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Van, Oeveren Margaret Ann. "Interpersonal functional flexibility : an antecedent of authoritative parenting?" Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/28305.
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It has been asserted that androgynous individuals are both competent and flexible and that, as such, they should be most likely to be authoritative parents (highly demanding/highly responsive) (Spence & Helmreich, 1978). However, studies examining the association between psychological androgyny and this optimal parenting strategy (Baumrind, 1982; Spence & Helmreich, 1978) have reached conflicting conclusions. The position taken in this study is that there is a logical association between androgyny and authoritative parenting at the construct level, but that the component of androgyny critical to this link is functional flexibility (the ability to appropriately deploy both masculine and feminine attributes across multi-interpersonal domains) rather than the simple possession of both masculine and feminine traits per se. In view of this argument, earlier studies share a significant limitation. Their operational definitions of androgyny fail to reflect the functional flexibility aspect of the construct definition, thus allowing individuals who possess both masculine and feminine traits but who are not functionally flexible to be classified as androgynous. This study had two objectives. The first was to retest Spence and Helmreich's (1978) hypothesis that androgyny is positively related to authoritative parenting using a measure which would assess functional flexibility. The second objective was to demonstrate that authoritative parenting requires flexibility with respect to a whole range of interpersonal abilities rather than simply masculine and feminine attributes. A sample of 96 mothers with children between the ages of 7 and 12 were asked to complete a battery of questionnaires which included Bern's (1974) Sex Role Inventory (BSRI), Paulhus and Martin's (1987) Battery of Interpersonal Capabilities (BIC), and the Block (1965) Childrearing Practices Report: Q-Sort (CRPR). Contrary to what was expected, neither androgyny nor flexibility with respect to the whole range of interpersonal attributes was positively associated with authoritative parenting. Certain problems with the content of the parenting measure may have contributed to the lack of association. To minimize some of the problems with its content the method of using the parenting Q-sort was revised. The new analyses involved categorizing mothers according to warmth and demandingness--a method similar to that used in earlier studies. In these further analyses few significant differences in parenting style were found between androgynous mothers and other mothers. The most notable difference arose when the sex of the child was considered. Although, overall, androgynous mothers were not more likely to be bad parents, they were more likely than other mothers to be permissive with their sons.Arts, Faculty of
Social Work, School of
Graduate
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Sharp, Danae Maree. "Androgens induce gender- & dose- specific effects on atherogenesis." Connect to full text, 2008. http://hdl.handle.net/2123/4158.
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Thesis (M. Sc. Med.)--University of Sydney, 2009.Submitted in fulfilment of the requirements for the degree of Master of Science in Medicine to the Discipline of Medicine, Faculty of Medicine. Degree awarded 2009; thesis submitted 2008. Title from title screen (viewed Apr. 14, 2008) Includes bibliography. Also available in print form.
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Suri, Narinder K. "Androgens and the endometrium." Thesis, University of Nottingham, 1988. http://eprints.nottingham.ac.uk/13915/.
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The role of C19 steroids in the human endometrium is at present unclear. In order to gain an insight into their action, radioimmunoassay procedures were developed which had sufficient specificity and accuracy to measure testosterone, 5α-DHT, oestradiol, progesterone and androstenedione in endometrial samples. Amounts of androstenedione were greater (range 1.2-20.8 ng/mg tissue) than other steroids. Samples were obtained from patients presenting with a variety of conditions: subfertility, postmenopausal bleeding, dysfunctional uterine bleeding and abdominal pain. Patients admitted for sterilisation were used as normal controls. A significant positive correlation (r = 0.80) was found between the levels of testosterone and 5α-DHT measured in the same tissue which suggests the presence of a 5α reductase enzyme. No relationship was observed in tissue steroid concentration and age of the patients. Steroid concentrations were found to be high in tissues obtained from patients with endometrial carcinomas whereas progesterone concentration being low in subfertiles. The oestrogen, progesterone and androgen receptor levels of endometrial tissues from subfertile women were also determined using the DCC technique and not the procedure based on protamine sulphate precipitation since endometrial tissue available was very small. No correlation was found between receptor binding sites and day of cycle for any of the three steroids analysed; nor was there any correlation between age and receptor binding sites. A cyclic variation followed by normal women was seen in the oestrogen and progesterone receptor concentrations in the menstrual cycle. Such a variation was also observed in subfertile women on clomiphene citrate therapy. It is concluded that normal endometrium contains measurable quantities of androgens and that a receptor for 5α-DHT is present. The difference in steroid concentrations between normal and pathological states suggest that C19 steroids may be induced in the development of abnormalities.
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Tyndall, Victoria. "Androgens and the ovary." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/5591.
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Between 10-15% of women suffer from polycystic ovary syndrome (PCOS), making it the most common cause of female infertility. Clinical features of PCOS include high circulating levels of ovarian androgens (T and A4), anovulation and obesity. The aetiology of this reproductive endocrinopathy is likely to be multifactorial, through the interplay of genetics, epigenetics and environmental factors. Primate research into sexual behaviour development noted that fetally androgenised monkeys developed symptoms like those of PCOS. There are now multiple animal models of PCOS using primates, sheep, rats and transgenic mice. The investigations described in this thesis use rodent models to examine the role of androgens in the pathogenesis of female infertility. An attempt to generate a granulosa cell specific androgen receptor knockout mouse model will first be described, followed by several studies into the developmental programming of female Wistar rat infertility and metabolism by steroid hormones. Initial investigations showed that testosterone proprionate (TP) administered to female rats during different windows of fetal and neonatal life alters the reproductive and metabolic axes of the adult animals. Fetal plus neonatal TP exposure led to complete ovarian dysgenesis, while postnatal exposure produced a PCOS-like phenotype. Animals which received TP postnatally were heavier and had an increased proportion of primordial follicles in their ovaries by postnatal day (pnd) 90 of life. Evaluation of this PCOS model showed that neonatally androgenised rats had ovarian follicles with larger antra and a greater ovarian stromal compartment. In addition, these animals were heavier when compared to controls. However, unlike human studies, neonatally androgenised rats showed no differences in circulating gonadotrophin or ovarian androgen levels. Nor did they show any programming effect of neonatal TP upon the theca interna by pnd 90. Further investigations to narrow the windows and dose of TP required to produce a PCOS phenotype showed that TP administered in an early window of neonatal life, between postnatal days (pnd) 1-6 not only led to anovulation, but potentially reprogrammed the hypothalamic-pituitary axis, as there was minimal gonadotrophin response to reduced ovarian negative feedback (inhibin B and estradiol) in these rats. Neonatal TP also affected the rat metabolic axis with adult animals becoming heavier after weaning without any change in food intake. Animals developed mesenteric and retroperitoneal obesity along with insulin resistance (IR). Increased hepatic glucocorticoid turnover and altered adipokine expression were also noted in neonatally androgenised females, possibly contributing to the pathogenesis of obesity. No effect of TP dose upon the severity of infertility or metabolic abnormalities in adult animals was observed. To delineate which features of the rat PCOS model resulted from androgenic, estrogenic or corticosteroid action, a final study used administration of different steroids during the early window of postnatal life: TP, estradiol valerate (EV), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and dexamethasone (DEX). The anovulatory PCO-like phenotype observed with TP was also seen in animals which received EV, but not those which received DHT, DHEA or DEX. TP and EV treatment also resulted in a reduction of ovarian follicle numbers and activated follicle proportions, with an increase in primordial follicle proportions. Although glucose tolerant, animals treated with TP and EV were highly IR. Unlike dexamethasone, DHT and DHEA also produced IR in adult animals, to a lesser extent than TP and EV. Taken collectively, the results described in this thesis demonstrate that the PCOS-like phenotype observed in the neonatally androgenised female rat is likely to be due to the estrogenic actions of testosterone, potentially through as yet unknown epigenetic mechanisms. The programming of the metabolic components described may additionally be due to the actions of androgens. Furthermore, these studies demonstrate a novel estrogenic effect of neonatal steroids upon primordial follicle populations and show that the neonatally androgenised rat may be a rational PCOS model in a poly-ovulatory species.
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Cloke, Brianna. "The role of Androgens and the Androgen receptor in human endometrial stromal cell decidualization." Thesis, Imperial College London, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.510758.
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Zahaf, Amina. "Rôle inattendu de la signalisation des androgènes dans le système nerveux central démyélinisé de la souris femelle : Identification de spécificités liées au sexe de l'animal." Thesis, université Paris-Saclay, 2022. http://www.theses.fr/2022UPASL046.
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La sclérose en plaques (SEP) est la plus commune des maladies démyélinisantes du système nerveux central (SNC). Elle se caractérise par une succession d'épisodes inflammatoires en partie liés à une dérégulation du système immunitaire et ciblant les cellules synthétisant la myéline, les oligodendrocytes. Ces épisodes sont d'abord suivis de phases de rémission correspondant à la régénération spontanée de la myéline détruite, encore appelée remyélinisation. Cependant, au fur et à mesure de la progression de la pathologie, la remyélinisation échoue notamment en raison d'une modification de l'environnement lésionnel qui devient inadapté au processus de réparation. Cette pathologie chronique et neurodégénérative est à l'heure actuelle considérée comme la première cause de handicaps lourds d'origine non traumatique chez l'adulte jeune. Elle concerne 3 femmes pour 1 homme. Au cours des dernières décennies, de nombreuses molécules visant le système immunitaire ont été identifiées afin de réduire la fréquence des attaques et leur sévérité. Ces molécules sont donc efficaces dans les formes récurrentes-rémittentes, mais deviennent inefficaces quand la maladie progresse. Le défi thérapeutique actuel est par conséquent l'identification de molécules qui permettraient également de favoriser la régénération de la myéline. Le rôle des hormones sexuelles mâles ou androgènes dans les modèles animaux de démyélinisation du SNC a fait l'objet de nombreuses études montrant leurs propriétés immunomodulatrices, neuroprotectrices et remyélinisantes chez le mâle. Puisque les souris femelles et les femmes produisent aussi des androgènes - bien qu'à un niveau beaucoup plus faible que les animaux mâles ou les hommes - l'objectif de mon projet de thèse était de déterminer la contribution des androgènes aux processus de protection et de régénération impliqués dans un contexte de démyélinisation chez les animaux femelles. Dans des modèles immuns (EAE) et non-immuns (LPC) de démyélinisation du SNC, les effets des androgènes ont été analysés par des immunomarquages et la visualisation de l'ultrastructure des axones et de la myéline, par des approches de tri des cellules immunitaires périphériques présentes dans les organes lymphoïdes et infiltrées dans le SNC. Les données indiquent des activités remyélinisantes, anti-inflammatoires et neuroprotectrices majeures des androgènes chez la femelle comme précédemment observé chez le mâle avec néanmoins plusieurs spécificités. Par ailleurs, une analyse transcriptomique de la moelle épinière des animaux EAE nous a conduit à identifier des gènes dont l'expression est dérégulée de façon cohérente avec les données histologiques et fonctionnelles. Ce projet suggère que le maintien d'un taux physiologique d'androgènes doit être pris en considération chez les patientes atteintes de SEPMultiple sclerosis (MS) is the most common demyelinating disease of the central nervous system (CNS). The pathology is characterized by successive inflammatory insults, which are related to the dysregulation of the immune system and target the cells synthesizing myelin in the CNS, the oligodendrocytes. These insults are followed by steps of remission corresponding to the spontaneous regeneration of myelin, also called remyelination. However, when the disease progress, remyelination fails namely due to a lesion environment becoming inappropriate. The pathology characterized as chronic and neurodegenerative concerns 3 women for 1 men and is currently considered as the first cause of non traumatic disabilities in the young adults. During the last decades, a substantial number of molecules targeting the immune system has been identified in order to reduce the frequency and severity of the insults. These molecules are efficient on the relapsing-remitting form of the disease, but they become inefficient with disease progression. The current therapeutic challenge is the identification of molecules also able to boost the regeneration of myelin. The role of the male sexual hormones or androgens in models of CNS demyelination has been thoroughly investigated in males, which led to show their immunomodulatory, pro-myelinating and neuroprotective properties. Since females also produce androgens - though at a much lower level than males - the objective of my PhD project was to delineate the contribution of androgens to the protective and regenerative processes involved in the context of CNS demyelination in female mice. In immune (EAE) and non-immune (LPC) models of CNS demyelination, the effects of androgens have been analyzed via immunostaining experiments, visualization of myelin and axon ultrastructure, fluorescence-activated sorting of peripheral immune cells present in the lymphoid organs or infiltrated in the CNS. The data indicate major remyelinating, anti-inflammatory and neuroprotective activities of androgens in females as previously observed in males with however some specificities. Moreover, transcriptomic analysis of the spinal cord from EAE animals led us to identify profiles of deregulated genes tightly correlated with the histological and functional data. Altogether these results suggest that the administration of appropriate doses of androgens would deserve to be further considered in female patients presenting with multiple sclerosis
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Shiwlochan, Amrita G. "Prenatal androgens and visceral fat." Honors in the Major Thesis, University of Central Florida, 2009. http://digital.library.ucf.edu/cdm/ref/collection/ETH/id/1327.
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This item is only available in print in the UCF Libraries. If this is your Honors Thesis, you can help us make it available online for use by researchers around the world by following the instructions on the distribution consent form at http://library.ucf.edu/Systems/DigitalInitiatives/DigitalCollections/InternetDistributionConsentAgreementForm.pdf You may also contact the project coordinator, Kerri Bottorff, at kerri.bottorff@ucf.edu for more information.Bachelors
Sciences
Anthropology
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Pettiford, Jasmine. "Effect of garlic-deriveds-allylmercaptocysteine on androgen receptor expression in androgen-independent prostate cancer." Thesis, Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41005545.
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Santana, Luís Carlos Leal. "Impacto de andrógenos sobre a proliferação e atividade de fibroblastos e células epiteliais em cultura celular /." Araraquara, 2016. http://hdl.handle.net/11449/138766.
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Orientador: Luis Carlos SpolidórioResumo: Hormônios esteroides sexuais participam de diversos eventos celulares e moleculares, e exercem influência sobre o epitélio e tecido conjuntivo do periodonto. A testosterona (T), principal hormônio androgênico, pode ser convertida em estradiol (E2) pela ação da enzima aromatase, ou em di-hidrotestosterona (DHT) pela ação da enzima 5α-redutase. Para elucidar o impacto de andrógenos sobre as células que compõem os tecidos conjuntivo e epitelial, fibroblastos e queratinócitos foram avaliados em relação aos efeitos de diferentes concentrações de T e DHT, além da exposição ao anastrozol (ANA), flutamida (FLU), fulvestranto (FUL), e às associações farmacológicas T+ANA, T+FLU e T+FUL. Os resultados do presente estudo indicaram que, de modo geral, hormônios esteroides androgênicos exercem efeitos opostos sobre eventos celulares de fibroblastos gengivais humano e células epiteliais HaCaT em cultura celular. Enquanto a T e a DHT agem promovendo o aumento da proliferação e atividade de fibroblastos, a exposição de células HaCaT a estes mesmos andrógenos resulta em inibição ou exiguidade do crescimento celular, atividade metabólica ou a capacidade de repovoamento da área de arranhão in vitro. Além disso, o tratamento farmacológico com ANA, FLU, FUL, e suas respectivas associações à T, parece influenciar eventos celulares de fibroblastos gengivais humano e células epiteliais HaCaT in vitro.
Abstract: Sex steroid hormones take part in different cellular and molecular process and exert their functions on the epithelium and connective tissue of the periodontium. Testosterone (T), the main androgenic hormone can be converted to estradiol (E2) through the aromatase enzyme action, or into dihydrotestosterone (DHT) by 5α-reductase activity. To elucidate the impact of androgens on the cells that constitute the connective and epithelial tissues, fibroblasts and keratinocytes were evaluated under the effects of different concentrations of T and DHT, besides to be both exposed to anastrozole (ANA), flutamide (FLU), fulvestrant (FUL), and the pharmacological associations T+ANA, T+FLU and T+FUL. The results of this study indicated that, in general, androgenic steroid hormones exert opposite effects on cellular events of human gingival fibroblasts and epithelial cells. While androgens act stimulating gingival fibroblasts, in HaCaT cells androgens promotes a shortage or inhibition of cell growth and activity. Furthermore, pharmacological treatment with ANA, FLU, FUL, and their associations to T, appears to influence cellular events of human gingival fibroblasts and HaCaT cells in vitro.
Mestre
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Xu, Huiping. "Electrophilic androgen receptor ligands as chemotherapeutic agents for prostate cancer." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1089126757.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xxviii, 261 p. Includes bibliographical references (p. 141-149). Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 July 6.
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Dockery, Frances. "Androgens and cardiovascular disease in men." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435055.
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Dean, Afshan. "Androgens and the masculinisation programming window." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6516.
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The commonest reproductive disorders of young men (namely low sperm counts, testicular germ cell cancer) may originate in fetal life similar to established disorders (cryptorchidism, hypospadias) that manifest at birth. These disorders are interlinked and may comprise a testicular dysgenesis syndrome (TDS), a concept supported by animal model studies. The latter have identified the likely time-frame within which TDS disorders may be induced, namely within the so-called masculinisation programming window (MPW). During this critical period, sufficient testosterone (androgen) must be produced by the fetal testis to program the male reproductive tract so that it will differentiate and grow normally after the MPW. Impaired androgen production or action within the MPW can result in smaller reproductive organs and their abnormal formation and function (e.g. cryptorchidism, hypospadias). The MPW is thus of fundamental importance in determining normal, or abnormal, male reproductive development and function for later life. There are two big unanswered questions about the MPW. First, what determines its timing? Second, what mechanisms are controlled by androgens specifically within this time-window and not at later time points? Three approaches were undertaken to address the first question experimentally in rats. First, investigation of whether the availability of androgens and or androgen receptors (AR) plays a role in determining the onset or ‘opening’ of the MPW. Second, investigation of whether the expression of AR co-regulators was a factor in determining androgen sensitivity during the MPW. Third, investigation of whether prostaglandins played a role in mediating androgen action in the MPW, as studies in the 1980s had suggested this possibility. To address what mechanisms are controlled by androgens specifically within the MPW, the expression of selected genes in the genital tubercle was investigated before, during and after the MPW in fetuses that had been exposed to treatments that modulated androgen action. Selection of genes was based on microarray studies and data reported in the literature (ie candidate genes). The studies reported in this thesis show that neither availability of androgens nor the AR are important in determining onset of the MPW, and providing exogenous androgens either prior to or during the MPW does not advance or enhance masculinisation. These studies also showed that females may have a slightly different window of susceptibility to androgen action than do males. Key AR co-regulators have been characterized in the male reproductive tract for the first time, two of which (BRG1, CBP) show changes in expression through development of the testis consistent with a role in Sertoli cells. Another AR co-regulator, RWDD1, was found to switch off in the absence of androgen action in the genital tubercle, pointing to a potential role during and/or after the MPW. Studies involving gestational exposure to indomethacin (a compound which inhibits prostaglandin synthesis) during the MPW showed no detectable effect on masculinisation. Finally, evaluation of candidate genes for mediating androgen action in the genital tubercle during the MPW, failed to identify their key involvement, thus they are unlikely to be involved in penis development and disorders such as hypospadias.
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Kearbey, Jeffrey Dale. "Preclinical pharmacokinetics and skeletal pharmacology of a selective androgen receptor modulator." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085168433.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages; contains xvii, 162 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 May 24.
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Choi, Jaesung (Peter). "The role of androgens acting via androgen receptor in uterine development and PTEN deletion induced uterine cancer." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14437.
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The androgen receptor (AR) is widely expressed in human and rodent uterus indicating an important role. However, the specific role(s) and mechanisms remain controversial. Hence, the thesis aimed to investigate the role of androgen actions via AR in uterine development, function and pathology. Firstly, the uterine development and fertility appeared normal in uterine gland specific AR inactivated uterus suggesting AR mediated endogenous androgen actions in uterine gland epithelium are not critical in normal uterus. However, in the absence of estrogens, androgens via uterine AR can promote full uterine regrowth. Secondly, PTENKO-induced uterine cancer incidence was significantly reduced by simultaneous global AR inactivation, indicating androgen actions via AR either systemically or locally within uterus modifies PTENKO-induced uterine cancer incidence. This could be due to reduced estrogen receptor alpha expression in uterus. Thirdly, glandular epithelial AR inactivation enhanced PTENKO-induced uterine pathology. This could be due to reduced progesterone receptor expression in uterus suggesting glandular epithelial AR could regulate PR expression. In conclusion, the thesis suggests a significant role for androgens via AR inducing uterine growth and pathology that could be mediated locally via AR present in glandular epithelial cells.
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Yang, Chih-Cheng. "Strategies to overcome progression of androgen refractory prostate cancer targeting Bcl-xL and androgen receptor." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1165358220.
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Sharp, Danae Maree. "ANDROGENS INDUCE GENDER- & DOSE- SPECIFIC EFFECTS ON ATHEROGENESIS." Thesis, The University of Sydney, 2009. http://hdl.handle.net/2123/4158.
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Cardiovascular disease (CVD) is the major cause of morbidity and mortality in developed countries. Men have a higher incidence and an earlier onset of CVD than age-matched women. It has been shown that young women have lower CVD incidence than young men and the increase in CVD rates in older (post-menopausal) women when estrogen levels decline suggests that estrogens are cardioprotective. This theory has been extensively investigated demonstrating a favourable reduction in LDL, reducing expression of cell adhesion molecules and promoting vasodilatation by inducing nitric oxide (NO) production in endothelial cells. However, not many studies have explored the alternate theory that male sex hormones, androgens (T & DHT), may promote CVD. Investigators examining male androgens in vivo have shown inconsistent results, with both adverse and protective effects on atherosclerosis formation. This study aimed to elucidate the role of androgens and their effects on the formation and progression of atherosclerotic plaque in males and females. Chapter 3 describes the establishment of the en face Oil Red O for quantitating atherosclerotic plaque. The Oil Red O technique was employed to compare the reliability and the consistency of the plaque area to the already established H&E staining method. This chapter focuses on the en face Oil Red O staining technique to see if the new method could give a faster, more efficient and reliable alternative to the very labour intensive H&E staining. From this study the en face Oil Red O staining technique was a more time and labour efficient method that is a reliable method to the already establish H&E staining when investigating atherosclerotic plaque levels. Chapter 4 examines the effect of exogenously administered male sex hormones, testosterone (T) and dihydrotestosterone (DHT), on atherosclerosis in male and female ApoE-/- mice. The aim of this experiment was to examine if the androgens had a dose- and or gender- specific effect on the plaque formation in the animals. The experimental design involved the use of three different doses of high (1cm implant), medium (0.5 cm implant) and low (0.25 cm implant) T or DHT and the mice were treated for a period of 16-weeks. The results showed that T had gender- and dose- specific effects. Briefly, there was no effect of T treatment on plaque formation in females. However, in males, the high dose of T decreased plaque but at the low dose T had the opposite effect by increasing plaque levels. The DHT results differed to the T results indicating different pathways of action. DHT treatment in the females demonstrated atheroprotective effects at the high and medium dose. The males had no effect at the high dose of DHT but the low dose was atherogenic. Chapter 5 aimed to explore the effect of DHT treatment in cells involved in early atherogenic processes using male and female HUVEC and MDM and to ascertain if AR cofactors are hormonal regulated. The results showed that there was no hormonal regulation in the MDM by DHT. Alternatively, in HUVEC there was a significant up-regulation of ARA24, ARA54, ARA160 and SRC-1 mRNA levels with DHT treatment and a down-regulation of p300 and NCoR1 mRNA levels. In particular, this chapter also investigated protein expression of the cofactor SRC-1 in HUVEC, which was increased in males with DHT treatment. SRC-1 protein levels were also examined with in vivo studies. Different doses of T and DHT were administered to male and female ApoE-/- mice. The 0.5 cm and 1 cm dose of T in the male showed an increase in the SRC-1 protein level and DHT, at the 0.25 cm and 0.5 cm implant increased SRC-1 protein levels. SRC-1 levels in female animals did not change with any dose of DHT, whereas the 0.25 cm T showed an increase in SRC-1 and 0.5 cm T implant decreased SRC-1 protein levels. This study demonstrates that AR cofactors can be hormonally regulated by androgens at the mRNA and protein level. Overall, male sex hormones have an effect on atherosclerosis formation. Androgens have important gender- and dose- specific effects on plaque formation, and can hormonally regulate AR cofactors at the mRNA and protein level. The results of this thesis have produced more questions than it has answered. This study requires further investigation into the benefits and consequences of using androgens, examining the underlying molecular pathways that may be involved with the AR cofactors and the use of exogenous androgen treatment for both men and women.
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Sharp, Danae Maree. "ANDROGENS INDUCE GENDER- & DOSE- SPECIFIC EFFECTS ON ATHEROGENESIS." University of Sydney, 2009. http://hdl.handle.net/2123/4158.
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Master of Science in MedicineCardiovascular disease (CVD) is the major cause of morbidity and mortality in developed countries. Men have a higher incidence and an earlier onset of CVD than age-matched women. It has been shown that young women have lower CVD incidence than young men and the increase in CVD rates in older (post-menopausal) women when estrogen levels decline suggests that estrogens are cardioprotective. This theory has been extensively investigated demonstrating a favourable reduction in LDL, reducing expression of cell adhesion molecules and promoting vasodilatation by inducing nitric oxide (NO) production in endothelial cells. However, not many studies have explored the alternate theory that male sex hormones, androgens (T & DHT), may promote CVD. Investigators examining male androgens in vivo have shown inconsistent results, with both adverse and protective effects on atherosclerosis formation. This study aimed to elucidate the role of androgens and their effects on the formation and progression of atherosclerotic plaque in males and females. Chapter 3 describes the establishment of the en face Oil Red O for quantitating atherosclerotic plaque. The Oil Red O technique was employed to compare the reliability and the consistency of the plaque area to the already established H&E staining method. This chapter focuses on the en face Oil Red O staining technique to see if the new method could give a faster, more efficient and reliable alternative to the very labour intensive H&E staining. From this study the en face Oil Red O staining technique was a more time and labour efficient method that is a reliable method to the already establish H&E staining when investigating atherosclerotic plaque levels. Chapter 4 examines the effect of exogenously administered male sex hormones, testosterone (T) and dihydrotestosterone (DHT), on atherosclerosis in male and female ApoE-/- mice. The aim of this experiment was to examine if the androgens had a dose- and or gender- specific effect on the plaque formation in the animals. The experimental design involved the use of three different doses of high (1cm implant), medium (0.5 cm implant) and low (0.25 cm implant) T or DHT and the mice were treated for a period of 16-weeks. The results showed that T had gender- and dose- specific effects. Briefly, there was no effect of T treatment on plaque formation in females. However, in males, the high dose of T decreased plaque but at the low dose T had the opposite effect by increasing plaque levels. The DHT results differed to the T results indicating different pathways of action. DHT treatment in the females demonstrated atheroprotective effects at the high and medium dose. The males had no effect at the high dose of DHT but the low dose was atherogenic. Chapter 5 aimed to explore the effect of DHT treatment in cells involved in early atherogenic processes using male and female HUVEC and MDM and to ascertain if AR cofactors are hormonal regulated. The results showed that there was no hormonal regulation in the MDM by DHT. Alternatively, in HUVEC there was a significant up-regulation of ARA24, ARA54, ARA160 and SRC-1 mRNA levels with DHT treatment and a down-regulation of p300 and NCoR1 mRNA levels. In particular, this chapter also investigated protein expression of the cofactor SRC-1 in HUVEC, which was increased in males with DHT treatment. SRC-1 protein levels were also examined with in vivo studies. Different doses of T and DHT were administered to male and female ApoE-/- mice. The 0.5 cm and 1 cm dose of T in the male showed an increase in the SRC-1 protein level and DHT, at the 0.25 cm and 0.5 cm implant increased SRC-1 protein levels. SRC-1 levels in female animals did not change with any dose of DHT, whereas the 0.25 cm T showed an increase in SRC-1 and 0.5 cm T implant decreased SRC-1 protein levels. This study demonstrates that AR cofactors can be hormonally regulated by androgens at the mRNA and protein level. Overall, male sex hormones have an effect on atherosclerosis formation. Androgens have important gender- and dose- specific effects on plaque formation, and can hormonally regulate AR cofactors at the mRNA and protein level. The results of this thesis have produced more questions than it has answered. This study requires further investigation into the benefits and consequences of using androgens, examining the underlying molecular pathways that may be involved with the AR cofactors and the use of exogenous androgen treatment for both men and women.
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McFadden, Michael Patrick. "Effects of prenatal androgen exposure on postnatal growth, estrous cyclicity and behavior in female beef cattle." Thesis, Virginia Tech, 1988. http://hdl.handle.net/10919/43050.
Full textAbstract:
This study assessed the effects of prenatal androgen exposure
during three periods, of gestation on the external genitalia,
estrous cyclicity, postnatal growth, social dominance and
sexual behavior of female beef cattle. Pregnant cows
recieved 17a methyl-testosterone (250 mg/d, sq) on d 40 to
100 (group 1), 70 to 130 (group 2) or 100 to 160 (group 3)
of gestation. Control cows (group 0) received no treatment.
Group 1 females exhibited completely masculinized external.
genitalia. No vulval opening was present and the
ano-genital distance (A-g) was similar to that of control
male calves. Group 2 females exhibited small vulval openings
and enlarged clitoral structures while group 3 females exhibited
normally appearing female external genitalia. Anogenital
distances for the heifers in groups 2 and 3 were
similar to those of the control heifers. Androgen exposure
during the three periods of gestation did not affect age at puberty (P<.80), estrous cycle length (P<.63) or postnatal
growth (P<.60) of the heifers.
At 9, 16 and 21 mo of age, social dominance values (SDV)
were determined for each heifer by 3 min random pair contests
for a restricted feed source. The animal with the greatest
feed source control time was awarded a win. Social dominance
value was calculated as 10 times the number of wins divided
by the number of competitions for each animal. Group 3
heifers had significantly greater SDV values than group 1 and
2 females (P<.03). SDV did not differ among groups at 16 mo
of age (P<.59). Group 1 females had greater SDV than group
2 females at 21 mo of age (P<:.04).
At 9, 16 and 21, mo of age, sexual behavior of the heifers
was characterized by exposure of the heifers to a teaser female in estrus. Sexual behavior, as indicated by the number
of mounts, head placements and interest time, was lower for
group 3 females compared to females in groups 1 and 2 at 9
mo of age (P<.04). There were no treatment differences for
any sexual behavior variable at 16 or 21 mo of age.
These results indicate that there is little potential
for increasing postnatal growth or altering the estrous
cyclicity of female cattle by exposure of the fetus to
testosterone during the periods of gestation selected in this
study. External genitalia of females were masculinized by
androgen exposure during d-40 to 100 of gestation. Social
dominance values were increased and sexual behavior was reduced in females by exposure to androgen during d 100 to 160 of gestation. Social dominance values were increased and sexual behavior was reduced
in females by exposure to androgen during d 100 to 160
of gestation.Master of Science
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Gao, Wenqing. "Pharmacology of selective androgen receptor modulators (SARMS)." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1085757928.
Full textAbstract:
Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 May 28.
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Simitsidellis, Ioannis. "Identifying the role of androgens in endometrial function." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25773.
Full textAbstract:
The endometrium is a complex multicellular tissue that undergoes dynamic alterations under the control of ovarian-derived sex steroid hormones. During the proliferative phase of the human menstrual cycle, oestrogen induces proliferation of the endometrial epithelium while during the progesterone-dominated secretory phase, the endometrial stromal compartment differentiates in preparation for pregnancy. This differentiation event is termed decidualisation and it is accompanied by immune cell infiltration, vascular remodelling and secretion of cytokines and growth factors, as well as a newfound capacity of active steroid synthesis in the endometrium. Defective decidualisation has been described in several endometrial-associated disorders such as endometriosis, a pathology of ectopic endometrial tissue in the peritoneal cavity, often associated with infertility. Rodent models have been used for the investigation of endometrial physiology and pathology due to the similarity in uterine tissue architecture, appropriate endometrial responses to steroid hormones and the opportunity to inform cellular mechanisms using genetic manipulation. While the impact of 17β-oestradiol and progesterone on endometrial function have been extensively studied, androgens have only recently emerged as potent potential regulators of the endometrium, however, their impact on cell function has not been fully elucidated. The aims of this study were to: Identify the impact of androgens on endometrial function using a mouse model of steroid depletion (ovariectomy) followed by administration of the potent androgen dihydrotestosterone (DHT). Investigate the capacity of endometrial stromal cells to synthesise androgens during decidualisation using human primary endometrial stromal cells (hESCs) decidualised in vitro. Elucidate the decidualisation response of hESCs from women with endometriosis after modulation of androgen receptor (AR) function during decidualisation. Novel results obtained provided evidence of a role for androgens in inducing a trophic effect in the mouse uterus characterised by: pronounced endometrial epithelial proliferation, altered expression pattern of AR, changes in the expression of genes involved in cell-cycle progression and stromal-epithelial cross-talk. In addition, androgen treatment resulted in a striking and unexpected increase in the number of endometrial glands. Decidualisation of hESCs resulted in time-dependent changes in expression of the androgen synthesising enzymes AKR1C3 and 5α-reductase (accompanied by biosynthesis of both testosterone and DHT in a dynamic time-dependent manner). Notably, blocking of AR action arising from local androgen signalling during decidualisation of hESCs culminates in sub-optimal decidualisation as detected by the expression of the classical decidualisation markers IGFBP1 and PRL. Women with endometriosis are reported to exhibit defective decidualisation, which may be accompanied with infertility. Treatment of hESCs from women with endometriosis with an AR agonist (DHT) or antagonist (flutamide) during decidualisation resulted in striking differences in decidualisation response as demonstrated in a case-study approach. Taken together, these findings highlight novel roles of androgens in regulating endometrial function by impacting on cell proliferation, gland formation and decidualisation. These striking new findings have implications for endometrial disorders such as endometriosis. Future studies will focus on the use of selective androgen receptor modulators, a novel class of compounds, with tissue-selective actions and without the undesired side-effects of potent androgens. The use of AR modulators would benefit from a personalised medicine approach, instructed by patient profiling to direct therapeutic targeting of endometrial disorders.
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Jimenez, Esbal. "Effects of Androgens on Reproduction in Female Pigs." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1206382656.
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Berg, Melanie Dawn. "Yolk androgens and development in American kestrel nestlings." [Boise, Idaho] : Boise State University, 2009. http://scholarworks.boisestate.edu/td/11/.
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Lesmana, Brian. "The Role of Androgens in Burn Wound Healing." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/21115.
Full textAbstract:
Background/Objective: Androgens are not currently part of the therapeutic guidelines in burns management. However, oxandrolone, an androgen analogue, has been reported to have significant benefits in burn wound recovery, but there are still concerns regarding its side effect profile. Preliminary studies have identified that the inactivation of androgen receptors (AR) slows wound healing post-burn injury. This finding is opposite to that of experimental evidence for androgens in cutaneous (non-burn) wound healing, on which they exert an inhibitory effect. Therefore, this study aimed to identify the role of androgen signalling in severe, hypermetabolic burn injury both at the local wound and systemic levels. Design: Experimental study. Setting: Research laboratory. Subjects: Male Balb/c mice; wild type (WT) and androgen receptor knockout (ARKO) using Cre/LoxP system. Interventions: 4 cm2 contact burn injury (representing 10% Total Body Surface Area (TBSA)). Main Results: ARKO mice demonstrated slower wound healing and poorer body weight maintenance and recovery. This was associated with preferential activation of white adipose tissue over brown adipose tissue, larger splenic size and smaller hepatic size. There was no difference in local wound inflammatory cytokine mRNA expression between WT and ARKO mice. Conclusions: Androgens play a positive modifying role in wound healing in the context of burn injury, a finding opposite to its reported inhibitory actions in cutaneous wound healing. This is likely resultant from an attenuation of the systemic hypermetabolic response. This contradictory, contextdependent action urges further research into the beneficiary effects of androgens in burns management, particularly its modulation of systemic inflammation and the host immune response.
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Pincott, Cynthia. "Observations on the association of androgen-receptor complexes with the nuclear matrix of human genital skin fibroblasts." Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=63847.
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Sperry, Todd Samuel. "Studies on the biochemical characteristics of two distinct nuclear androgen receptors in Atlantic croaker, Micropogonias undulatus /." Digital version accessible at:, 1999. http://wwwlib.umi.com/cr/utexas/main.
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Khoo, Sue-Anne. "Effects of intermittent androgen suppression therapy on cognitive functioning and quality of life in men with metastatic prostate cancer /." [St. Lucia, Qld.], 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16253.pdf.
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Scott, Hayley M. "The role of androgens in testicular development and dysgenesis." Thesis, University of Edinburgh, 2007. http://hdl.handle.net/1842/2687.
Full textAbstract:
Disorders of male reproductive health which manifest at birth (cryptorchidism, hypospadias) or in young adulthood (testicular germ cell cancer and low sperm counts), are common and may be increasing in incidence. These disorders have a common fetal origin and share risk factors; consequently they are hypothesized to comprise a testicular dysgenesis syndrome (TDS). TDS arises when maldevelopment (dysgenesis) of the fetal testis results in hormonal malfunctions and abnormal development and function of the somatic cells. It is thought that the suppressed intratesticular testosterone levels associated with TDS may account for subsequent low sperm counts, via a reduction in perinatal Sertoli cell proliferation/number. Sertoli cells do not express androgen receptors (AR) in fetal life in the human or rat, so it is hypothesised that any androgen effects on Sertoli cell number occur indirectly, via the AR positive peritubular myoid cells. Evidence from the di (n‐butyl) phthalate (DBP)‐treated rat model for TDS suggests that reduced androgen action may play a role in testicular dysgenesis as in patients with complete androgen insensitivity syndrome (CAIS; ‘testicular feminization’), in whom focal areas of testicular dysgenesis have been reported. The studies in this thesis sought to establish if reduced androgen levels/action in the fetal rat testis contribute to putative testicular dysgenetic features, namely reduced Sertoli cell number, occurrence of multinucleated gonocytes or abnormal aggregation of fetal Leydig cells, the precursor of focal dysgenesis. Pregnant rats were exposed to treatments or co‐treatments expected to manipulate testicular testosterone levels (DBP, testosterone propionate; TP) or action (flutamide, DMBA) or to induce intrauterine growth restriction (dexamethasone), another risk factor for TDS. The aforementioned endpoints were analysed in fetal testes and related to testicular testosterone levels and peripheral androgen action (anogenital distance). The same endpoints were evaluated in mice with inactivation of the androgen receptor (tfm or ARKO mice). As androgen action is assumed to be mediated indirectly, via the peritubular myoid cells, changes in peritubular myoid cell number and function were investigated in testes with suppressed androgens. In vitro studies were also used to investigate the role of androgens in Sertoli cell proliferation. Fetal rat testis explants were cultured with various chemicals designed to manipulate androgen action and Sertoli cell proliferation. Potential non‐androgen related mechanisms of DBP action were investigated using Taqman RT‐PCR to determine the mRNA expression of key developmental genes after exposure to DBP. Sertoli cell number was reduced after exposure to treatments that reduced testicular testosterone levels, i.e. DBP alone or as a co‐treatment, TP and dexamethasone. Sertoli cell numbers in ARKO mice were also significantly reduced. The occurrence of multinucleated gonocytes and large Leydig cell clusters were induced after exposure to DBP, alone or as a co‐treatment, but not after exposure to TP or dexamethasone, and these dysgenetic endpoints did not occur either in tfm or ARKO mice. Rats exposed in utero to DBP have reduced testicular testosterone levels, however peritubular myoid cell number was unaffected by DBP, though AR expression in the peritubular myoid cells was delayed, and laminin and vimentin expression in Sertoli cells was altered after DBP exposure. DMRT‐1 and DAX‐1 mRNA expression levels were significantly reduced after DBP exposure, but this reduction was no longer evident once mRNA expression was corrected for Sertoli cell number. In conclusion, these studies provide strong evidence that androgens play a role in regulation of Sertoli cell number/proliferation, and this is supported by a comparable reduction in Sertoli cell number in ARKO and tfm mice. However, since the treatments that reduce testicular testosterone in the rat, may also have a direct affect on the Sertoli cells, this alternate mechanism of action cannot be ruled out, and the administration of a treatment that reduces testicular testosterone without directly affecting Sertoli cells is required. These studies also show that reduced testicular testosterone levels are associated with multinucleated gonocyte formation and fetal Leydig cell aggregation, although this evidence it is not supported by parallel findings from the TP and dexamethasone exposed rats or the ARKO and tfm mice, as neither of these endpoints were identified as being affected in these animals. Aside from the delay in AR expression, there were no obvious changes in peritubular myoid cell number or the peritubular myoid cell markers examined in testes deprived of androgens, although there are other markers that could be investigated. mRNA analysis of the developmental genes investigated after DBP exposure, demonstrated no change in expression after correction for Sertoli cell number, suggesting that they do not play a role in the dysgenetic features observed in DBP exposed testes.
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Dobson, Katharine Rebecca. "Studies into the effects of androgens on bone formation." Thesis, University of Sheffield, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301007.
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Huaikai, Sai. "The Role of Androgens in Burn Injury Wound Healing." Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/23771.
Full textAbstract:
Androgens are known to inhibit cutaneous wound healing in men and male mice. However, in children with major burn injuries, a synthetic androgen was reported clinically to improve wound healing. Hence, the mechanism of androgen action on the burn injury wound healing process remains unclear. Therefore, the overall aim of the study was to identify the local and systemic role of the pure androgen dihydrotestosterone (DHT) in complex major burn injury. After major burn injury, mice received systemic androgen treatment via subdermal depot implantation of DHT. Wound healing rate and body weight were compared between untreated and DHT treated mice over 21 days. The serum level of inflammatory cytokines/chemokines were measured using multiplex immunoassays. In addition, splenocyte enumeration was performed by flow cytometry to determine the splenic resident immune cell populations involved in the wound healing process. In the results, DHT treated mice lost less weight and displayed accelerated wound healing but had no impact on post burn metabolism. DHT treatment shortened the systemic inflammatory response with reduced splenic weight and monocytes numbers on day 14 and day 21. DHT treatment also reduced wound infiltrating macrophage numbers. Therefore, systemic DHT treatment facilitates burn wound healing by accelerating the resolution of inflammation, but not through alterations of post-burn hypermetabolic response. To investigate the local effect of androgens on major burn injury wound healing, tissue engineered scaffolds were developed. Scaffolds were made by electrospinning 5% polycaprolactone (PCL) solution containing either 5 mg/ml of the androgen, dihydrotestosterone (DHT) or the anti-androgen flutamide (F). Drugs released from the scaffold into PBS were monitored in vitro over 31 days with the concentration of F analysed by UV spectrophotometry and that of DHT by liquid chromatography – mass spectrometry (LCMS). The surface morphology of the scaffolds before and after drug delivery was examined using scanning electron microscope (SEM). Seven days after wound debridement, the burn wounds were dressed with either blank, F or DHT loaded scaffolds. Wound healing rate, body weight, body composition and food intake were measured for 28 days while local wound area, re-epithelialization, cell proliferation and collagen deposition were investigated. Drug-loaded electro-spun PCL scaffold was developed successfully with controlled release of DHT and F. In vitro drug delivery curve showed that both DHT and F can be released constantly at 35µg/day and 20µg/day respectively, over 31 days. F scaffolds significantly promoted burn injury wound healing with enhanced re-epithelialization and collagen deposition but had no effects on cell proliferation. However, unlike cutaneous injury, mice with DHT scaffolds demonstrated an increased epithelial cell proliferation, resulting in a comparable wound healing to blank scaffolds. Although local F scaffold treatment accelerated burn injury wound healing, it had no effects on body weight or body composition. With the understanding of systemic and local androgen actions on burn injury wound healing, we investigated dual treatments combining androgen/anti-androgen. Based on our preliminary data, mice treated with DHT implant + F scaffold failed to accelerate wound healing. However, when mice were treated with DHT+ F mixed scaffold, there was an enhancement of burn wound healing with increased epithelial cell proliferation and migration. Additionally, mice treated with DHT+F mixed scaffold better preserved body weight post major burn injury, highlighting its potential to be utilized as a therapeutic approach in the treatment of major burn injury. In summary, these studies demonstrated the systemic and local role of androgen in major burn injury wound healing and provided the foundation for translational studies examining DHT as a potential therapeutic target for major burn injury patients.
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Caldwell, Aimee Sarah Lee. "Unravelling The Role Of Androgens In Polycystic Ovary Syndrome." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/18129.
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Polycystic Ovary Syndrome (PCOS) is a multifaceted hormonal disorder which affects 5-15% of reproductive-aged women worldwide. While classically recognised as an ovarian disorder, PCOS is associated with a variety of reproductive, endocrine and metabolic features including ovulatory dysfunction, infertility, hyperandrogenism, obesity, and an increased risk of type 2 diabetes mellitus and cardiovascular disease. The most consistently present of these is hyperandrogenism – supraphysiological levels of androgens such as testosterone (T) and dihydrotestosterone (DHT). Typically thought of as male steroid hormones, androgens have been shown to play important role in the maintenance of normal female reproductive function. Despite the high prevalence of hyperandrogenism amongst patients, the role of androgens in the etiology and pathogenesis of PCOS has yet to be determined. The aim of this work was to unravel the association between excess androgen exposure and the development and advancement of the PCOS phenotype in mouse model of androgen-induced PCOS. The first study contained within this work (Chapter Three) provides the first comprehensive characterization of a range of reproductive, endocrine and metabolic traits associated with PCOS in four distinct mouse models: a model of prenatal androgenisation utilising the potent non-aromatizable androgen DHT administered during days 16-18 of gestation, and three diverse models of postnatal androgen exposure employing a long-term treatment with either DHT, the proandrogen dehydroepiandrosterone (DHEA), or letrozole (an aromatase inhibitor) for 90 days beginning at 3 weeks of age. Prenatal androgenisation produced some reproductive and endocrine traits, but failed to induce the metabolic abnormalities seen in PCOS. DHEA treatment did not reproduce any features associated with PCOS while treatment with letrozole produced few PCOS-like characteristics and some aberrant changes not typical of the syndrome. Additionally, letrozole treatment did not reproduce any metabolic attributes of PCOS. On the other hand, postnatal exposure to excess androgen, by way of DHT treatment, produced a breadth of reproductive, endocrine and metabolic traits that mimic those seen in human PCOS. This study revealed that a treatment regime of long-term postnatal exposure to DHT reproduced the strongest PCOS-like phenotype in our mice and provides a robust animal model in which to study the pathogenesis of PCOS. The second study (Chapter Four) aimed to explore the involvement of genomic androgen receptor (AR)-mediated actions in the development of these PCOS traits. As a prenatally androgenised mouse model of PCOS had previously been reported to exhibit impaired neuroendocrine hypothalamic feedback of the hypothalamic-pituitary-gonadal (HPG) axis, we took this opportunity to utilise mice from our own prenatal model to investigate the neuroendocrine regulation of the HPG axis in PCOS in addition to the effects of AR inactivation on the PCOS phenotype. PCOS was induced in wild-type (WT) and androgen receptor knockout (ARKO) mice using DHT administered on days 16-18 of gestation. A subset of these mice were also exposed to 17β-estradiol for 7 days prior to collection, via a subdermal implant, to investigate the impaired estradiol negative feedback on the hypothalamus. WT mice with DHT-induced PCOS displayed several reproductive abnormalities including aberrant cycling and ovulatory dysfunction in addition to adipocyte hypertrophy and hepatic steatosis. However, diestrus serum luteinising hormone and follicle stimulating hormone, and estradiol-induced negative feedback as well as hypothalamic expression of several neuropeptides were unaffected by DHT treatment in WT mice. Mice both homozygous and heterozygous for the global inactivation of the AR (ARKO), did not display any PCOS traits when exposed to excess androgens during prenatal life. This study showed the importance of AR signalling in the development of PCOS and revealed that even AR haplosufficiency is adequate to prevent induction of PCOS by prenatal hyperandrogenism. Finally, the third study (Chapter Five) aimed to shed further light on the AR-mediated androgen actions in PCOS with a focus on identifying the tissue-specific targets of these actions. Employing our postnatal model of PCOS induction, this study investigates the effects of: 1) global loss of AR signalling (ARKO), 2) neuronal knockout (NeurARKO) and 3) granulosa cell-specific AR inactivation (GCARKO) on the development of the PCOS phenotype induced by exposure to exogenous DHT. As in our prenatal model, ARKO mice were fully protected from all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of a variety of reproductive and metabolic traits including classic polycystic ovaries, dysfunctional ovulation, obesity and dyslipidemia. In contrast, loss of AR signalling in granulosa cells did not impede the pathogenesis of PCOS-like features in GCARKO mice. To further examine the role of extra-ovarian AR signalling in PCOS, reciprocal ovary transplants were carried out in WT and ARKO mice. Results from ARKO hosts with transplanted WT ovaries revealed that excess androgen exposure requires functional extra-ovarian, and not intra-ovarian, AR signalling in order to produce features of PCOS. This study provides strong evidence that neuroendocrine genomic AR signaling is an important mediator in the development of PCOS. The studies contained within this thesis are the first to provide a comprehensive analysis of a mouse model of PCOS encompassing a breadth of reproductive, endocrine and metabolic features. This work has identified the optimal model in which to study this complex, multifactorial condition which affects a significant number of women worldwide. Additionally, our results have shown that the effects of androgens on the pathogenesis of PCOS are mediated via the androgen receptor in a dose-dependent manner such that two functional copies are required for DHT to reproduce features of PCOS in the mouse. Finally, in a crucial study to investigate the locus of androgen actions we have revealed the previously overlooked importance of extra-ovarian neuroendocrine androgen action in the origins and progression of PCOS, despite it being thought of primarily as an ovarian disorder. Overall, these studies have provided valuable insights into both the role of androgens in Polycystic Ovary Syndrome and potential new targets for the development of mechanism-based treatments of this disorder.
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Kamal, A. M. "Endometrial cancer : involvement of androgens and metastasis inducing proteins." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3004396/.
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The alarming escalation of endometrial cancer incidence with associated parallel rise in mortality has increased the urge to find reliable prognostic markers in order to improve risk stratification of patients and therefore promote more individualised treatment strategies. The principal goal of this thesis was to examine the prognostic role of steroid hormone receptors, particularly AR, and metastasis inducing proteins S100A4, S100P and AGR2 in endometrial cancer and to investigate the hormonal regulation of these proteins. A comprehensive expression profile for each of these target proteins was described in a total of 161 well characterised human endometrial samples, using immunohistochemistry. The transcription of the target genes was further assessed in a subset of these samples using the RT-qPCR. Four established human endometrial cancer cell lines were then characterised for the expression of the steroid receptors and the metastasis inducing proteins, in order to select the most appropriate cell line for in vitro hormone modulation. Ishikawa cell line was subsequently utilised to study the effect of the potent natural androgen, 5α-dihydrotestosterone (DHT), and oestradiol on the expression of the aforementioned target genes. An immuno-scoring system was proposed and validated for more accurate quantification of steroid hormone receptor proteins in the endometrium. The expression of AR and ERα was significantly higher in the epithelium of postmenopausal endometrium compared with that of the premenopausal proliferative phase basalis layer. This expression pattern persisted in the hyperplastic epithelium, and also in low grade cancers. In contrast, the high grade cancers showed a significant loss of AR, PR and ERβ compared with the low grade cancers, whilst maintaining weak to moderate ERα. Unlike PR, AR expression in metastatic lesions was significantly higher than that in primary tumours. AR expression correlated positively with favourable clinicopathological features and a lower proliferation index. Loss of AR with/without a simultaneous loss of PR was associated with significantly lower disease free, cancer specific and overall survivals. AR was an independent prognostic indicator for endometrial cancer progression. S100A4, S100P and AGR2 proteins were upregulated in endometrial cancer. A substantial change in the expression profile of S100A4 was observed in endometrial cancer compared with the normal postmenopausal endometrium. The increased expression of S100A4 protein was represented by a significant increase in the nuclear and cytoplasmic expression of the malignant epithelial cells with a concomitant high expression in the associated stroma. High immunoexpression of S100A4 was positively associated with deep myometrial invasion and shorter cancer specific and overall survival but was not identified as an independent prognostic indicator. The expression of S100P was generally low and limited to the cytoplasm of the normal postmenopausal glandular epithelium. Significant nuclear translocation was observed in endometrial cancer cells simultaneously with a reduction in cytoplasmic expression. The loss of cytoplasmic S100P (not nuclear) was associated with unfavourable prognostic indicators such as lymphovascular space invasion. Elevated AGR2 expression was observed in premalignant atypical hyperplasia and peaked in low grade cancers. There was a significant association between highAGR2 and positive ERα, PR, and AR in endometrial cancers. Secreted AGR2 was detected in the serum and uterine washes from endometrial cancer patients. AGR2 protein was immunoexpressed in 93/100 (93%) of the endometrial cancer samples and was associated with a longer overall survival of the patients. In vitro studies on hormonal modulation showed that a supra-physiological dose of DHT was required to induce AR expression in Ishikawa cells. At such dose, DHT had a stimulatory effect on Ishikawa cell proliferation, an action exerted via ER. Whilst S100A4 and S100P mRNA level in Ishikawa cells did not show a significant change in response to oestradiol or DHT treatments, AGR2 mRNA level was downregulated after 24-hour treatment with DHT (but not oestradiol) which was, at least partially, via AR. In conclusion, AR may be a clinically relevant prognostic indicator and a potential therapeutic target in endometrial cancer. Although S100A4 and AGR2 were not recognised as independent prognostic indicators, both have shown significant association with patient outcome. S100A4 protein can be potentially targeted by one of the newly developed S100A4 neutralising peptide to characterize its role in endometrial cancer invasion. An association between S100P and patient outcome was not identified; however, the change in the cellular localisation of S100P may have implications in endometrial carcinogenesis. DHT can modulate AR and AGR2 directly or via ER.
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Chong, Jessica. "The role of androgens in the female genital tract." Thesis, Boston University, 2013. https://hdl.handle.net/2144/21137.
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Thesis (M.A.) PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.The view of androgens as a chiefly male- associated hormone is long outdated, and there is an increasing wealth of evidence for the role of androgens in women. Androgens, in addition to estrogen and other hormones, play several various and critical roles in females, particularly in the development and function of the female genital tract. Countless, targeted studies have been conducted in efforts to elucidate how androgens affect the development and function of the female genitalia, most notably in regards to the vagina, uterus, and ovaries. However, though the significance of female androgens is relatively well established, knowledge on this subject is still developing and somewhat fragmented. The objective of this review is to present a comprehensive view of the role of androgens in the development and function of the female genital tract, summarize new studies, and integrate the most current information in order to gain a broadened and enhanced understanding of the importance and implications of androgens in females.
2031-01-01
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Mason, Rachel Ann. "Effects of estrogens and androgens on bone cell metabolism /." Title page, table of contents and abstract only, 1997. http://web4.library.adelaide.edu.au/theses/09PH/09phm411.pdf.
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Lindström, Sara. "Genetic variation and prostate cancer : population-based association studies in Sweden /." Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1329.
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Čeponis, Jonas. "Jaunų ir vidutinio amžiaus vyrų reprodukcinės sveikatos ryšys su antropometrija, metaboline bei psichologine būkle." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2014. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2014~D_20140714_134831-56285.
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Epidemiologiniais tyrimais nustatytos androgenų sąsajos su įvairiais metaboliniais veiksniais bei širdies ir kraujagyslių ligų rizika paskatino susidomėjimą naujais vyrų reprodukcinės sveikatos aspektais. Iki šiol Lietuvoje nebuvo nustatytos normalios vyrų androgenų koncen¬tracijos ribos, nebuvo atlikta reprodukcinės sveikatos, antropometrinių ir metabolinių rodiklių sąsajų analizės tyrimų. Pasaulyje iki šiol trūksta nuoseklios informacijos apie metabolinių ir antropometrinių rodiklių ryšius su lytiniais hormonais, ypač homogeniškose tiriamųjų imtyse. Trūksta informacijos apie androgenų sąsajas su pažintinėmis funkcijomis, emocine būkle ir gyvenimo kokybės vertinimu. Daugelis tyrimų, kuriais vertintas pakaitinio gydymo testosteronu efektyvumas – trumpalaikiai, juose dau¬giausiai dėmesio skirta struktūriniams, o ne funkciniams rodikliams.
Šiuo tyrimu siekta aprašyti jaunų bei vidutinio amžiaus vyrų reprodukcinės sveikatos sąsajas su antro¬pometrijos, metabolinės bei psichologinės būklės rodikliais. Tai iki šiol didžiausia savo apimtimi Lietuvos vyrų androgenų sąsajų analizė. Šiuo darbu siekiama sistemingai atsakyti į iškeltus aktualius klau¬simus, nustatyti normalios ir optimalios androgenų koncentracijos ribas, homogeniškose amžiumi tiriamųjų grupėse įvertinti šių hormonų koncen¬tracijos grupių sąsajas su kūno sudėties ir medžiagų apykaitos rodikliais bei nustatyti, kokius sergančiųjų androgenų nepakankamumu funkcinius pokyčius sąlygoja ilgalaikis optimalus pakaitinis... [toliau žr. visą tekstą]Associations between androgens and various metabolic factors, as well as cardiovascular morbidity shown in recent epidemiological studies sparked interest in new aspects of male reproductive health. Reference values for normal androgen levels in Lithuanian population have not yet been established and no relationship studies on reproductive health and anthropometric, as well as metabolic parameters have been performed. Unequivocal information on associations among the aforementioned factors is lacking globally, especially those performed in homogenous populations. More information on androgen associations with cognitive function, emotional state and evaluation of quality of life is required. Most of the studies on effectiveness of testosterone replacement therapy were of short duration and mostly focused on structural, rather than functional parameters. The purpose of the study was to describe associations between reproductive health and anthropometric, metabolic, as well as psychological parameters in young and middle-aged men. This is the largest androgen association analysis in Lithuanian population. This work seeks for systematic responses to questions of interest: to establish reference values for normal and optimal androgen levels, to evaluate their relationship with anthropometric and metabolic factors in populations that are homogenous by age, and to assess the functional changes that long-term optimal testosterone replacement therapy may induce in patients with... [to full text]
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Coss, Christopher C. "Selective Androgen Receptor Modulator (SARM) Action: Androgen Therapy Revisited." Columbus, Ohio : Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1227282252.
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Yu, Frank Hong. "The effects of hydroxyflutamide on action and production of androgens in rats induced to superovulate." Thesis, University of British Columbia, 1990. http://hdl.handle.net/2429/29409.
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In two experiments, immature female Sprague-Dawley rats treated with superovulatory doses of pregnant mare serum gonadotropin (PMSG) were used to study the effects of antiandrogen, hydroxyflutamide, on steroid production, particularly the biologically active androgens, testosterone, 5α-dihydrotestosterone, and androstenedione. In the first experiment, the animals were given either 5 mg hydroxyflutamide or vehicle alone at 30 and 36 h following 40 IU PMSG. Compared to the vehicle group, hydroxyflutamide treatment significantly reduced the percentage of degenerate oocytes recovered from oviducts (p<0.05). Serum levels of aromatizable androgens, testosterone and androstenedione, and their aromatized product, estradiol-17ß significantly decreased (p<0.05) in hydroxyflutamide-treated group; however, the serum concentrations of nonaromatizable androgen, 5α-dihydrotestosterone, was not statistically different between the two groups. In the second experiment, ovaries stimulated with 4 or 40 IU PMSG were obtained 48 h later and cultured in the presence and absence of hydroxyflutamide (10⁻⁵M) and/or testosterone (10⁻⁷ M) to study [4⁻¹⁴C] pregnenolone metabolism to major steroids. In 40 IU stimulated ovaries, hydroxyflutamide significantly decreased the metabolism of pregnenolone to progesterone (p<0.01) and androstenedione (p<0.01) while the production of estradiol-17ß increased significantly (p<0.05); however, pregnenolone conversions to testosterone and 5α-dihydrotestosterone were not statistically different between the untreated and hydroxyflutamide-treated cultures. Testosterone completely reversed the hydroxyflutamide-induced alteration of pregnenolone metabolism. In contrast, there was no difference in the pregnenolone conversion patterns between the untreated and hydroxyflutamide or hydroxyflutamide plus testosterone groups in the culture of ovaries stimulated with 4 IU PMSG. Present results confirm previous reports that antiandrogen, hydroxyflutamide, decreases the percentage of abnormal oocytes recovered from superovulating rats, and indicates that this hydroxyflutamide effect may be partly mediated by altered ovarian steroidogenesis, specifically the reduced hypersecretion of aromatizable androgens, testosterone and androstenedione, and/or estradiol-17ß.Medicine, Faculty of
Obstetrics and Gynaecology, Department of
Graduate
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Elhaji, Youssef A. "Androgen receptor mutation in breast cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0002/MQ44162.pdf.
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Söderström, Torbjörn. "Molecular endocrinology of target enzymes in androgen metabolism : implications for prostate cancer /." Stockholm : Karolinska Univ. Press, 2001. http://diss.kib.ki.se/2001/91-89428-12-9/.
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Stubbs, Andrew Peter. "Sex steroids in human hepatocellular carcinoma : metabolism, receptor expression and binding protein modulation." Thesis, King's College London (University of London), 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299135.
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Makieva, Sofia. "Investigating the role of androgens in myometrial biology during pregnancy." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/15950.
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Understanding the physiology of pregnancy enables effective management of pregnancy complications that could otherwise be life threatening for both mother and fetus. A functional uterus (a) retains the fetus in utero during pregnancy without initiating stretch-induced contractions and (b) is able to dilate the cervix and contract the myometrium at term to deliver the fetus. The onset of labour is associated with successful cervical remodelling and contraction of myometrium, arising from concomitant activation of uterine immune and endocrine systems. A large body of evidence suggest that the action of local sex hormones may drive changes occurring in the uterine microenvironment at term. Although there have been a number of studies considering the potential role(s) played by progesterone and estrogens at the time of parturition, the role of androgens has received less scrutiny. The overarching aim of this thesis was to investigate the potential roles of androgens in myometrial biology at the time of pregnancy. We examined both the genetranscription dependent (genomic) and independent (non-genomic) action of androgens on the uterine smooth muscle, employing in vitro, ex vivo, and in vivo approaches. We found that the androgen receptor (AR) mRNA was significantly increased in the myometrium during labour when compared to the term non-labouring myometrium. Our gene expression studies revealed that ligand-dependent AR signalling in the myometrium might play a role in regulation of uterine smooth muscle cell contractility. We explored the effect of androgens on contraction of uterine smooth muscle strips obtained from both human myometrial biopsies collected at term and murine uterine horns. We found that testosterone (T) and dihydrotestosterone (DHT) in a range of 10-100 μM concentrations rapidly relaxed spontaneous and oxytocin-initiated contractions. The relaxant effect was not mediated by the classical intracellular AR nor was cell-surface initiated as shown by experiments employing a specific AR antagonist (flutamide) and a cell-surface impermeable androgen (TBSA). We investigated whether the relaxant effect was specific to androgens or a generic effect of sex hormones. We demonstrated that both estradiol (E2) and progesterone (P4) were also capable of relaxing the human and murine myometrium at the same dose range. In addition, a sex hormone “cocktail” (all four sex hormones combined at 10 μM dose each) mimicked the relaxant effect that each individual sex hormone elicited at a 40 μM dose, implying that the effect was possibly attributable to the steroid structure of the sex hormones. To study the underlying molecular events that mediate the relaxant effect of sex hormones observed ex vivo, we employed two human myometrial cell lines namely PHM1-41s and UtSMCs. We demonstrated that the androgen-induced relaxation in vitro was not induced by cell death but was mediated by a physiological mechanism whereby incubation with the androgen impaired the stimulated-Ca2+ entry into the uterine myocytes, which in turn resulted in poor phosphorylation of myosin light chain protein. Finally, we conducted a pilot study to explore the hypothesis that administration of androgen could relax the uterine muscle in vivo. We utilised a mouse model of infection-induced preterm labour, where infection was induced by intrauterine administration of liposaccharide (LPS) on day 17 of murine pregnancy. Our preliminary data showed that intrauterine administration of DHT on day 17 did not significantly reduce the rate of LPS-induced preterm birth in the doses tested in this study. In conclusion, the androgen-induced in vitro tocolysis appears to be sex hormone-specific rather than androgen-specific. Therefore, sex hormones might have the potential to be used for effective in vivo tocolysis to inhibit premature-initiated contractions. Our investigation of the androgen-dependent signalling in the myometrium contributed to the development of novel hypotheses regarding the role of androgens in the regulation of the phenotypic transition of MSMCs during pregnancy. These hypotheses remain to be confirmed in future studies.
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Qureshi, Asjid Iqbal. "The role of androgens in prenatal folliculogenesis in polycystic ovaries." Thesis, University of London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428952.
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Swales, A. "The effect of oestrogens and androgens on mammalian oocyte maturation." Thesis, University of Edinburgh, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.662647.
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Exposure to raised steroid levels in culture had a significant effect on the global DNA methylation levels of oocytes. Although, no alterations in gene expression were previously identified this did not rule out the possibility that the observed changes to DNA methylation levels were the result of an effect on DNMT proteins. To begin investigating this, the localisation of DNMT1o was assessed after exposure to high levels of androgens and oestrogens. Under physiological conditions the DNMT1o protein is present in the nucleus in growing oocytes and translocates to the cytoplasm as maturation progresses. Steroid exposure was found to alter the localisation profile of DNMT1o, making this a candidate mechanism by which the global DNA methylation levels are influenced by raised androgens and oestrogens. The mechanisms controlling genomic imprinting during oocyte and embryo development are still being investigated. An increased understanding of genomic imprinting during development has been achieved through analysis of the gametes, embryos and offspring of mice with null mutations for Dnmt or Mbd genes. Although, Mbd2-/- mice have been reported to have a reduced litter size, the cause of this maternal effect is currently unknown. This study did not find any significant difference between maternal genotypes in the number of oocytes ovulated, fertilisation rate or percentage of 2-cell embryos developing to the blastocyst stage during IVF. Thus, the observed phenotype of small litter size may not be the result of impaired oocyte maturation or early embryo development occurring in the absence of MBD2. The increasing use of assisted reproductive techniques means that a full understanding of the role of the environment on oocyte developmental competence is vital.
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Sirab, Nanour. "Interaction entre la voie Hedgehog et les hormones stéroïdiennes dans les cellules normales et cancéreuses de la prostate." Thesis, Paris Est, 2010. http://www.theses.fr/2010PEST0050.
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Le cancer de la prostate (CaP) est le cancer le plus fréquent chez l'homme et représente la deuxième cause de mortalité par cancer. Cette pathologie est sensible aux androgènes des stades localisés aux stades métastatiques. Après le traitement des formes avancés de ce cIl est admit aujourd'hui que les androgènes seuls ne sont pas suffisants pour déclencher le cancer de la prostate. En effet, le rôle des œstrogènes dans la carcinogenèse prostatique est suggéré par plusieurs études. L'activation de la voie de signalisation Hedgehog (Hh) joue un rôle important dans le développement de plusieurs cancers, y compris le CaP. Une meilleure compréhension des mécanismes qui régulent l'activation de cette voie dans le CaP est nécessaire afin de définir de nouvelles stratégies thérapeutiques plus efficaces.Dans ce travail, nous mettons en évidence l'interaction entre la voie Hh et les hormones stéroïdiennes dans les cellules prostatiques. Nous avons observé : i) une activation de la voie Hh par l'œstrogène (sulfate d'œstrone (SE1)), atténuée par l'anti-œstrogène (ICI) et par l'inhibiteur de la voie Hh (KAAD-cyclopamine), ii) une régulation négative de la voie Hh par l'androgène (dihydrotestostérone (DHT)) et l'œstrogène (17β-œstradiol (E2)). Nous avons démontré que l'inhibition de la voie Hh induite par DHT et E2 est dépendante des récepteurs des androgènes (RA). Cependant, l'effet de SE1 sur la voie Hh pourrait être dépendante des récepteurs des œstrogènes (ER). Enfin, nous avons observé une inhibition de l'activité des RA par KAAD-cyclopamine. Les dérivés de cyclopamine pourraient donc représenter une nouvelle classe d'agents thérapeutiques ciblant le RA dans le cancer de la prostate. Une meilleure caractérisation des cibles potentielles de ces molécules semble être intéressanteProstate cancer (PCa) is the most frequent male malignancy and the second most common cause of cancer-related death in men. This cancer is androgen sensitive in its development and progression to metastatic disease. Despite this, increasing evidence suggest that androgens alone are not able to induce PCa and estrogen signaling has a key role in prostate cancer progression. Hedgehog (Hh) pathway activation is important in the growth and development of various carcinomas including PCa. A better understanding of Hh pathway regulating mechanisms in PCa is important in order to identify new therapeutic strategies for this pathology. In this study we investigate the interaction between Hh pathway and steroid hormones in prostate cells. We showed: i) Hh pathway activation by the estrogen (estrone sulfate E1S), attenuated by the anti-estrogen (ICI) and by the Hh pathway inhibitor (KAAD-cyclopamine) ii) Hh pathway negative regulation by the androgen (dihydrotestostérone (DHT)) and the estrogen (17β-estradiol (E2)). Moreover, we showed that Hh pathway inhibition is androgen receptor (AR) dependent. However, E1S effect on this pathway might be estrogen receptor (ER) dependent. Finally, our results suggest that targeting AR signaling by cyclopamine derivatives could be promising therapeutic alternative in prostate cancer, which needs a further investigation
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Vingren, Jakob L. "Effect of Chronic Alcohol Abuse and Resistance Training on the Skeletal Muscle Androgen Receptor Concentration of Rats." Thesis, University of North Texas, 2004. https://digital.library.unt.edu/ark:/67531/metadc4540/.
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The purpose was to examine the effect of chronic alcohol abuse on the androgen receptor content (AR) in skeletal muscle, and to determine if this effect was influenced by resistance training. Thirty-four male rats (456 ± 1 g; mean ± SE) were divided into 4 groups: Sham exercise-Ethanol, Sham exercise-Normal diet, Exercise-Ethanol, and Exercise-Normal diet. Both Exercise groups underwent a 6-week "squat" resistance training protocol and both Ethanol groups received an alcohol-rich diet throughout the 6-week period. Western blot analysis showed no effect of alcohol or resistance training on the AR of the extensor digitorum longus. For the rectus femoris, alcohol caused a decline in the AR (p=0.01). This reduction was not attenuated by resistance training. The AR of the soleus was not affected by chronic alcohol abuse alone; however, the resistance training induced increase in the AR was prevented by chronic alcohol abuse (p=0.03).
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Gannon, Anne-Louise. "Determining the role of androgen receptor and glucocorticoid receptor in the rodent adrenal cortex through conditional gene targeting." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31072.
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Androgens are well documented as important regulators of male health, primarily in the maintenance and development of male sexual characteristics. However, a decline in circulating androgens has also been associated with co-morbidities such as obesity, cardiac disease and metabolic syndrome. Previous research has focussed upon the body wide impact of adrenal androgens, however whilst androgen receptor (AR) is abundantly expressed in the adrenal cortex of both rodents and humans, surprisingly little is known about androgen action on the adrenal cortex itself. This gap in our understanding is at least in part due to the perceived lack of suitable animal models. Rodents have largely been overlooked as a model system as their adrenals are unable to produce androgens due to lack of 17α Hydroxylase and 17, 20 lyse activity and they therefore do not have a zona reticularis. However, historical studies using castrated mice showed that removal of androgens leads to the redevelopment of an additional cortex zone known as the transient X-zone. The foetal adrenal is thought to give rise the adult adrenal cortex in human and rodents. These foetal cells are maintained for a period postnatally and regress differently depending on species and sex. In the human this zone is known as the ‘foetal zone’, and the rodent homologue termed the ‘X-zone’. The mechanisms underpinning the regression of the X-zone and its purpose and maintenance postnatally still aren’t clearly understood. To provide a comprehensive overview of androgen signalling in the adrenal cortex, multiple mouse models were utilised. First, Cre/loxP technology was used to ablate AR specifically from the adrenal cortex. Further androgen manipulation was achieved through castration (removal of androgens) and human chorionic gonadotropin (hCG) treatment (increased androgens). The initial study investigates the impacts on the male mouse adrenal. Histology analysis revealed the presence of an X-zone in all experimental cohorts following loss of AR or circulating androgens, confirmed by 20- α-hydroxysteroid dehydrogenase (20 alpha-HSD) expression. These data demonstrate that androgens signalling via AR is required for X-zone regression during puberty. However, interrogation of morphology of hCG treated cohorts revealed no phenotypic changes compared to controls, this demonstrates that hyper stimulation with androgens does not negatively impact the adrenal cortex or influence X-zone morphology. Differences in X-zone morphology and 20 alpha-HSD localization prompted cortex measurements which revealed significant differences in X-zone depth and cell density depending on ablation of AR, circulating androgens or both. This suggests that androgens and androgen receptor are working together and also independently to regulate the adrenal cortex. This result was strengthened through analysis of steroid enzyme genes and cortex markers, which revealed that normal AKR1B7 expression was absent following loss of androgens but not androgen receptor. A final part of this study examined the impacts long term androgen receptor ablation and long term castration in ageing animals. A final part of this study examined the impacts long term androgen receptor ablation and long term castration in ageing animals. These results demonstrate that following prolonged loss of androgens that there is no major disruption to the adrenal cortex. Morphology analysis and X-zone measurements revealed that X-zone regression was occurring in mice with long term castration, characterized by a reduction in size and pockets of vacuolization throughout the X-zone. This phenotype is also observed in ageing females with X-zone regression via vacuolization. These data suggest that following prolonged loss of androgens, the male adrenal is feminized and behaves as such. In contrast, AR ablation only, results in an enlarged adrenal with large spindle cell lesions and X-zone expansion confirmed by X-zone measurements. Initial experiments have demonstrated that androgens can work independently of AR to regulate the adrenal cortex. Together these data suggests that AR is required to control the appropriate action of circulating androgens in the adrenal cortex, with loss of AR resulting in off target signalling from circulating androgens in the adrenal leading to spindle cell hyperplasia, X-zone expansion and X-zone mislocation. A second set of studies were carried out to determine the role of androgen signalling in the female adrenal, specifically, if loss of AR leads to the absence of normal X-zone regression during pregnancy. To answer this question the same selective AR ablation model was used. Analysis of litters comparing observed and expected genetic distribution revealed significantly fewer females being born carrying complete ablation of adrenal AR. Morphology analysis of these mice revealed severe cortex disruption and spindle cell hyperplasia similar to that observed in mutant males. Investigation of adrenals following pregnancy revealed that X-zone regression still occurred despite loss of AR. This result shows that X-zone regression in the female is under different regulation compared to male adrenal and occurs via an androgen-independent signalling mechanism. However, loss of AR still leads to anatomical dysregulation of the adrenal cortex. AR ablation revealed changes in glucocorticoid receptor (GR) expression in the adrenal cortex. To dissect this relationship further a final study was conducted, attempting to ablate GR from the adrenal cortex also using the Cyp11a1 Cre. Initial observations of these mice revealed excessive hair loss through barbering, curved spines and stressed behaviour when monitored in the cage under normal conditions. Immunohistochemistry was used to confirm GR ablation in the adrenal cortex, however, to our surprise, GR expressing cells were not steroidogenic and thus were not targeted by the Cre recombinase. Despite no GR ablation in the adrenal, morphology analysis revealed severe disruption to the adrenal cortex. The Cyp11a1 Cre not only targets the adrenal but is expressed in the hindbrain. To determine if GR ablation in the hindbrain explains the phenotype, we next used PCR analysis interrogating hindbrain genomic DNA to determine if there was recombination of GR. Results confirmed GR recombination in the hindbrain. Due to the observation of stressed behaviour and adrenal cortex disruption, we wanted to determine if this was a result of hyperactivity of the adrenal cortex. Serum corticosterone was analysed and was elevated in these animals. These data revealed that GR ablation in the hindbrain results in adrenal cortex disruption and an elevated stress response, potentially highlighting a new model to investigate stress disorders and their impact on the hypothalamic-pituitary-adrenal axis. Together this data defines new roles for AR signalling in the adrenal cortex and the role of the hindbrain GR signalling in regulating adrenal morphology and function.
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Wainwright, Steven R. "Androgens and neuroplasticity : contributions to the pathogenesis and treatment of depression." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/55848.
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Depression is a devastating neuropsychiatric disease that has profound effects on neural structure and function, however the pathogenesis and modes of effective treatment remain poorly understood. Stress is the primary preceding factor in depression, leading to profound deficits in neurophysiology, particularly in the hippocampus. Depressed patients show reduced hippocampal neuroplasticity, while antidepressant treatment enhances both neurogenesis and the expression of proteins that mediate plasticity such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). Interestingly, men are half as likely as women to develop depression, where androgens appear to confer resiliency in males, as hypogonadal men are more likely to develop depression and supplementation of testosterone shows antidepressant efficacy. Little is known about the neurological underpinnings of this profound sex difference, however androgens influence the stress response and enhance hippocampal neurogenesis. The experiments in this thesis aimed to examine the role of androgens in the pathogenesis and treatment of depression using an animal model, with a specific eye toward the impact on hippocampal neurogenesis and neuroplasticity, and whether neuroplasticity mediated through PSA-NCAM is essential to antidepressant efficacy. In Chapter 2, surgically-induced hypogonadism potentiates the expression of depressive-like endophenotypes in male rodents within a chronic unpredictable stress (CUS) model of depression. Hypogonadal males showed potentiated behavioural, endocrine, and neurophysiological depressive-like phenotypes, including reductions in hippocampal neurogenesis and the expression of PSA-NCAM, compared to intact males. In Chapter 3, the hypogonadism-induced susceptibility to depressive-like phenotypes following CUS is largely inhibited by supplementation with testosterone. Testosterone treatment ameliorated physiological and endocrine phenotypes while showing independent antidepressant-like effects and facilitating the efficacy of an antidepressant drug in some measures. In Chapter 4, the enzymatic cleavage of the polysialic acid moiety from NCAM completely inhibits the behavioural efficacy of antidepressant treatment, while also serving to attenuate the survival of newly generated hippocampal neurons. Collectively, this body of research demonstrates the protective effects of androgens against the development of depression in males, coinciding with enhanced hippocampal neuroplasticity, and delineates an essential role for neuroplasticity mediated through PSA-NCAM in antidepressant action.Medicine, Faculty of
Graduate
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Galioto, Rebecca. "The effects of androgens on lymphocyte infiltration into the porcine endometrium." Connect to resource, 2007. http://hdl.handle.net/1811/28350.
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Thesis (Honors)--Ohio State University, 2007.Title from first page of PDF file. Document formatted into pages: contains 10 p.; also includes graphics. Includes bibliographical references (p. 10). Available online via Ohio State University's Knowledge Bank.
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Gonçalo, Aires de Oliveira. "Social modulation of androgens in humans : Psychological mechanisms and adaptative function." Doctoral thesis, ISPA - Instituto Universitário das Ciências Psicológicas, Sociais e da Vida, 2015. http://hdl.handle.net/10400.12/4319.
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Tese de Doutoramento apresentada ao ISPA - Instituto UniversitárioEsta tese procura clarificar os processos subjacentes às discrepâncias entre a direcção da resposta de androgénios à competição encontrada em estudos empíricos e as predicções das teorias para a modulação social de androgénios. Sugerimos que estes resultados imprevistos podem resultar de interacções com variáveis cognitivas e elegemos especificamente a avaliação cognitiva como um forte candidato a moderador da resposta de testosterona (T) aos desafios sociais. Várias experiências foram realizadas para testar esta hipótese. No Capítulo II e III, testou-se o efeito da familiaridade do oponente e da avaliação do resultado da competição como ameaça/desafio, na resposta de T a uma competição contra um membro do mesmo sexo. Nas mulheres foi encontrado um maior aumento dos níveis de T quando eram derrotadas por um oponente não familiar e quando o resultado era avaliado como ameaçador. Este efeito de moderação não foi detectado para os homens. Continuou-se a investigação sobre os efeitos da familiaridade do oponente e avaliação de ameaça no Capítulo IV, mas com um ciclídeo. Num paradigma de repetidas invasões territoriais por machos estranhos e familiares, encontrou-se uma maior resposta de androgénios no macho residente para as intrusões realizadas por um estranho, comparada com as de um macho familiar. O efeito do componente de expectativas da avaliação cognitiva, na resposta de T à competição em mulheres, foi testado através da manipulação das expectativas dos participantes em relação ao resultado da competição antes da tarefa competitiva (Capítulo V). Os vencedores inesperados baixaram os níveis de T depois da competição, mostrando uma inversão da resposta predicta pelos modelos teóricos. No Capítulo VI, testou-se o efeito directo das alterações afectivas nos níveis de T usando excertos de filmes emocionais. Um decréscimo significativo de T foi observado nos participantes da condição de tristeza, numa direcção congruente com as predicções da literatura. Finalmente, no Capítulo VII, abordou-se a função adaptiva das mudanças de androgénios induzidas pela competição proposta pelos modelos teóricos. Especificamente, testou-se o efeito do resultado da competição e dos níveis pós-competitivos de T na capacidade do individuo detectar faces emocionais ameaçadoras. Os nossos resultados sugerem que os vencedores foram mais rápidos e melhores a discriminar faces de raiva do que os perdedores. A discriminação de raiva foi também melhorada quando os níveis de T pós-competição eram elevados. No geral, estes resultados apoiam a hipótese de uma moderação cognitiva da resposta de T em mulheres. As implicações destes resultados para as teorias de modulação social de andrógenios são discutidas numa perspectiva comparada e integrativa.
ABSTRACT : This thesis aims to clarify the processes underlying the discrepancies between the direction of the androgen response to competition found in empirical studies and predictions of the theories for the social modulation of androgens. We suggest that these unpredicted results could result from interactions with cognitive variables and specifically select appraisal as a strong candidate to moderate the testosterone (T) response to social challenges. Several experiments were conducted to test this hypothesis. On Chapter II and III, we have tested the effect of opponent familiarity and the evaluation of the competition outcome as a threat/challenge on the T response to a competition with a member of the same sex. We have found that women show greater increases in T levels when they were defeated by an unfamiliar opponent and evaluated the outcome as threat. This moderation effect was not detected for men. We have continued the research on the effects of opponent familiarity and threat assessment on Chapter IV, but this time using a cichlid fish. In a paradigm of repeated territorial intrusions by stranger and familiar males, the resident male’s androgen response was higher for the intrusions performed by a stranger compared to those performed by a familiar male. The effect of the expectations component of appraisal on the T response to competition in women was tested by manipulating the expectations of the participants on the outcome of the competition before the competitive task (Chapter V). We have found that the unexpected winners decreased their T levels, showing a reversal of response predicted by the theoretical models. On Chapter VI, we have tested the direct effect of affective changes on T levels using emotional film clips. T significantly decreased for those participants assigned to the sadness condition, a direction that is congruent with predictions of the literature. Finally, on Chapter VII, we have addressed the adaptive function of the androgen changes elicited by the competition, as proposed by the theoretical models. Specifically, we have tested the effect of the competition outcome and post-competition T levels on the individual’s capacity to detect threatening emotional faces. Our findings suggest that winners were faster and better in discriminating angry faces than losers. Anger discrimination was also enhanced when post-competition T levels were high. Together these findings support the hypothesis of a cognitive moderation of the T response to competition in women. Results are discussed in terms of their implication to the theories for the social modulation of androgens in a comparative and integrative perspective.
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Huber, Dustin Michael. "ANDROGENS SUPPRESS OSTEOCLAST FORMATION INDUCED BY RANK LIGAND AND M-CSF." University of Cincinnati / OhioLINK, 2001. http://rave.ohiolink.edu/etdc/view?acc_num=ucin999020063.
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