK1/2. RhoA overexpression reinforced the effect of oestrogen on promoting EMT and proliferation, and RhoA knockdown impaired the effect of oestrogen. oestrogen receptor α (ERα) was involved with the regulation of oestrogen on EMT and proliferation and up‐regulated RhoA activity and expression of RhoA and ROCK1/2. The function of ERα was modulated by the change in RhoA expression. Furthermore, phosphorylated ERK that was enhanced by oestrogen and ERα promoted the protein expression of RhoA/ROCK pathway. Endometriosis mouse model revealed that oestrogen enhanced the size and weight of endometriotic lesions. The expression of RhoA and phosphorylated ERK in mouse endometriotic lesions was significantly elevated by oestrogen. We conclude that abnormal activated RhoA/ROCK pathway in endometriosis is responsible for the function of oestrogen/ERα/ERK signalling, which promoted EMT and proliferation and resulted in the development of endometriosis.

Oesophageal adenocarcinoma is a rapidly increasing problem in which treatment options are limited. Previous studies have shown that oesophageal adenocarcinoma cells and tissues express oestrogen receptors (ERs) and show growth suppression and apoptosis in response to ER modulator agents such as tamoxifen. ERs are known to be expressed in a number of isoforms that act together to regulate cell growth and cell death. In this study, we used western blotting to profile the expression of ERα and ERβ isoforms, and expression of the oncologically related molecules p53, HER2, and EGFR, in a panel of oesophageal adenocarcinoma cell lines. The cytotoxicity of tamoxifen in the cell lines was determined with Annexin V-FITC flow cytometry, and correlations between cytotoxicity and receptor expression were assessed using Spearman’s rank-order correlation. Oesophageal adenocarcinoma cell lines showed varying cytotoxicity in response to tamoxifen. The ER species ERα90, ERα50, and ERα46, as well as p53, were positively associated with a cytotoxic response. Conversely, ERα74, ERα70, and ERβ54 were associated with a lack of cytotoxic response. The ER species detected in oesophageal adenocarcinoma cells may work together to confer sensitivity to ER modulators in this disease, which could open up a new avenue for therapy in selected patients.

Summary Candida albicans is a commensal of the urogenital tract and the predominant cause of vulvovaginal candidiasis (VVC). Factors that increase circulatory estrogen levels such as pregnancy, the use of oral contraceptives, and hormone replacement therapy predispose women to VVC, but the reasons for this are largely unknown. Here, we investigate how adaptation of C. albicans to estrogen impacts the fungal host-pathogen interaction. Estrogen promotes fungal virulence by enabling C. albicans to avoid the actions of the innate immune system. Estrogen-induced innate immune evasion is mediated via inhibition of opsonophagocytosis through enhanced acquisition of the human complement regulatory protein, Factor H, on the fungal cell surface. Estrogen-induced accumulation of Factor H is dependent on the fungal cell surface protein Gpd2. The discovery of this hormone-sensing pathway might pave the way in explaining gender biases associated with fungal infections and may provide an alternative approach to improving women's health., Graphical abstract, Highlights • Estrogen promotes the virulence of Candida albicans by reducing phagocytosis • Estrogen-adapted C. albicans binds more Factor H on its cell surface • Estrogen-induced innate immune evasion of C. albicans is dependent on Gpd2 • Overexpression of GPD2 promotes the virulence of C. albicans, Women with high estrogen levels have an increased risk of developing genital thrush caused by Candida albicans. Kumwenda et al. show that C. albicans grown in estrogen is not recognized and killed efficiently by white blood cells. This reduced immune recognition could enable C. albicans to proliferate and cause infection.

Background and Aims: Sex hormones are widely recognised to act as protective factors against several viral infections. Specifically, females infected by the hepatitis C virus display higher clearance rates and reduced disease progression than those found in males. Through modulation of particle release and spread, 17β-oestradiol controls HCV’s life cycle. We investigated the mechanism(s) behind oestrogen’s antiviral effect. Methods: We used cell culture-derived hepatitis C virus in in vitro assays to evaluate the effect of 17β-oestradiol on the innate immune response. Host immune responses were evaluated by enumerating gene transcripts via RT-qPCR in cells exposed to oestrogen in the presence or absence of viral infection. Antiviral effects were determined by focus-forming unit assay or HCV RNA quantification. Results: Stimulation of 17β-oestradiol triggers a pre-activated antiviral state in hepatocytes, which can be maintained for several hours after the hormone is removed. This induction results in the elevation of several innate immune genes, such as interferon alpha and beta, tumour necrosis factor, toll-like receptor 3 and interferon regulatory factor 5. We demonstrated that this pre-activation of immune response signalling is not affected by a viral presence, and the antiviral state can be ablated using an interferon-alpha/beta receptor alpha inhibitor. Finally, we proved that the oestrogen-induced stimulation is essential to generate an antiviral microenvironment mediated by activation of type I interferons. Conclusion: Resulting in viral control and suppression, 17β-oestradiol induces an interferon-mediated antiviral state in hepatocytes. Oestrogen-stimulated cells modulate the immune response through secretion of type I interferon, which can be countered by blocking interferon-alpha/beta receptor alpha signalling.

STUDY QUESTION Does adjuvant letrozole in ovarian stimulation for IVF decrease the uterine peristalsis frequency (UPF) prior to fresh embryo transfer (ET)? SUMMARY ANSWER Adjuvant letrozole in ovarian stimulation for IVF does not reduce the UPF significantly prior to fresh ET. WHAT IS KNOWN ALREADY Throughout the cycle, uterine peristalsis aids spermatozoa transport to the fallopian tube and may affect implantation. At fresh ET, UPF is negatively correlated with implantation and clinical pregnancy rates and is believed to be modulated by oestradiol and progesterone. High levels of oestradiol, from multiple follicular development, in ovarian stimulation have been reported to increase UPF, whereas progesterone is considered to be an utero-relaxant. The influence of androgens is unclear. Co-treatment with letrozole during gonadotropin ovarian stimulation limits the supra-physiological oestradiol rise and may therefore reduce UPF prior to fresh ET. STUDY DESIGN, SIZE, DURATION This study was carried out on subjects participating in a single-centre double-blinded randomized controlled trial of the impact of letrozole on follicle development and endocrine profiles, and investigated the impact of adjuvant letrozole in ovarian stimulation for IVF on UPF prior to fresh ET and the correlations of UPF with endocrine markers. Between 2016 and 2017, 39 women expected to be normal responders were randomized to co-treatment with letrozole or placebo. Of these, 33 women completed this element of the study. The study was carried out according to the Helsinki Declaration and the ICH-Good-Clinical-Practice. PARTICIPANTS/MATERIALS, SETTING, METHODS Eligible women were randomized 1:1 to adjuvant treatment with letrozole 5 mg/day or placebo in an antagonist protocol using a fixed dose of recombinant (r) FSH 150 IU/day. Final maturation was triggered with hCG 6500 IU and luteal support with vaginal progesterone was administered from the day following oocyte aspiration. Less than 1 h prior to fresh ET, 6-min duration transvaginal ultrasound recordings of the uterus in sagittal section were performed and blood samples were drawn. MAIN RESULTS AND THE ROLE OF CHANCE A total of 33 women completed the study (letrozole n = 17; placebo n = 16). Age, BMI and ovarian reserve markers were similar between the groups. On the day of ET, serum oestradiol levels were significantly suppressed in the letrozole group to a mean of 867 ± 827 pmol/l compared to 3110 ± 1528 pmol/l in the placebo group (P LIMITATIONS, REASONS FOR CAUTION Limitations of the study included the limited sample size and the lack of a power calculation specifically determined for this endpoint. WIDER IMPLICATIONS OF THE FINDINGS The supra-physiological levels of oestradiol generated during ovarian stimulation were significantly suppressed in the intervention group. However, UPF prior to fresh ET was similar in both groups. Modulating the luteal phase sex steroids with adjuvant letrozole had little measured impact on UPF. Any beneficial effect of adjuvant letrozole during ovarian stimulation is unlikely to be due to significant modulation of UPF. STUDY FUNDING/COMPETING INTEREST(S) M.D.H.’s salary was funded by an unrestricted research grant from Gedeon Richter. The expenses of the study were funded by a scientific collaboration: ReproUnion, co-financed by the European Union, Interreg Öresund-Kattegat-Skagerrak and Ferring Pharmaceuticals. The assays for the analyses were funded by Roche Diagnostics and an unrestricted research grant from Merck Life Science AS, Denmark. The authors have no competing interests to declare regarding this study. TRIAL REGISTRATION NUMBER Clinicaltrials.gov: NCT02939898, EudraCT no.: 2015-005683-41.

Oestrogens are possible therapeutic option for obesity. Today, their usage is limited due to their female-specific gynaecological action and tumour-promoting properties. There is an option for oestrogen delivery based on a concept of peptide carrier that selectively delivers oestrogen to specific tissues. Improved GLP-1 action could be accomplished by oestrogen receptor-mediated delivery.

BackgroundExogenous sex steroids within hormonal contraception and menopausal hormone therapy (MHT) have been used for family planning and management of menopausal symptoms, without consideration of their effects on the vaginal microbiota. This is largely because their use predates our understanding of the importance of the vaginal microbiome on human health. We conducted a systematic review (PROSPERO: CRD42018107730) to determine the influence of exogenous sex steroids, stratified by oestrogen-containing or progestin-only types of contraception, and MHT on the vaginal microbiome, as measured by molecular methods.MethodsEmbase, PubMed and Medline were searched for relevant literature published through to December 1st 2020. Eligible studies reported on the effect of specific exogenous sex steroids on the vaginal microbiome using a molecular method. Data regarding the ‘positive’, ‘negative’ or ‘neutral’ effect of each type of contraceptive or MHT on the vaginal microbiome was extracted and summarised. A positive effect reflected sex steroid exposure that was associated with increased abundance of lactobacilli, a change to, or maintenance of, an optimal vaginal microbiota composition, or a decrease in bacterial diversity (specifically reflecting a low-diversity optimal microbiota state), relative to the control group. An exogenous sex steroid was designated as having a negative effect on the vaginal microbiome if it resulted in opposing effects (i.e. loss of lactobacilli, a non-optimal microbiota state). When no significant change was found, this was considered neutral/inconclusive.ResultsWe identified 29 manuscripts reporting on the effect of exogenous sex steroids on the vaginal microbiome; 25 investigating hormonal contraceptives, and 4 investigating MHT. Oestrogen-containing contraception, particularly reflecting the combined oestrogen and progestin-containing contraceptive pill, had a positive effect on the composition of the vaginal microbiota. Progestin-only contraception, particularly reflecting depo-medroxyprogesterone acetate, had mixed effects on the microbiota. Among post-menopausal women using MHT, exogenous oestrogen applied topically was associated with increased prevalence of lactobacilli.ConclusionOur findings suggest that oestrogen-containing compounds may promote an optimal vaginal microbiota, which could have clinical applications. The impact of progestin-only contraceptives on the vaginal microbiota is less clear; more data is needed to determine how progestin-only contraceptives contribute to adverse reproductive and sexual health outcomes.

Simple Summary Breast cancer is the most common cancer affecting women, and the importance of NR function in breast cancer biology has been recognized since the turn of the 20th century. The nuclear receptor family of transcription factors is associated with cancer development and progression, informs diagnostic and prognostic outcomes, and is an established therapeutic target. Across all subtypes of breast cancer, crosstalk between NR pathways and other signalling pathways has also been demonstrated. Recent critical findings into modulating these NRs, particularly Type 1 NRs, have led to clinical trials and a greater understanding of their mechanism of action. Here, we reviewed the current preclinical insights into the role of Type 1 NRs in breast cancer that have served as a catalyst for clinical translation. Abstract The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.

Sex determination triggers the differentiation of the bi-potential gonad into either an ovary or testis. In non-mammalian vertebrates, the presence or absence of oestrogen dictates gonad differentiation, while in mammals, this mechanism has been supplanted by the testis-determining gene SRY. Exogenous oestrogen can override this genetic trigger to shift somatic cell fate in the gonad towards ovarian developmental pathways by limiting the bioavailability of the key testis factor SOX9 within somatic cells. Our previous work has implicated the MAPK pathway in mediating the rapid cellular response to oestrogen. We performed proteomic and phosphoproteomic analyses to investigate the precise mechanism through which oestrogen impacts these pathways to activate β-catenin—a factor essential for ovarian development. We show that oestrogen can activate β-catenin within 30 min, concomitant with the cytoplasmic retention of SOX9. This occurs through changes to the MAP3K1 cascade, suggesting this pathway is a mechanism through which oestrogen influences gonad somatic cell fate. We demonstrate that oestrogen can promote the shift from SOX9 pro-testis activity to β-catenin pro-ovary activity through activation of MAP3K1. Our findings define a previously unknown mechanism through which oestrogen can promote a switch in gonad somatic cell fate and provided novel insights into the impacts of exogenous oestrogen exposure on the testis.

It has been proposed that men hospitalised with COVID‐19 be treated with oestrogen or progesterone to improve COVID‐19 outcomes. Transgender women (male‐to‐female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE‐2 expression in testicles of trans‐women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans‐women undergoing gender‐affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis‐gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin‐like 3 antibody (Leydig cell) and ACE‐2 IHC. Cells per high‐powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0–2 scale. On immunohistochemistry staining for Leydig cells and ACE‐2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE‐2 to protect men from COVID‐19 infection.

STUDY QUESTION Is it possible to develop a simplified physiological in vitro system representing the key cell-types associated with a receptive endometrial phenotype? SUMMARY ANSWER We present a new concept to investigate endometrial receptivity, with a 3D organotypic co-culture model to simulate an early and transient acute autoinflammatory decidual status that resolves in the induction of a receptive endometrial phenotype. WHAT IS KNOWN ALREADY Embryo implantation is dependent on a receptive uterine environment. Ovarian steroids drive post-ovulation structural and functional changes in the endometrium, which becomes transiently receptive for an implanting conceptus, termed the ‘window of implantation’, and dysregulation of endometrial receptivity is implicated in a range of reproductive, obstetric, and gynaecological disorders and malignancies. The interactions that take place within the uterine microenvironment during this time are not fully understood, and human studies are constrained by a lack of access to uterine tissue from specific time-points during the menstrual cycle. Physiologically relevant in vitro model systems are therefore fundamental for conducting investigations to better understand the cellular and molecular mechanisms controlling endometrial receptivity. STUDY DESIGN, SIZE, DURATION We conducted an in vitro cell culture study using human cell lines and primary human cells isolated from endometrial biopsy tissue. The biopsy tissue samples were obtained from three women attending gynaecological outpatient departments in NHS Lothian. The work was carried out between December 2016 and April 2019, at the MRC Centre for Reproductive Health, Queen’s Medical Research Institute, University of Edinburgh. PARTICIPANTS/MATERIALS, SETTING, METHODS An endometrial stromal cell (ESC) line, and endometrial epithelial cells (EECs) isolated from endometrial biopsy tissue and expanded in vitro by conditional reprogramming, were used throughout the study. Immunocytochemical and flow cytometric analyses were used to confirm epithelial phenotype following conditional reprogramming of EECs. To construct an endometrial organotypic co-culture model, ESCs were embedded within a 3D growth factor-reduced Matrigel structure, with a single layer of conditionally reprogrammed EECs seeded on top. Cells were stimulated with increasing doses of medroxyprogesterone acetate, cAMP and oestradiol, in order to induce ESC decidual transformation and endometrial receptivity. Decidual response and the induction of a receptive epithelial phenotype were assessed by immunocytochemical detection and quantitative in-cell western analyses, respectively. MAIN RESULTS AND THE ROLE OF CHANCE A transient up-regulation of the interleukin-33 receptor protein, ST2L, was observed in ESCs, indicating a transient autoinflammatory decidual response to the hormonal stimulation, known to induce receptivity gene expression in the overlying epithelium. Hormonal stimulation increased the EEC protein levels of the key marker of endometrial receptivity, integrin αVβ3 (n = 8; *P < 0.05; ***P < 0.0001). To our knowledge, this is the first demonstration of a dedicated endometrial organotypic model, which has been developed to investigate endometrial receptivity, via the recapitulation of an early decidual transitory acute autoinflammatory phase and induction of an epithelial phenotypic change, to represent a receptive endometrial status. LIMITATIONS, REASONS FOR CAUTION This simplified in vitro ESC-EEC co-culture system may be only partly representative of more complex in vivo conditions. WIDER IMPLICATIONS OF THE FINDINGS The 3D endometrial organotypic model presented here may offer a valuable tool for investigating a range of reproductive, obstetric, and gynaecological disorders, to improve outcomes for assisted reproductive technologies, and for the development of advances in contraceptive methods. STUDY FUNDING/COMPETING INTEREST(S) This work was supported in part by a Medical Research Council Centre Grant (project reference MR/N022556/1). R.F. was the recipient of a Moray Endowment award and a Barbour Watson Trust award. C.-J.L. is a Royal Society of Edinburgh Personal Research Fellow, funded by the Scottish Government. The authors have no conflicts of interest to declare.

Background: Alzheimer's disease (AD) is a neurodegenerative disease of the elderly, being recognized worldwide as the most common cause of dementia. However, the harm generated by this disease to women and men is disproportionate, in women the disease is recorded twice as much. Numerous research studies have tried to find an answer regarding the causes of this disproportionality. So far, some fundamental differences between macroscopic, microscopic and biochemical structures of female vs. male brain have been investigated. First of all, emphasis was placed on macroscopic structural differences. In this study, a particular role was attributed to APOE4 gene which was shown to be an increased risk factor of AD in women who possess this allele. Hormonal changes in women, such as decreased postmenopausal estrogen, greatly influence disease incidence and prevalence. All these factors tell about the increased susceptibility of women to this disease. However, the definite mechanisms of this disease are incompletely elucidated and further studies are needed. Conclusions: The identification of pathobiochemical mechanisms based on gender, that influence the incidence and prevalence of Alzheimer's disease is essential. Thus, it could be a target in the development of effective preventive therapeutic strategies from the prodromal phase of the disease. In this context, the development of personalized treatment according to gender specifics should be considered in future.

Gynaecological diagnoses were carried in three adult female orangutans (Pongo spp.) using ultrasound, and their estrous states were estimated by measuring urinary sex steroid hormone concentrations using enzyme immunoassay. Ultrasound diagnosis revealed that the endometrial thickness and follicle size were correlated with the oestrogen‐3‐glucuronide concentrations in the follicular phase. In addition, administration of the ovulation inducer human chorionic gonadotropin (hCG) had the strongest effect on the pregnanediol‐3‐glucuronide (PdG) concentration when the follicle size was 22.3 mm, suggesting that the follicle reaches this size before ovulation. The similarity between this and the maximum ovarian follicle size in humans (approximately 20 mm) indicates that the ancestral reproductive characteristics may have been retained in these species., In orangutans, endometrium thickness and follicle size were correlated with estrogen concentration. And follicle may increase to around 22.3 mm prior to ovulation. Orangutans and humans have similar reproductive physiology.

Summary Pharmacological interventions to aid weight loss have historically targeted either appetite suppression or increased metabolic rate. Brown adipose tissue (BAT) possesses the capacity to expend energy in a futile cycle, thus increasing basal metabolic rate. In animal models, oestrogen has been implicated in the regulation of body weight, and it is hypothesized that oestrogen is acting by modulating BAT metabolism. A systematic search was performed, to identify research articles implementing in vivo oestrogen‐related interventions and reporting outcome measures that provide direct or indirect measures of BAT metabolism. Meta‐analyses were conducted where sufficient data were available. The final library of 67 articles were predominantly in rodent models and provided mostly indirect measures of BAT metabolism. Results of this review found that oestrogen's effects on body weight, in rats and possibly mice, are likely facilitated by both metabolic and appetitive mechanisms but are largely only found in ovariectomized models. There is a need for further studies to clarify the potential effects of oestrogen on BAT metabolism in gonad‐intact and castrated male animal models.

The incidence of post-menopausal osteoporosis is increasing globally. In post-menopausal osteoporosis, there is deficiency in oestrogen level resulting in bone loss and fractures. Bone formation is under the control of different hormones. In the present review, we highlight few pathways such as RANKL/RANK, apoptosis and Wnt/β-catenin signalling pathways and phytoestrogens involved in the bone metabolism. RANKL/RANK signalling is responsible for regulating the formation and activation of multinucleated osteoclasts from their precursors which is responsible for the survival of normal bone remodelling. Apoptosis regulates the development, growth and maintains the bone tissues. The Wnt pathway is an important pharmacological target for bone anabolic drugs and its future discovery. In today’s world, herbal remedies are used to treat post-menopausal osteoporosis as these products contain phytoestrogens. These phytoestrogens are oestrogen like compounds which influence bone metabolism. The phytoestrogens provide better therapeutic effect in reducing the RANKL, osteoclastogenesis, inflammatory markers, and increase the osteogenic markers in the bone cells or osteoblasts. We discuss the mechanism of action of few phytoestrogens such as genistein, daidzein and equol which are beneficial for improvement of the bone health. Daidzein enhances osteoblast growth via the upregulation of BMP expression in primary osteoblast cells and it is a potential antiosteoporotic agent. Genistein also possesses antioestrogenic property by virtue of its competitive binding to the same receptors as oestradiol. Equol regulates the bone loss via hemopoiesis and inflammatory cytokine production. Thus, phytoestrogens could be efficiently used as osteoprotective agents for the treatment of individuals with post-menopausal osteoporosis.

Non-ossifying fibroma (NOF) has been an intriguing entity since its first description. It is the most common bone tumour, is usually asymptomatic affecting children and adolescents, is composed of a heterogeneous cell population, and undergoes spontaneous regression after puberty. In a recent article in The Journal of Pathology, Baumhoer and colleagues demonstrate mutations activating the RAS-MAPK pathway (KRAS, FGFR1 and NF1) in similar to 80% of the tumours. Activation of the RAS-MAPK pathway by somatic mutations is found in a plethora of tumour types, both benign and malignant, while germline mutations cause a wide range of syndromes collectively termed the RASopathies. Their findings indicate that NOF, for long thought to be reactive, should be considered a true neoplasm. Moreover, their data suggest that only a subset of cells in the lesion contain the mutation. A second cell population consisting of histiocytes and osteoclast-like giant cells appears to be reacbenign and locally aggressive bone tumours and seems essential for tumourigenesis. The spontaneous regtive. This intimate relation between WT and mutant cells is also frequently encountered in other ression remains enigmatic and it is tempting to speculate that pubertal hormonal signalling, especially increased oestrogen levels, affect the balance between mutant and WT cells. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Background: Breast cancer (BC) is the most common cancer among women and leading contributor to cancer mortality, hence constitutes a major public health issue worldwide. In Scotland, over 4,000 women are diagnosed with BC every year and around a 1,000 die from this disease. Monitoring incidence, mortality and survival trends is key for surveillance of disease progression. BC is heterogeneous, with multiple subtypes defined by molecular markers, such as the oestrogen receptor (ER), that have different aetiology, targeted treatments and prognosis, yet standard reporting of incidence and mortality rates is not usually done using tumour marker data. The Scottish Cancer Registry was the first registry in the UK to collect molecular marker data and therefore, constitutes an excellent opportunity to explore incidence and survival trends over time by molecular subtypes. This PhD aims to describe temporal trends in BC incidence and survival by molecular subtypes in Scotland to inform public health prevention programmes, diagnostic and therapeutic services. Methods: A systematic review was conducted to determine the extent of available data on BC incidence trends by ER in population-based studies of women of European ancestry. In addition, the Scottish Cancer registry data on over 72,000 women diagnosed with incident primary BC from 1997 to 2016 (the focus of most analyses for this dissertation) was used to describe trends in incidence and survival in Scotland. Age-standardised incidence rates (ASiR) and age-specific incidence were estimated by BC subtype after imputation of molecular marker data. Joinpoint regression and age-period-cohort (APC) models were used to assess whether significant differences were observed in incidence trends by ER, the human epidermal growth factor receptor 2 (HER2) and the immunohistochemistry (IHC) defined molecular subtypes. Kaplan-Meier (KM) estimates and traditional and extended Cox proportional hazards models were computed to assess breast cancer specific survival (BCSS) by BC subtypes. Sensitivity analysis was carried out to compare results for the Cox models from complete case analysis (CCA) and multiple imputation analysis (MIA). The effect of individual, tumour characteristics and treatments on BCSS for each subtype was also investigated. Trends in 5-year survival by age, grade and stage characteristics for the different subtypes (ER+ and ER-) were investigated to identify the characteristics of women showing greatest and lowest improvements over time. Other causes of death were also explored and cumulative incidence functions (CIF) were investigated. Results: The systematic review showed that ER+ BC incidence increased and ER- BC incidence decreased in the last four decades (EAPCs ranging from 0.8% to 3% for ER+ tumours and -2.1% to -3.4% for ER- tumours) and that the rise in overall incidence trends is mainly driven by increases of ER+ tumours in women of screening age. In Scotland, BC incidence rates showed the same divergent pattern between ER+ and ER- tumours observed in other countries. ER+ tumour incidence increased by 0.4% per year from 1997 to 2011 and increases were mainly among routinely screened women aged 50 to 69 years. In contrast, ER- tumour incidence decreased among all ages by -2.5% per year over the study period. Apart from the period effects observed, APC models showed that older cohorts of women born in 1912-1940 had lower incidence rate ratios (IRR) for ER+ tumours, and younger cohort of women born in 1960-1986 had lower IRR for ER- tumours, compared to women from the 1941-1959 birth cohorts. Results for the IHC defined subtypes showed that luminal A tumours, that account for more than half of all tumours, had similar patterns to those observed for ER+ tumours, with increases until 2011. In contrast, luminal B tumours declined over time, particularly in women over 50 years of age. There was no clear trend for HER2-enriched or triple negative breast cancers (TNBC) overall but TNBC tumours seemed to increase in younger women aged 20 to 49 years. BCSS also differed between subtypes with ER+ tumours having better survival than ER- tumours, luminal A tumours having the best survival of all IHC defined subtypes and TNBC having the worst survival. Age, grade, stage, screening and surgery were the most important prognostic factors irrespective of tumour subtype, with women who had older age, higher grade, stages III-IV, tumours not screen detected and who did not have surgery having worse survival. Deprivation was also associated with lower BCSS, with women living in the most deprived areas of Scotland having increased BC-specific mortality when compared to women in the least deprived areas and this relationship was observed for all subtypes with slightly higher HR for HER2-enriched subtypes (but wider CI). Five-year BCSS trends showed improvements in the last two decades, especially for women aged 50 to 69 years. The greatest gains in survival were seeing in women with advanced tumours (high grade or stage III-IV tumours) and ER-tumours seemed to have greatest improvements than ER+ tumours, although their survival remained lower than for ER+ tumours. The improvements observed for women with high grade and stage III-IV tumours were observed in both screen and not screen detected tumours but the rise was sharper amongst women with screen detected tumours. Women younger than 50 years showed similar improvements than those observed in women aged 50 to 69 years. Older women aged 70 years or more showed no consistent survival improvements over time and over 50% of women in that age had a primary cause of death other than BC with cardiovascular diseases (CVD) being a major contributor (22% of all deaths). Conclusions: This project is the first in the UK to describe incidence and survival trends by molecular subtypes of BC using population-based data. Divergent incidence trends found in Scotland are similar to those observed in other countries and confirm different aetiology of BC molecular subtypes. Increases in the incidence of hormone sensitive tumours are likely to be driven by the implementation of mammographic screening programmes, population aging and changes in risk factors (RFs) that have differential effects on the subtypes, such as, reproductive factors and obesity. Survival improvements in Scotland are likely due to multiple contributors with two major factors such as screening and the improvement and development of new treatments likely playing a role. This PhD has allowed us to further understand disease progression of the different subtypes in Scotland and has identified groups of women (those with advanced tumour characteristics, living in the most deprived regions of Scotland or women aged 70 years or older) with lower survival and/or lower improvements in survival trends that could benefit from further prevention and treatment programmes. This PhD also highlights the importance of monitoring future incidence and survival by molecular subtypes to inform clinical planning and cancer control programmes.

New Findings What is the central question of this study? Would ovariectomy cause prolonged changes in ventilation and sustained loss of acute, intermittent hypoxia‐induced neuroplasticity or would these outcomes be restored with time? What is the main finding and its importance? Our main findings demonstrate that ovariectomy elicits minimal alteration in overall breathing function but impairs acute, intermittent hypoxia‐induced plasticity for ≤ 12 weeks. Abstract Sex hormones are necessary to enable respiratory neuroplasticity, including phrenic long‐term facilitation (pLTF), a form of respiratory motor plasticity elicited by acute, intermittent hypoxia (AIH). Female rats exhibit a progressive increase in phrenic nerve amplitude after AIH characteristic of pLTF only during pro‐oestrus, the stage of the oestrous cycle notable for elevated circulating oestradiol levels. Removal of the ovaries [ovariectomy (OVX)], the primary source of circulating oestradiol, also eliminates AIH‐induced pLTF after 1 week. Ovariectomy is used routinely as a model to examine the impact of sex hormones on CNS structure and function, but the long‐term impact of OVX is rarely examined. Extra‐ovarian sites of oestradiol synthesis, including multiple CNS sites, have been identified and might possess the capacity to restore oestradiol levels, in part, over time, impacting respiratory function and the expression of respiratory neuroplasticity. We examined both ventilation in awake, freely behaving female rats, using barometric plethysmography, and the expression of AIH‐induced pLTF in anaesthetized, ventilated female rats 2 and 12 weeks after OVX and compared them with age‐matched ovarian‐intact female rats. Our findings indicate that chronic OVX had little impact on baseline breathing or in the response to respiratory challenge (10% O2, 5% CO2, balance N2) during plethysmography. However, OVX rats at both 2 and 12 weeks demonstrated a persistent loss of AIH‐induced pLTF relative to control animals (P

Rhodococcus equi ATCC13557 was selected as a model organism to study oestrogen degradation based on its previous ability to degrade 17α-ethinylestradiol (EE2). Biodegradation experiments revealed that R. equi ATCC13557 was unable to metabolise EE2. However, it was able to metabolise E2 with the major metabolite being E1 with no further degradation of E1. However, the conversion of E2 into E1 was incomplete, with 11.2 and 50.6% of E2 degraded in mixed (E1-E2-EE2) and E2-only conditions, respectively. Therefore, the metabolic pathway of E2 degradation by R. equi ATCC13557 may have two possible pathways. The genome of R. equi ATCC13557 was sequenced, assembled, and mapped for the first time. The genome analysis allowed the identification of genes possibly responsible for the observed biodegradation characteristics of R. equi ATCC13557. Several genes within R. equi ATCC13557 are similar, but not identical in sequence, to those identified within the genomes of other oestrogen degrading bacteria, including Pseudomonas putida strain SJTE-1 and Sphingomonas strain KC8. Homologous gene sequences coding for enzymes potentially involved in oestrogen degradation, most commonly a cytochrome P450 monooxygenase (oecB), extradiol dioxygenase (oecC), and 17β-hydroxysteroid dehydrogenase (oecA), were identified within the genome of R. equi ATCC13557. These searches also revealed a gene cluster potentially coding for enzymes involved in steroid/oestrogen degradation; 3-carboxyethylcatechol 2,3-dioxygenase, 2-hydroxymuconic semialdehyde hydrolase, 3-alpha-(or 20-beta)-hydroxysteroid dehydrogenase, 3-(3-hydroxy-phenyl)propionate hydroxylase, cytochrome P450 monooxygenase, and 3-oxosteroid 1-dehydrogenase. Further, the searches revealed steroid hormone metabolism gene clusters from the 9, 10-seco pathway, therefore R. equi ATCC13557 also has the potential to metabolise other steroid hormones such as cholesterol.

RESUMEN : A nivel mundial, el cáncer de mama es la neoplasia maligna más diagnosticada, por delante incluso del cáncer de pulmón, y la principal causa de muerte por cáncer en mujeres en todo el mundo. Desde hace décadas, se sabe que una mayor exposición a estrógenos, ya sean naturales o sintéticos, se relaciona con un aumento de los tumores mamarios; es por esto que la modulación de la actividad estrogénica siempre ha sido un objetivo farmacológico perseguido y explotado, siendo la hormonoterapia un pilar clave en el abordaje terapéutico del cáncer de mama estrógeno-dependiente. La cirugía, la radioterapia y/o la quimioterapia también forman parte de ese abordaje clásico, sin embargo, son técnicas que presentan limitaciones tales como resistencias o graves efectos secundarios. Por todo lo anterior, se ha generado la necesidad de investigar nuevas líneas terapéuticas con las que obtener una mejor respuesta al tratamiento con menores efectos secundarios. Gracias al uso de nuevas técnicas genómicas y proteómicas, se ha profundizado en las características moleculares, las alteraciones genéticas subyacentes y los eventos biológicos que permiten el desarrollo de los tumores mamarios. Además, se ha visto que el sistema inmunológico juega un papel activo en el control y la progresión del cáncer, y su respuesta se caracteriza por un fenómeno que se conoce como inmunoedición. A través del conocimiento de todas estas vías, se han podido identificar nuevas posibles dianas terapéuticas, como los anticuerpos monoclonales o moléculas basadas en la inmunoterapia, con las que mejorar el pronóstico y la supervivencia de los pacientes. En este sentido, la inmunoterapia y las vacunas terapéuticas destinadas a dirigir el programa inmunológico citotóxico contra las células tumorales son particularmente prometedoras. El objetivo de esta revisión bibliográfica es analizar estas nuevas dianas, describir la base fisiológica en la que se sustentan y comentar los ensayos clínicos y los posibles escenarios terapéuticos que se están desarrollando en la actualidad. ABSTRACT : Breast cancer is the most diagnosed worldwide tumour, even before lung cancer and it is the leading cause of cancer death for women worldwide. It is being known for decades that a higher exposure to either natural or synthetic oestrogen is related to an increase incidence of breast cancer. So that the modulation of the oestrogen activity has always being an exploited and pursued objective and the hormone therapy a key foundation in the oestrogen-dependent breast cancer treatment. The surgery, the radiotherapy and the chemotherapy also belong to this classic treatment approach. However, these techniques also share some challenges such as the resistance or the severe side effects. Being said so, a search for new lines of therapy is needed to obtain better results with lesser side effects. A deeper understanding of the molecular characteristics, the underlying genetic disorders and the biological triggers that allow the breast cancer development is being performed thanks to the new genomic and proteomic techniques. Furthermore, the immunological system has been seen playing an active role in the control of the cancer progression and its response has been characterised as a phenomenon known as immuno-editing. New potential therapeutic targets such as monoclonal antibodies or immunotherapy-based molecules have been identified through the knowledge of all these lines, being able to improve the patient’s prognosis and survival. Accordingly, the immunotherapy and the therapeutic vaccines aimed to address the cytotoxic immunologic program against the tumorous cells are particularly promising. Analysing these new targets is the objective of this bibliographic review, also to describe their physiological foundation and discuss the clinical trials and the potential therapeutic scenarios that are currently being developed. Grado en Medicina

The incidence of SARS-CoV2 infections is around 15% higher in premenopausal women compared to age matched men, yet the fatality rate from COVID-19 is significantly higher in men than women for all age strata. Sex differences have also been observed in recent epidemics including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), with SARS-CoV 2 virus infection sex differences appear more dramatic. The regulation and expression of the angiotensin converting enzyme 2 (ACE2) is the key for this special coronavirus SARS-CoV-2 to enter the cell. 17β-oestradiol increases expression level and activity of angiotensin converting enzyme-2 (ACE2) and the alternative signaling pathway of Ang II via the angiotensin II receptor type II (AT2R) and the Mas receptor is more dominant in female sex than in male sex. Maybe a hint to explain the higher infection risk in women. The same hormonal milieu plays a major role in protecting women where morbidity and mortality are concerned, since the dominant female hormone, oestradiol, has immune-modulatory properties that are likely to be protective against virus infections. It is also known that the X chromosome contains the largest number of immune-related genes, potentially conferring an advantage to women in efficient immune responsiveness. Lifestyle factors are also likely to be contributory. Premenopausal women could possibly face higher exposure to infection (hence higher infection rates) because economic conditions are often less favorable for them with less opportunity for home office work because of jobs requiring mandatory attendance. Due to the additional task of childcare, it is likely that contact times with other people will be longer. Women generally make healthier lifestyle choices, thus reducing the disease burden that confers high risk of mortality in COVID-19 infected men. This narrative review aims to present key concepts and knowledge gaps on the effects of oestrogen associated with SARS-CoV2 infection and COVID-19 disease.

Significance Here, we show that DMRT1 dosage is the key sex determination factor in birds and is essential for testis development. Furthermore, we provide additional evidence that birds, in contrast to mammals, have acquired cell-autonomous sex identity (CASI) and that the sex hormone environment does not significantly influence avian secondary sexual characteristics. This finding highlights an evolutionary divide between mammals and nonmammalian vertebrates. In mammals, the sex chromosomes determine the type of gonad formed, and sex hormones largely define the secondary sexual phenotype. In birds, the sexual phenotype is directly determined by the sex chromosome content of individual cells in different tissues. Our findings help advance our understanding of the evolution of sex determination systems and the nature of sex identity., In birds, males are the homogametic sex (ZZ) and females the heterogametic sex (ZW). Primary sex determination is thought to depend on a sex chromosome gene dosage mechanism, and the most likely sex determinant is the Z chromosome gene Doublesex and Mab-3–Related Transcription factor 1 (DMRT1). To clarify this issue, we used a CRISPR-Cas9–based monoallelic targeting approach and sterile surrogate hosts to generate birds with targeted mutations in the DMRT1 gene. The resulting chromosomally male (ZZ) chicken with a single functional copy of DMRT1 developed ovaries in place of testes, demonstrating the avian sex-determining mechanism is based on DMRT1 dosage. These ZZ ovaries expressed typical female markers and showed clear evidence of follicular development. However, these ZZ adult birds with an ovary in place of testes were indistinguishable in appearance to wild-type adult males, supporting the concept of cell-autonomous sex identity (CASI) in birds. In experiments where estrogen synthesis was blocked in control ZW embryos, the resulting gonads developed as testes. In contrast, if estrogen synthesis was blocked in ZW embryos that lacked DMRT1, the gonads invariably adopted an ovarian fate. Our analysis shows that DMRT1 is the key sex determination switch in birds and that it is essential for testis development, but that production of estrogen is also a key factor in primary sex determination in chickens, and that this production is linked to DMRT1 expression.

In recent times, endocrine disrupting chemicals (EDCs) have been associated with the rise in neurodevelopmental disorders such as autism, attention deficit hyperactivity disorder (ADHD) and decreased intelligence quotient (IQ) in children. This effect is suspected to be induced at pre-/peri-natal development, via an alteration in hormonal signaling, thus interfering with neuronal differentiation, with subsequent effect on normal brain development and function in exposed children. This issue increases the need for chemical screening for potential developmental neurotoxicity (DNT) effect. The current available EDC induced DNT test guideline is based on in-vivo testing that requires animal use. Here, a multipotent neural progenitor cell line, the C17.2 cell-line, generated from neural stem cells of the external germinal layer of mouse cerebellum, with potential to differentiate to neurons or astrocytes, is introduced for in-vitro EDC induced DNT testing. This project focused on optimizing the C17.2 cell-line for the detection of EDC-induced DNT with emphasis on the disruption of the oestrogen, androgen, and thyroid hormone systems. It aimed at validating the involvement of oestrogen, androgen, and thyroid hormone on molecular and cellular endpoints relevant for the differentiation of the C17.2 cells. Herein, the cells were exposed to the hormonal agonist and antagonist at a range of concentrations for a 10-day differentiation period. After exposure, LDH, viability assay and morphological changes (percentage of neurons in culture and neurite outgrowth) were evaluated. The results showed no morphological changes induced by androgen receptor (AR) agonist/antagonist at relevant physiological concentrations. The thyroid receptor (TR) agonist and antagonist on the other hand showed a response in the form of increased neurite outgrowth in relation to the negative control at a concentration range of 40-200 nM and 40 nM respectively. The oestrogen receptor (ER) antagonist at 100 nM also increased percentage neuron in culture. Additionally, in-silico analysis of microarray and RNA sequencing data were used to map out target genes regulated by ER, AR and TR and involved in neurodevelopment. With this approach, 29 marker genes were identified. Validation of the marker genes by means of gene expression (qPCR) was carried out, ER and TR agonist/antagonist were observed to modulate the expression of examined genes. In summary, the model could not be established for detecting EDC induced DNT via androgenic and oestrogenic pathway, while it is a promising model for identifying DNT induced by thyroid hormone signalling disruption.

While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused on catecholamines and the sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:24 issue:2 pages:274-286 ispartof: location:England status: published

Highlights • Zoledronic acid can prevent recurrence and improve survival when given in early breast cancer. • Anti-cancer effects were only observed in post-menopausal women with confirmed low oestrogen. • We discuss molecular and immune regulated mechanisms that could explain this phenomenon. • Oestrogen affects anti-resorptive properties of zoledronic acid in bone. • Oestrogen may inhibit zoledronic acid induced anti-tumour immune responses., Late stage breast cancer commonly metastasises to bone and patient survival averages 2–3 years following diagnosis of bone involvement. One of the most successful treatments for bone metastases is the bisphosphonate, zoledronic acid (ZOL). ZOL has been used in the advanced setting for many years where it has been shown to reduce skeletal complications associated with bone metastasis. More recently, several large adjuvant clinical trials have demonstrated that administration of ZOL can prevent recurrence and improve survival when given in early breast cancer. However, these promising effects were only observed in post-menopausal women with confirmed low concentrations of circulating ovarian hormones. In this review we focus on potential interactions between the ovarian hormone, oestrogen, and ZOL to establish credible hypotheses that could explain why anti-tumour effects are specific to post-menopausal women. Specifically, we discuss the molecular and immune cell driven mechanisms by which ZOL and oestrogen affect the tumour microenvironment to inhibit/induce tumour growth and how oestrogen can interact with zoledronic acid to inhibit its anti-tumour actions.

Background Ovarian ependymoma is a rare malignancy. Because of the extreme rarity, certain features of the neoplasm, including its clinical behaviour and optimal therapy, are incompletely characterized. Case presentation A 32-year-old pregnant woman at term presented with a left ovarian neoplasm that occurred in the early stage of pregnancy. She underwent left adnexectomy during the caesarean section, and the neoplasm was histologically and immunohistochemically identified to be ovarian ependymoma. Immunohistochemical staining with oestrogen receptors and progesterone receptors showed strong positive staining. According to reports in the literature, the pathological type of ovarian ependymoma in our patient was the extra-axial type. Interestingly, the foetus was also found to have bilateral ependymal cysts during pregnancy. The patient received no further surgical treatment or adjuvant therapy. She and her 14-month-old baby both have no evidence of disease at present. The follow-up of both mother and child is still continuing. Conclusions The case presented here illustrates high levels of oestrogen during pregnancy may stimulate viable malignant ependymal cells to proliferate. Hence, young women with extra-axial-type ependymomas may not be suitable for fertility preservation. Moreover, hormone-based therapies can be a potentially effective treatment for women with extra-axial ependymomas.

Simple Summary The ongoing clinical need to improve cancer therapies warrants a better understanding of the mechanisms behind cancer growth and its spread to distant organs. To this end, research into the impact of sex hormones, such as oestrogens and testosterones, in cancers has led to improvements in the way sex hormone-responsive cancers are treated. Pigment epithelium-derived factor (PEDF) is a protein with anti-cancer properties that is also sensitive to sex hormones. The aim of this review is to explore what is currently known about sex hormones and PEDF in cancers in order to better understand the anti-cancer role of PEDF in sex hormone-responsive cancers. Abstract Oestrogens and androgens play important roles in normal and cancerous tissue and have been shown to negatively regulate pigment epithelium-derived factor (PEDF) expression in sex hormone-responsive tumours. PEDF suppresses tumour growth and its downregulation by oestrogen is implicated in tumorigenesis, metastasis, and progression. PEDF expression is reduced in cancerous tissue of the prostate, breast, ovary, and endometrium compared to their normal tissue counterparts, with a link between PEDF downregulation and sex hormone signalling observed in pre-clinical studies. PEDF reduces growth and metastasis of tumour cells by promoting apoptosis, inhibiting angiogenesis, increasing adhesion, and reducing migration. PEDF may also prevent treatment resistance in some cancers by downregulating oestrogen receptor signalling. By interacting with components of the tumour microenvironment, PEDF counteracts the proliferative and immunosuppressive effects of oestrogens, to ultimately reduce tumorigenesis and metastasis. In this review, we focus on sex hormone regulation of PEDF’s anti-tumour action in sex hormone-responsive tumours.

Miomi su najčešće dobroćudni tumori maternice građeni u prvom redu od glatkih mišića. Ne pojavljuju se prije puberteta, rastu pod utjecajem hormona (estrogena) u reproduktivnoj dobi, a s pojavom menopauze im učestalost opada. Rijetko ih pronalazimo pojedinačno, već se obično pojavljuju kao multipli (više mioma istovremeno). Uzrok nastanka mioma nije poznat, no estrogen pospješuje njegov rast. Mogu biti karakterizirani cijelim rasponom simptoma, a najčešći simptom koji se javlja je metroragija i zbog njega je najčešće potreban kirurški zahvat. Najčešći indikacija za histerektomiju je obilno i nepravilno krvarenje iz maternice uzrokovano miomima. Kako simptomi mogu biti bolni i nelagodni te remete kvalitetu života, potrebno je što prije postaviti točnu dijagnozu pacijentice. Najprije uzimamo osobnu i obiteljsku anamnezu te svakoj ženi pristupamo individualno. Liječenje mioma ovisi o više faktora, a to su: dob pacijentice, paritet, sadašnjoj trudnoći, želji za trudnoćom, općem zdravlju pacijentice, simptomima te veličini i smještaju mioma. Postoje tri vrste liječenja, a najčešći izbor liječenja kirurški je pristup. Danas primalja ima važnu ulogu u pripremi pacijentice za operaciju, ali i nakon nje. Educira ju, savjetuje i skrbi za nju tijekom boravka u bolnici, pregleda u privatnim ordinacijama ili u bilo kojoj drugoj zdravstvenoj ustanovi te ima velik utjecaj na psihološko stanje pacijentice. Fibroids are the most common benign tumours of the uterus primarily composed of smooth/slick muscles. They do not occur before puberty as they grow influenced by the oestrogen hormone in the reproductive age and with the beginning of menopause, their frequency diminishes. They are rarely seen individually but rather occur as multiples (more fibroids at the same time). The cause of the creation of the fibroid is not known, but what is known is that the oestrogen helps its growth. They can be characterised by a wide range of symptoms, the most common being metrorraghia which requires a surgery. The most common indication for hysterectomy is abundant and irregular bleeding of the uterus caused by fibroids. As the symptoms can be painful and uncomfortable as well as disruptive of the quality of life, the correct diagnosis of the patient is necessary. Primarily, there is a need to gather personal and familial anamnesis and approach each patient individually. Fibroid treatment depends on several factors, and these are: the age of the patient, symptoms as well as the size and position of the fibroid. Today, the midwife has an important role in the preparation of the patient for the operation and afterwards. They educate the patient, advise her and take care of her during her stay in the hospital, during the check-ups in the private hospital or other health institution and has a huge impact on the psychological state of the patient.

Colorectal carcinoma (CRC) has been of great interest among researchers, and multiple causes have been proposed and accepted; however, cholecystectomy (CMY) as a potential cause for CRC, particularly in the female gender has not been studied in detail, despite multiple evidence suggesting a positive association. This review is directed at investigating the association between CMY and CRC in the female gender and aims at finding a potential cause for this association. CRC involves cancer of the sigmoid and rectum. The composition of the bile acids is altered in patients after CMY, and the resultant secondary bile acids (BA) without a functioning gall bladder are exposed directly to the intestines, which could lead to cancer. An increase in fecal secondary bile acids is also described as high in the CMY population and has been linked to cancer. Right-sided GI cancers were attributed to CMY, although many earlier studies did not find this to be true. It is interesting to note a strong association between CRC and CMY in the female western population.

ObjectiveTo evaluate the feasibility of a multicentre randomised controlled trial (RCT) comparing oestrogen treatment with no oestrogen supplementation in women undergoing pelvic organ prolapse (POP) surgery.Design and settingA randomised, parallel, open, external pilot trial involving six UK urogynaecology centres (July 2015–August 2016).ParticipantsPostmenopausal women with POP opting for surgery, unless involving mesh or for recurrent POP in same compartment.InterventionWomen were randomised (1:1) to preoperative and postoperative oestrogen or no treatment. Oestrogen treatment (oestradiol hemihydrate 10 μg vaginal pessaries) commenced 6 weeks prior to surgery (once daily for 2 weeks, twice weekly for 4 weeks) and twice weekly for 26 weeks from 6 weeks postsurgery.Outcome measuresThe main outcomes were assessment of eligibility and recruitment rates along with compliance and data completion. To obtain estimates for important aspects of the protocol to allow development of a definitive trial.Results325 women seeking POP surgery were screened over 13 months and 157 (48%) were eligible. Of these, 100 (64%) were randomised, 50 to oestrogen and 50 to no oestrogen treatment, with 89 (44/45 respectively) ultimately having surgery. Of these, 89% (79/89) returned complete questionnaires at 6 months and 78% (32/41) reported good compliance with oestrogen. No serious adverse events were attributable to oestrogen use.ConclusionsA large multicentre RCT of oestrogen versus no treatment is feasible, as it is possible to randomise and follow up participants with high fidelity. Four predefined feasibility criteria were met. Compliance with treatment regimens is not a barrier. A larger trial is required to definitively address the role of perioperative oestrogen supplementation.Trial registration numberISRCTN46661996.

This research was aimed at estimating the effect of oral supplementation of Tamoxifen on productive efficiency, carcass characteristics, hormonal profile and gonadal structure of two broiler breeds. One hundred and eighty chicks of each breed of Avian48 and Arbor Acres were divided into three groups: control group, TAM10 group, supplied with 10 mg Tamoxifen/kg of body weight at 3, 5, 7 and 9 days of life, and TAM20 group, supplied at the same intervals with 20 mg Tamoxifen/kg of body weight. Both levels of Tamoxifen improved productive performance at early ages, but Arbor Acres produced better results with TAM20 levels than TAM10, while Avian48 breeds reacted adversely. On the contrary, Tamoxifen supplementation significantly decreased feed intake and feed conversion (after the first two weeks of life) compared to control with a higher level of decrease reported for TAM20 treatments than TAM10 and for Arbor Acres compared to Avian48 breed. Carcass traits were not affected significantly with Tamoxifen supplementation compared to control although Arbor Acres responded better to TAM20 and Avian48 for TAM10. With regard to the effect of Tamoxifen (TAM) on sex hormones, it could be concluded that TAM10 treatments showed a stimulating effect on the level of such hormones as compared with the TAM20 group with the most favourable results being clearly detectable in 42-day-old birds although both concentrations of Tamoxifen did not differ significantly from control. However, treatment of broiler chickens with Tamoxifen in different doses caused a gradual decrease in follicle production rate and eventually led to an increase of the atretic follicles in different stages of atresia. Finally, we can conclude that Tamoxifen supplementation can improve performance and carcass efficiency of broilers without changing the hormonal profile, however much research is required to estimate the best concentration required for each breed.

Objectives Novel coronavirus disease (COVID-19) is rapidly spreading all over the world. Although in many cases the infection causes very weak symptoms, it can be severe in patient with diverse chronical diseases and immunological compromising patients. Pregnancy is a unique condition in which mother and fetus peacefully collaborate. Diverse endocrine-immune mechanisms, mostly under progesterone control work together to protect the fetus from maternal immunocompetent cell activation driven rejection. The physiological shift to Th2 dominant environment, while favourable for fetus, it makes mothers susceptible to infective pathogens, making pregnancy during COVID-19 pandemic challenging. Materials and methods Studies involving COVID-19 in pregnancy and those analysing changes of immune system induced by COVID-19 were searched in databases such as PubMed, Scopus, Google Scholar and ScienceDirect. Databases were searched using a keyword COVID-19/coronavirus, that was combined with following terms: immune system, pregnancy, oestrogen, or progesterone. Search included studies published up to 01.07.2020. Almost 1,500 articles were found, but only 18 met criteria. Results Most frequent symptoms of COVID-19 in mothers infected in the late pregnancy were fever and cough accompanied with lymphopenia and elevated C-reactive protein. Mothers reported to have severe disease had comorbidities and were obese. Low rate of neonatal complications of maternal Sars-Coc-2 infection without neonatal mortality was observed. Conclusions Currently available data didn’t show significant relationship between COVID-19 severity and pregnancy and there is no strong evidence that mother’s infection can lead to adverse pregnancy outcome, but further studies are needed to determinate the possible effects of COVID-19 gained during earlier pregnancy.

Heat shock protein 90 (HSP90) modulates exercise‐induced cutaneous vasodilation in young men via nitric oxide synthase (NOS), but only when core temperature is elevated ~1.0°C. While less is known about modulation of this heat loss response in women during exercise, sex differences may exist. Further, the mechanisms regulating cutaneous vasodilation can differ between exercise‐ and passive‐heat stress. Therefore, in 11 young women (23 ± 3 years), we evaluated whether HSP90 contributes to NOS‐dependent cutaneous vasodilation during exercise (Protocol 1) and passive heating (Protocol 2) and directly compared responses between end‐exercise and a matched core temperature elevation during passive heating. Cutaneous vascular conductance (CVC%max) was measured at four forearm skin sites continuously treated with (a) lactated Ringers solution (control), (b) 178 μM Geldanamycin (HSP90 inhibitor), (c) 10 mM L‐NAME (NOS inhibitor), or (d) combined 178 μM Geldanamycin and 10 mM L‐NAME. Participants completed both protocols during the early follicular (low hormone) phase of the menstrual cycle (0–7 days). Protocol 1: participants rested in the heat (35°C) for 70 min and then performed 50 min of moderate‐intensity cycling (~55% VO2peak) followed by 30 min of recovery. Protocol 2: participants were passively heated to increase rectal temperature by 1.0°C, comparable to end‐exercise. HSP90 inhibition attenuated CVC%max relative to control at end‐exercise (p, We evaluated whether HSP90 contributes to NOS‐dependent cutaneous vasodilation during exercise and passive heating in young women. We directly compared these responses at end‐exercise and the matched core temperature elevation during passive heating. We showed that HSP90 modulates cutaneous vasodilation NOS‐dependently during exercise in young women, while there was no effect of HSP90 inhibition during passive heating, despite a similar NOS contribution.

COVID-19 due to the SARS-CoV-2 infection is a multi-systemic immune syndrome affecting mainly the lungs, oropharyngeal region, and other vascular endothelial beds. There are tremendous ongoing efforts for the aim of developing drugs against the COVID-19 syndrome-associated inflammation. However, currently no specific medicine is present for the absolute pharmacological cure of COVID-19 mucositis. The re-purposing/re-positioning of already existing drugs is a very important strategy for the management of ongoing pandemy since the development of a new drug needs decades. Apart from altering angiotensin signaling pathways, novel drug candidates for re-purposing comprise medications shall target COVID-19 pathobiology, including pharmaceutical formulations that antagonize proteinase-activated receptors (PARs), mainly PAR-1. Activation of the PAR-1, mediators and hormones impact on the hemostasis, endothelial activation, alveolar epithelial cells and mucosal inflammatory responses which are the essentials of the COVID-19 pathophysiology. In this context, Ankaferd hemostat (Ankaferd Blood Stopper, ABS) which is an already approved hemostatic agent affecting via vital erythroid aggregation and fibrinogen gamma could be a potential topical remedy for the mucosal management of COVID-19. ABS is a clinically safe and effective topical hemostatic agent of plant origin capable of exerting pleiotropic effects on the endothelial cells, angiogenesis, cell proliferation and vascular dynamics. ABS had been approved as a topically applied hemostatic agent for the management of post-surgical/dental bleedings and healing of infected inflammatory mucosal wounds. The anti-inflammatory and proteinase-activated receptor axis properties of ABS with a considerable amount of oestrogenic hormone presence highlight this unique topical hemostatic drug regarding the clinical re-positioning for COVID-19-associated mucositis. Topical ABS as a biological response modifier may lessen SARS-CoV-2 associated microthrombosis, endothelial dysfunction, oropharyngeal inflammation and mucosal lung damage. Moreover, PAR-1 inhibition ability of ABS might be helpful for reducing the initial virus propagation and mocasal spread of COVID-19.