Hormonal regulation of the gerbil female propstate: morphology, cytochemistry and immunocytochemistry

Orientador: Sebastião Roberto TabogaTese (doutorado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: A próstata feminina é uma glândula funcionalmente ativa encontrada em diversas espécies de mamíferos, incluindo humanos e roedores. Em fêmeas adultas de gerbilos, a próstata apresenta localização parauretral, exibindo íntimo contato com a parede da uretra mediana e distal. Esta glândula é homóloga a próstata ventral de roedores machos, sendo formada por um conjunto de glândulas e ductos inseridos em um estroma fibromuscular. Em machos, a fisiologia prostática é regulada por hormônios esteróides, principalmente andrógenos e estrógenos. Em fêmeas, os fatores que influenciam a atividade prostática são pouco conhecidos, embora existam indícios de que alterações hormonais decorrentes da senescência estejam associadas à instalação de lesões prostáticas. Assim, o objetivo deste trabalho foi avaliar os fatores que promovem a regulação hormonal da próstata feminina do gerbilo (Meriones unguiculatus) em condições de hiperandrogenismo e de supressão da atividade estrogênica. Os resultados obtidos com as análises estruturais, ultra-estruturais, sorológicas e imunocitoquímicas permitiram concluir que a próstata feminina do gerbilo é sensível à ação de andrógenos e de agentes anti-estrogênicos. O estímulo androgênico provocou crescimento anormal da próstata, aumento da atividade secretória, além de causar displasia prostática e síndrome de ovário policístico. O tratamento com letrozol resultou em aumento dos níveis séricos de testosterona, hiperplasia glandular, incremento da atividade secretória e crescimento displásico, simulando os efeitos causados por andrógenos exógenos. Os efeitos causados pelo tamoxifeno indicam que este agente endócrino atuou como agonista estrogênico na próstata, causando hipertrofia glandular, diminuição da atividade secretória e desenvolvimento de lesões prostáticas, tais como prostatites e adenocarcinoma. Deste modo, pode-se concluir que a utilização de drogas hormonalmente ativas resulta em uma série de efeitos complexos que comprometem a fisiologia de órgãos hormônio-dependentes, como a próstata feminina e os ovários. O desequilíbrio hormonal provocado pela administração destas drogas causa profundas alterações na morfologia prostática, de maneira muito similar ao que ocorre durante o desenvolvimento de lesões espontâneas em mulheres no período pós-menopausa. Assim, essas terapias devem ser utilizadas com cautela, visto que longos períodos de tratamento podem resultar em lesões malignas da próstata femininaAbstract: The female prostate is a functionally active gland found in several species of mammals, including humans and rodents. In adult female gerbils, the prostate presents a paraurethral location, showing close contact with the wall of urethra in its median and distal portions. This gland is homologue to the ventral prostate of male rodents and it is formed by a cluster of glands and ducts inserted into a fibermuscular stroma. In males, the prostatic physiology is regulated by steroid hormones, mainly androgen and estrogen. In females, the factors that influence the prostatic activity are unclear, although there are evidences that the hormonal alterations caused by aging are associated with the installation of prostatic lesions. Thus, the objective of this work is to evaluate the factors that promote the hormonal regulation of the gerbil (Meriones unguiculatus) female prostate in hyperandrogenic conditions and estrogenic activity suppression. The results obtained with the structural, ultrastructural, serologic and immunocytochemical analyses showed that the gerbil female prostate is responsive to androgenic and the anti-estrogenic action. The androgenic stimulus has caused an abnormal prostatic growth, increase in secretory activity, and has also caused prostatic dysplasia and polycystic ovary syndrome. The letrozole treatment has stimulated an increase in testosterone serum levels, glandular hyperplasia, increment of the secretory activity and dysplasic growth, simulating the effects provoked by exogenous androgens. The effects caused by tamoxifen indicate that this endocrine agent has acted as an estrogenic agonist on the prostate, causing glandular hypertrophy, decrease in secretory activity and prostatic lesions. Hence, it is possible to conclude that the use of hormonally active drugs results in a series of complex effects that endanger the physiology of hormone-dependent organs, like female prostate and ovaries. The hormonal unbalance caused by the administration of such drugs results in alterations in prostatic morphology similar to what occurs during the development of spontaneous lesions in post-menopausal women. Thus, the utilization of such therapies must occur in a careful manner because a long-term treatment can cause malignant lesions in female prostateDoutoradoBiologia CelularDoutor em Biologia Celular e Estrutura

Caracterização morfo-funcional da prostata de femeas do gerbilo Meriones unguiculatus e avaliação dos efeitos da testosterona sobre os componentes teciduais do orgão

Orientador : Sebastião Roberto TabogaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de BiologiaResumo: A próstata não é um órgão exclusivo do organismo masculino, pois está presente em fêmeas adultas de várias espécies de roedores e também na espécie humana. A próstata feminina tem sido considerada homóloga à próstata ventral masculina, sendo composta por um pequeno conjunto de glândulas e ductos entremeados a uma matriz músculo-fibrosa. Atualmente, sabe-se que é de fundamental importância que se compreendam melhor os processos fisiológicos que mantém esta glândula funcionalmente ativa no organismo feminino, uma vez que ela está sujeita as mesmas patologias que comprometem a próstata masculina durante o climatério. Desta forma, o objetivo do presente estudo foi caracterizar histológica, cito química e ultra:..estruturalmente os componentes teciduais da próstata feminina do gerbilo Menones unguiculatus adulto normal e experimentalmente tratado com testosterona, por um intervalo de 21 dias. Para isso, as próstatas coletadas foram fixadas e incluídas para microscopia de luz e eletrônica de transmissão. Testes citoquímicos foram desenvolvidos para evidenciar fibras colágenas (f ricrômico de Masson, Picrossírius-Hematoxilina), reticulares (Reticulina de Gõmõri) e elásticas (Resorcina-Fucsina de Weigert); secreções glicoprotéicas (periodic Acid & Schiff); e fenótipos nucleares prostáticos (Reação de Feulgen). Também foram desenvolvidas colorações usuais para a análise morfológica geral da glândula. A análise morfométrico-estereológica das próstatas femininas normais e tratadas foi realizada para avaliar estatisticamente as alterações sofridas pela glândula após a administração hormonal. Os resultados indicam que a próstata feminina normal do gerbilo é morfologicamente semelhante à próstata feminina humana, apresentando os mesmos tipos celulares e o mesmo padrão estrutural característico, o que lhe permite ser um bom modelo experimental para os estudos da próstata. Além disso, as próstatas tratadas com testosterona apresentaram um grande desenvolvimento nas primeiras fases de administração hormonaJ, chegando até a quadruplicar seu número inicial de ácinos e duetos. As células epiteliais apresentaram-se mais altas e volumosas, tomando-se mais ativas nos processos secretórios. O estroma tomou-se mais denso, apesar de não ter apresentado alterações significativas em sua freqüência relativa. No entanto, ao final do tratamento observou-se um sucessivo dec1ínio no desenvolvimento prostático. As próstatas tratadas com testosterona por 21 dias apresentaram um número de ácinos e duetos próximo ao apresentado pela próstata normal e um epitélio secretor menos desenvolvido. Esses resultados sugerem que a testosterona exerceu um efeito positivo inicial sobre a próstata feminina do gerbilo, tomado-se menos eficaz nas fases finais do tratamento. Deste modo, acredita-se que a exposição contínua à testosterona possa ter provocado a ativação de fatores endógenos de reguiação, capazes de inibir parte do estímulo androgênico sobre a próstata feminina nas fases finais da administração hormonalAbstract: The prostate is not an exclusive male organism, because it is also present in adults females of several rodents species and even in women. The female prostate has been considered homologous to the male ventral prostate, it is composed by sma1l clusters of glands and ducts intermixed to a musculofibrous matrix. It is known nowadays the fundamental importance of the better understanding of the physiological process that maintaÍfi this gland functiona1ly active in the female organism, once that it suffers the same diseases that compromises the male prostate during the climacteric. By this way, the goal of this study was to characterize histologica1ly, cytochemica1ly and ultrasttucturally the tissues components of normal and experimentally treated with testosterone female prostate of gerbil Meriones unguiculatus, during 21 days. In order to do this work, the collected prostates were fixed and embedded for light microscopy and transmission electron microscopy. Cytochemical tests were employed to evidence collagen fibers (Masson's Trichrome, Picrosirius Hematoxylin), reticular fibers (Gõmõri' s Reticulin) and elastic system (Weigert's Resorcin Fuchsin); glycoprotein secretory products (periodic Acid & Schiff); prostatic nuclear and mitotic phenotypes (Feulgen's Reaction). It has also been done usual staining to general morphological analysis of the prostate. The morphometric stereological analysis of the normal and treated female prostate was realized to value statistica1ly the alteration suffered by the glands after hormonal administration. The results show that the normal female prostate of the gerbil is morphologica1ly similar to the male prostate, they have the same cell types and the same characteristics sttuctural pattem, what a1lows it is a good experimental model to studies of the prostate. In addition, the treated prostates with testosterone show a great development during the first phases of the hormonal administration, increasing foU! times the initial number of acini and ducts. The epithelial cells show themselves high and voluminous, becoming more actives in the secretion processes. The stroma has become thicker in spite of it has not been demonstrated significative modification in its relative frequency. Meanwhile, at the end of the treatment it has been observed a successive decrease in the prostatic deve1opment. The prostates treated with testosterone during 21 days have shown a similar number of acini and ducts to normal prostate and secretory epithelium less deve1oped. These results suggest that testosterone has produced a initial positive effect in the gerbil female prostate, becoming less efficient in the last phases of the treatment. By this way, it is supposed that the continued exposition to testosterone could have provoked the activation of endogens factors, that are able to inhibit part of androgenic stimuli upon the female prostates at the last phases of the hormonal administrationMestradoBiologia CelularMestre em Biologia Celula

Effects of exposure to estradiol and estradiol plus testosterone on the mongolian gerbil (Meriones unguiculatus) female prostate

The female prostate is a differentiated organ found in several mammal species, including humans and rodents. This gland has been related to important functions on female reproductive biology. Although the factors, which regulate prostate's development and activity are not well known, its functionality has been related to steroid hormones. It is well established that cyclic changes of estradiol and progesterone levels promote histophysiological adaptations of the whole female body. In contrast, only a few is found about those adaptations in female prostate. Thus, this study aimed to evaluate the effect of estradiol and estradiol+testosterone association on gerbil female prostate in order to verify, which hormonal associations are necessary to its homeostasis. For this, adult females had the ovaries surgically removed. After recovering, they received estradiol and estradiol+testosterone doses through 30 days, each 48 h. The prostatic tissue underwent morphological and morphometric-estereological analysis. Hormonal restriction caused great gland involution and decreased secretory activity, aspects that were reverted by exposure to estradiol and estradiol+testosterone. However, these hormones were not able to re-establish the normal prostate histoarchitecture. The immunoreaction of steroid receptors (ER-α, ER-β, and AR) responded differently among the experimental and control groups, and PCNA assay showed a decrease in epithelial cell proliferation within groups that had hormone privation. Therefore, we conclude that estradiol and testosterone are able to influence prostate morphophysiology and the maintenance of gland homeostasis depends on a balance among these and other hormones. © 2013 Wiley Periodicals, Inc

Prenatal exposure to testosterone masculinises the female gerbil and promotes the development of lesions in the prostate (Skene

Androgenic imbalance may disrupt prostate development, leading to morphological alterations in adulthood and predisposing this gland to develop diseases during ageing. However, little is known about the endocrine disruption of the prostate that is caused by androgenic compounds, especially in female experimental models. Therefore, this study aimed to evaluate the prostates of aged female gerbils exposed to testosterone at certain periods in intrauterine and postnatal life, to determine whether exposure at a particular age increases susceptibility to prostatic lesions in these animals. To this end, morphological, stereological, immunohistochemical and immunofluorescence analyses were employed. It was found that females exposed to testosterone during intrauterine life were masculinised, showing increased anogenital distance, absence of the vaginal opening and ectopic development of prostatic tissue. Several areas of adenomatous hyperplasia, generally associated with inflammatory foci and mainly located in the ectopic prostatic tissue around the vaginal wall, were also observed. In conclusion, the results showed that abnormal prenatal exposure to testosterone severely affects the reproductive systems of female animals by disrupting normal prostate morphogenesis and increasing susceptibility to the development of prostatic diseases during ageing.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Priority Activities in Child and Adolescent Tuberculosis to Close the Policy-Practice Gap in Low- and Middle-Income Countries

Over the past 15 years, and despite many difficulties, significant progress has been made to advance child and adolescent tuberculosis (TB) care. Despite increasing availability of safe and effective treatment and prevention options, TB remains a global health priority as a major cause of child and adolescent morbidity and mortality—over one and a half million children and adolescents develop TB each year. A history of the global public health perspective on child and adolescent TB is followed by 12 narratives detailing challenges and progress in 19 TB endemic low and middle-income countries. Overarching challenges include: under-detection and under-reporting of child and adolescent TB; poor implementation and reporting of contact investigation and TB preventive treatment services; the need for health systems strengthening to deliver effective, decentralized services; and lack of integration between TB programs and child health services. The COVID-19 pandemic has had a significant negative impact on case detection and treatment outcomes. Child and adolescent TB working groups can address country-specific challenges to close the policy–practice gaps by developing and supporting decentral ized models of care, strengthening clinical and laboratory diagnosis, including of multidrug-resistant TB, providing recommended options for treatment of disease and infection, and forging strong collaborations across relevant health sectors