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Orientador: Cezinande de Meira / Resumo: Diferentes tratamentos hormonais com a utilização de estrógenos e progestágenos são comumente utilizados para aumentar a oferta de receptoras nos programas de TE. Porém, pouco se sabe sobre a ação destes hormônios na expressão gênica e proteica dos receptores endometriais de estrógeno e progesterona em éguas acíclicas. O presente estudo teve como objetivo avaliar os efeitos de três tratamentos hormonais utilizados durante a preparação de éguas acíclicas sobre o edema, tônus uterino e expressão gênica e proteica de receptores de estrógeno e progesterona endometriais. Éguas em anestro foram divididas em três grupos: Dose Total 10 mg BE+P4, (n=7), Dose Total 5 mg BE+P4 (n=7), Priming Hormonal (n=7) e comparadas com o grupo de éguas cíclicas (n=7). Foram avaliados: a expressão proteica e gênica relativa dos transcritos para os receptores de estrógeno e progesterona presentes no endométrio por meio das técnicas de imunohistoquímica e RT-qPCR; e as características morfológicas do útero por palpação retal e ultrassonografia em modo B. Os tratamentos hormonais utilizados no presente estudo foram eficazes em promover edema e tônus uterinos semelhante ao que ocorre em éguas cíclicas. Adicionalmente, o grupo Priming Hormonal demonstrou induzir características uterinas similares as observadas nos grupos 5 mg BE+P4 e no grupo controle, após 14 dias de intervalo. O tratamento hormonal com dose total de 10 mg de BE+P4 LA utilizando para o preparo de éguas acíclicas, demonstrou ser similar ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Different hormonal treatments with the use of estrogen and progestogen are commonly used to increase the supply of receiving the TE programs. However, little is known about the effect of these hormones on gene and protein expression of endometrial receptors for estrogen and progesterone in non-cyclic mares. This study aimed to evaluate the effects of three hormonal treatments used for the preparation of non-cyclic mares on the edema and uterine tone and gene and protein expression of estrogen and endometrial progesterone receptors. Mares anestrus were divided into three groups: total dose 10 mg EB + P4 (n = 7) total dose 5 mg EB + P4 (n = 7) Hormonal Priming (n = 7) and compared with the group of cyclic mares (n = 7). Were evaluated: protein expression and gene transcripts related to the estrogen and progesterone receptors present in the endometrium by the techniques of immunohistochemistry and RT-qPCR; and the morphological characteristics of the uterus by rectal palpation and ultrasound in B mode. Hormonal treatments used in this study were effective in promoting edema and uterine tone similar to what occurs in cyclic mares. Additionally, the Hormonal Priming group demonstrated induce uterine similar characteristics observed in the groups 5 mg EB + P4 and control group, after 14 days apart. Hormonal treatment with a total dose of 10 mg EB + P4 LA using for the preparation of non-cyclic mares, was shown to be similar in tone and uterine edema, protein expression and relative... (Complete abstract click electronic access below) / Mestre

<p dir="ltr">The vaginal microbiome and female sex hormones are both involved in the development and progression of gynecological pathologies. The individual mechanisms by which the vaginal microbiome leads to disease progression and how female sex hormones are known. However, the mechanisms by which the vaginal microbiome regulates female sex hormones, such as progesterone, are not well understood. This study seeks to understand how the vaginal microbiome regulates progesterone receptor (PGR) expression via secondary analysis of host and vaginal microbiome multi-omics data from the Partners PrEP cohort. This dataset consists of cervicovaginal samples of women enrolled in the Partners PrEP study. Partial Least Squares Regression (PLSR) models were created for each biological data type (microbial composition, metabolomics, metaproteomics) to assess how these factors regulate PGR expression. Significant factors were identified through variable importance of projection (VIP) and correlation analysis. Partial correlation analysis and follow-up PLSR models incorporating clinical and demographic variables were performed to assess the robustness of the vaginal microbiome-PGR associations. The PLSR models indicated lower PGR expression was associated with <i>G. vaginalis,</i> and higher PGR expression was associated with <i>Lactobacillus </i>species. Cytosine, guanine, and tyrosine were among metabolites significantly associated with higher PGR expression and experimentally determined to be produced by <i>Lactobacillus</i> species. Conversely, citrulline and succinate were associated with lower PGR expression and experimentally determined to be produced by <i>G. vaginalis</i>. The models indicated that bacterial metabolic pathways involved in glucose metabolism, such as glucagon signaling and starch and sugar metabolism, may regulate PGR expression. Demographic phenotypes were also considered from the dataset and did not significantly alter the association between the biological explanatory variables and PGR expression. The results indicate that guanine, cytosine, succinate, starch and sucrose metabolism, and glycolysis gluconeogenesis may be regulators of PGR abundance and function. The models suggest vaginal microbiome factors could play a role in gynecological conditions where progesterone signaling is suppressed. Future experimental work is needed to validate the results of these models and support their use as predictive tools to understand the role of the vaginal microbiome.</p>

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Age-related declines of androgens and libido in males have been observed for decades. This dissertation sought to elucidate the mechanisms by which hormones may act differentially upon their receptors in the hypothalamus of aging compared to young males. I also examined how sexual experience modulates the ability of hormones to facilitate sexual behavior with aging. Experiment one measured androgen receptors (AR) and estrogen receptor α (ERα) cells in male rats at young, middle-aged and old age. I found that AR cell numbers in hypothalamic regions studied underwent significant age-related increases. Numbers of heavily ERα labeled cells, but not total ERα cells, increased with age. This study demonstrates that the aging brain has the capacity to synthesize hormone receptors which is increased possibly due to decreased testosterone concentrations. Experiment two examined the effect of sexual experience on serum hormones and cells of AR and ERα in hypothalamic regions in young and middle-aged males. The results showed that AR cell numbers increased with aging but did not change with experience. No age- or experience-related alteration in ERα expression occurred. However, serum testosterone increased and estradiol decreased with age. Experience increased total and free testosterone. Interactions of age and experience on total testosterone, estradiol, and luteinizing hormone were found. These results show long-lasting effects of sexual experience on hormones, but not on their receptors in the hypothalamus. Experiment three investigated effects of exogenous testosterone on sexual behavior in young and middle-aged males. The results showed a decline in sexual behavior parameters with age. After castration with testosterone treatment, there were few differences in sexual behavior measures between young and middle-aged males. AR cell numbers were higher and ERα cell numbers lower in testosterone compared to vehicle-treated males of both ages, and few effects of age occurred. These findings indicate that testosterone and aging interact in a complex manner to control numbers of cells expressing hormone receptors in the brain and on the subsequent control of sexual behavior. This insight provides a better understanding of the relationship between molecular changes in the brain and behavior, and suggests new therapeutic targets to human testosterone treatment. / text

Wie sich in den letzten Jahren gezeigt hat, ist Fettgewebe nicht nur ein inerter Fettspeicher, sondern produziert auch eine Vielzahl endokrin wirksamer Substanzen, die unter anderem auch an der Blutdruckregulation beteiligt sind. Da Adipositas ein wichtiger Risikofaktor für die Entwicklung der Hypertonie ist, sollte im Rahmen dieser Dissertation ein System zur quantitativen Untersuchung der Genexpression in Primärkulturen humaner Adipocyten entwickelt werden und dessen Funktionalität am Beispiel der hormonellen Regulation der Gene des Renin-Angiotensin-Systems demonstriert werden. Dies beinhaltete die Etablierung der Adipocytenisolierung und -kultivierung, eines Stimulationsassays, die Entwicklung einer der besonderen Größe und dem hohen Fettgehalt der Zellen angepaßten Zellzahl- und Vitalitätsbestimmungsmethode, die Untersuchung vier verschiedener RNA-Extraktionsmethoden auf ihre Eignung für Adipocyten und die Etablierung eines besonders sensitiven RT-PCR Systems zur Untersuchung der Genexpression mittels einer fluoreszenzmarkierten Sonde. Exemplarisch konnte anhand der Renin-Angiotensin-System-Gene die Funktionalität der Methoden demonstriert werden, indem nicht nur die Genexpression aller Komponenten des Renin-Angiotensin-Systems in humanen Adipocyten nachgewiesen wurden, sondern auch gezeigt werden konnte, dass Hydrocortison sowohl die Genexpression als auch die Dichte des Angiotensin II Typ 1-Rezeptors in der Adipocytenmembran stimuliert. Dieser Aspekt könnte möglicherweise nicht nur bei der besonderen Adipositasform des Cushing-Syndroms, sondern auch für die Entstehung der zentralen Adipositas von Bedeutung sein. / Adipose tissue has functions above-and-beyond storing fat. It also produces a variety of different endocrine substances, some of which influence blood pressure regulation. Obesity is a well known risk factor for the development of hypertension Thus, the genes regulating expression of vasoactive molecules in adipose tissue, possibly contributing to an increase in blood pressure are of great interest. The aim of this work was to develope a system for quantitative gene expression analysis in primary cultured human adipocytes and to demonstrate its utility for studying the hormonal regulation of genes encoding the renin-angiotensin-system. We established procedures for the isolation and culture of human adipocytes, as well as a stimulatory assay. We also developed methods for the determination of cell number and vitality. Above this, four RNA extraction protocols were evaluated regarding their suitability for adipocytes, and a very sensitive RT-PCR system for gene expression analysis using fluorescent labeled probes was established. As an example for the functionality of these methods we showed that all genes of the renin-angiotensin-system are expressed in human adipocytes. We also demonstrated that hydrocortisone stimulates the gene expression as well as the density of the angiotensin II receptor type 1 on cultured human adipocytes. This finding may be of interest for the development of the obesity phenotype found in cushing syndrome, but could also contribute to the development of central obesity.

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In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment.