No description available.

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 received 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. / Master of Science

No / BACKGROUND: Androgenetic alopecia, or male pattern baldness, is a common, progressive disorder where large, terminal scalp hairs are gradually replaced by smaller hairs in precise patterns until only tiny vellus hairs remain. This balding can cause a marked reduction in the quality of life. Although these changes are driven by androgens, most molecular mechanisms are unknown, limiting available treatments. The mesenchyme-derived dermal papilla at the base of the mainly epithelial hair follicle controls the type of hair produced and is probably the site through which androgens act on follicle cells by altering the regulatory paracrine factors produced by dermal papilla cells. During changes in hair size the relationship between the hair and dermal papilla size remains constant, with alterations in both dermal papilla volume and cell number. This suggests that alterations within the dermal papilla itself play a key role in altering hair size in response to androgens. Cultured dermal papilla cells offer a useful model system to investigate this as they promote new hair growth in vivo, retain characteristics in vitro which reflect their parent follicle's response to androgens in vivo and secrete mitogenic factors for dermal papilla cells and keratinocytes. OBJECTIVES: To investigate whether cultured dermal papilla cells from balding follicles secrete altered amounts/types of mitogenic factors for dermal papilla cells than those from larger, normal follicles. We also aimed to determine whether rodent cells would recognize mitogenic signals from human cells in vitro and whether factors produced by balding dermal papilla cells could alter the start of a new mouse hair cycle in vivo. METHODS: Dermal papilla cells were cultured from normal, balding and almost clinically normal areas of balding scalps and their ability to produce mitogenic factors compared using both human and rat whisker dermal papilla cells as in vitro targets and mouse hair growth in vivo. RESULTS: Normal scalp cells produced soluble factors which stimulated the growth of both human scalp and rat whisker dermal papilla cells in vitro, demonstrating dose-responsive mitogenic capability across species. Although balding cells stimulated some growth, this was much reduced and they also secreted inhibitory factor(s). Balding cell media also delayed new hair growth when injected into mice. CONCLUSIONS: Human balding dermal papilla cells secrete inhibitory factors which affect the growth of both human and rodent dermal papilla cells and factors which delay the onset of anagen in mice in vivo. These inhibitory factor(s) probably cause the formation of smaller dermal papillae and smaller hairs in male pattern baldness. Identification of such factor(s) could lead to novel therapeutic approaches.

L’hormone anti-Müllerienne (AMH), une glycopréotéine exclusivement produite par les cellules de la granulosa (CG) des follicules ovariens de la femme, est un marqueur unique de du statut folliculaire ovarien. Contrairement à l’inhibine B, l’estradiol et la FSH, l’AMH est produite par un large éventail de follicules allant des follicules primaires aux follicules à petit antrum. Cependant, les mécanismes précis régulant la production d’AMH par les CG restent mal connus. Nous avons montré que la sélection folliculaire précoce au cours de la phase de transition lutéo-folliculaire, un phénomène fréquemment retrouvé chez les femmes ayant un vieillissement ovarien, caractérisé par la présence d’au moins un follicule surdéveloppé au cours de la phase folliculaire précoce, n’altérait pas la puissance de la relation entre le compte folliculaire antral et les concentrations sériques d’AMH. En revanche, cette situation perturbait significativement celle entre le nombre de follicules antraux et les taux sériques de FSH, d’inhibine B et d’estradiol. Nous avons par la suite mis en évidence, en utilisant un nouvel outil, nommé Follicular Output RaTe (FORT), que le pourcentage de follicules qui répondent effectivement à la FSH exogène en atteignant la maturation pré-ovulatoire, était négativement et indépendamment lié aux taux sériques d’AMH, ce qui va dans le sens de l’hypothèse d’un effet inhibiteur de l’AMH sur la sensibilité des follicules à la FSH. Ensuite, nous avons regardé si la production d’AMH par ovaire et par follicule était altérée chez les femmes n’ayant plus qu’un seul ovaire suite à une ovariecomie unilatérale. En effet, tout indique que chez ces femmes, des réarrangements majeurs de la folliculogenèse sont mis en place pour maintenir une fonction ovarienne malgré la perte brutale d’une partie du pool folliculaire. Ainsi, par une analyse extensive et comparative de la folliculogenèse utilisant des marqueurs hormono-folliculiares, nous n’avons pu mettre aucune modification significative chez les femmes avec un ovaire unique, comparativement aux contrôles. A l’aide du modèle précédemment utilisé, nous avons constaté une augmentation de la sensibilité des follicules antraux à la FSH exogène, évaluée par le FORT, chez des femmes avec un seul ovaire, comparativement aux femmes avec 2 ovaires. Ces résultats supportent l’hypothèse d’une augmentation de la sensibilité folliculaire à la FSH, qui pourrait faire partie des possibles mécanismes compensatoires en jeu dans le maintien d’une folliculogenèse efficace chez les femmes ayant eu une ovariectomie unilatérale.Finalement, à l’aide de 2 approches complémentaires, in vitro and in vivo, nous avons montré que la FSH et l’AMPc stimulaient la transcription de l’AMH, et que la LH avait un effet additif. Nous avons montré que les gonadotrophines et l’AMPc agissaient à travers la protéine kinase A et la P38 MAP Kinase, impliquant notamment les facteurs de transcription GATA binding factor-4 et le steroidogenic factor-1. Par ailleurs, nous avons également mis en évidence que l’expression d’AMH pouvait être régulée de manière différentielle par l’estradiol, en fonction du type de récepteur aux estrogènes exprimés par les CG. Ainsi, la chute d’expression de l’AMH au sein des CG des follicules matures, qui expriment essentiellement ERβ, est probablement liée à un effet de l’estradiol. En résumé, ces travaux de thèse ont permis d’apporter de nouvelles données sur la régulation de la croissance folliculaire et sur la production d’AMH chez la femme. / Anti-Müllerian hormone (AMH), a glycoprotein that is exclusively produced by the granulosa cells (GC) of ovarian follicles in the adult female, is a unique biomarker of ovarian follicular status. In contrast with inhibin B, estradiol and FSH, AMH is produced in a wide range of follicles that goes from the primary to the small antral stages of folliculogenesis. However, the precise mechanisms that drive AMH expression by GC remain poorly understood.We showed that untimely and/or accelerated antral follicle growth during the luteal–follicular transition, a phenomenon that is frequent in ovarian-aged women and that is characterized by the presence of at least one overdeveloped antral follicle during the first days of the follicular phase does not alter the strength of the relationship between antral follicle count and serum AMH levels but does affect the relationship between serum FSH, inhibin B and estradiol levels and the number of antral follicles. The heftiness of AMH in relation to advanced antral follicle growth provides a further explanation for the reported stronger association between serum AMH levels and antral follicle counts as compared with the other hormonal markers of the ovarian fertility status. We subsequently demonstrated, using an innovative tool, the Follicular Output RaTe (FORT), that the percentage of follicles that effectively respond to exogenous FSH by reaching pre-ovulatory maturation is negatively and independently related to serum AMH levels, which is in keeping with the hypothesis that AMH inhibits follicle sensitivity to FSH. Given this hypothesis, we wondered if per-ovary and per-follicle AMH production could be altered in patients having a single ovary as a result of unilateral oophorectomy. Indeed, all indicate that major rearrangements of folliculogenesis occur to preserve and maintain ovarian function despite the abrupt halving of follicular stockpile in these patients. We performed an extensive and comparative evaluation of the folliculogenesis using homono-follicular markers failing to show major changes in unilaterally oophorectomized when compared with control women. Using the same model, we demonstrated an increased antral follicle responsiveness to exogenous FSH, as assessed by FORT, in normo-ovulating unilaterally oophorectomized women undergoing controlled ovarian hyperstimulation. These results support the hypothesis that increased FSH sensitivity ranks among the possible compensating mechanisms at stake in the maintenance of successful folliculogenesis after unilateral oophorectomy.Finally, using complementary approaches, in vitro and in vivo, we showed that FSH and cAMP enhance AMH transcription, and LH has an additive effect. Gonadotropins and cAMP act through protein kinase A and p38 MAPK signaling pathways and involve the GATA binding factor-4 and steroidogenic factor-1 transcription factors, among others. The expression profile of AMH and the dynamics of serum AMH after gonadotropin stimulation have been interpreted as a down-regulating effect of FSH upon AMH production by GC. We also demonstrated that AMH expression can be differentially regulated by estradiol depending on the estradiol receptors by GC. Therefore the decrease in AMH expression by GC of mature follicles, which mainly express ERβ, is likely due to the effect of estradiol.In short, this Ph.D. work offers new insight into the regulation of the follicular growth and AMH production in woman.

Androgens are critical for the development and maintenance of adult male characteristics such as muscle mass and sexual function. Consequently, the established decline with age of serum testosterone (T) in males has major health implications. While the androgen receptor (AR) is the major mediator of genomic androgen action and is required for the development of the male phenotype, reproductive organs and the maintenance of male secondary sexual characteristics, it is the entrance of androgens into the cell that mediates the activation of the AR and the subsequent modulation of expression of androgen regulated genes. Testosterone, biologically the most important androgen in male serum, circulates either free, loosely bound to albumin or tightly bound to sex hormone binding globulin (SHBG). Each of these forms of serum T have different abilities to enter cells, and which proportion of serum T is capable of entering cells and initiating the androgen signalling cascade, thereby leading to the activation of the AR has not been precisely defined. The AR amino terminal domain (NTD) is responsible for the majority of the ability of the AR to activate genes but the relative roles of the two activation functions in the AR NTD (activation functions 1 and 5; AF1 and 5) have not been precisely defined while the role of the AF2 surface which forms in the ligand binding domain upon agonist binding is responsible for interactions with key coregulators and also with the NTD in the amino-carboxyl (N/C) interaction. Our laboratory has recently identified a region within AF5 between amino acids 500-535 to which somatic mutations in castrate resistant prostate tumour samples collocate. Due to the lack of functional information on the AF5 region and the NTD in general, the function of this region and the functional consequences of the mutations remain to be defined. The objectives of this thesis were to develop a specific mammalian cell based bioassay capable of reliable measuring T in serum and to determine the ability of this bioassay to measure a physiologically relevant fraction of T in serum. Additionally, this thesis aimed to determine the relative contributions and roles of the activation functions of the AR to overall AR transcriptional activity along with the functional consequences for AR signalling of prostate cancer mutations which have previously been identified in the AF5 region of the AR NTD. The mammalian-cell based bioassay developed in this thesis is capable of sensitively and reliably measuring serum T. However, evaluation of this bioassay utilising approximately 1000 serum samples from the Florey Adelaide Male Aging Study reveals that this bioassay measures a fraction of T in serum that most closely relates to serum T. Furthermore, this measure does not correlate more strongly with grip strength, sexual function or waist circumference than the existing immunoassay-based measures of serum T, highlighting the limitations of utilising a static mammalian cell-based androgen bioassay to measure physiological levels of serum T in males. The investigation of the roles of the activation functions in the AR in this thesis have revealed that while the AF1 domain is responsible for the majority of the transactivation activity of the AR, AF5 and AF2 govern the sensitivity and cellular response of the AR to androgens by providing protein and interdomain interaction interfaces. Furthermore, the evidence in this thesis demonstrates that the AR requires interdomain communication for sensitive AR signalling. Finally, the findings in this thesis demonstrate that the AF5 surface is required for the N/C interaction and coregulator interactions while advanced prostate cancer mutations identified within this region confer increased transactivation activity of the AR in the presence of high cellular levels of coregulators. Collectively, the findings in this thesis provide several novel insights into the mechanism of action of serum androgens and challenges several long held assumptions of androgenic action in males. These findings also delineate a mechanism of treatment failure in advanced prostate cancer, provide a novel model for the events leading to sensitive AR transactivation and contribute to the understanding of physiologically relevant levels of serum T. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2008

Magister Scientiae (Medical Bioscience) - MSc(MBS) / Endocrine disrupting compounds (EDCs) are exogenous compounds/chemicals in the environment that interfere with the synthesis, secretion, distribution and function or elimination of natural hormones in the body. Environmental estrogens are a subclass of EDCs that may mimic or inhibit the effect of endogenous estrogen and can therefore influence developmental and reproductive health in humans and animals. EDCs have been reported to adversely affect the reproductive, immune, endocrine and nervous systems of wildlife and humans. The effects of EDCs include gonadal abnormalities, altered male/female sex ratios, reduced fertility and cancers of the male and female reproductive tract to mention a few. These effects are difficult to detect. Although it is essential to screen for EDCs in aqueous environmental samples, most countries have failed to implement this as part of their routine water quality monitoring programs due to various constraints such as the high cost of assays and the lack of infrastructure and skills required to do the assays. Therefore, there is a clear need for more user-friendly, more economically viable and time saving assays that can be used for routine monitoring of environmental EDCs. The aim of this study was to investigate the comparison between chemical and tissue culture methods to monitor environmental estrogens. 28 environmental water samples were collected from various sites around South Africa and analyzed for EDCs using a battery of rapid in vitro tests. Samples collected for the current study were selected based on various human impacts and also to give approximately 50% high and 50% low estrogen values. The 28 environmental water samples were separated into two groups based on the estradiol ELISA. The estradiol ELISA was chosen because estradiol is the principal estrogen found in all mammalian species during their reproductive years. For this separation, an estradiol level of 5 pg/ml was used as cut-off. Of the 28 samples investigated, 15 had estradiol levels higher than 5 pg/ml and were designated as high estradiol. The remaining 13 samples contained estradiol at 5 pg/ml or less and they were designated as low estradiol The first objective of this study was to compare different rapid ELISAs for EDC monitoring to determine if the data obtained with these assays are similar/identical. The data obtained from the estrogenic ELISAs was related/similar and showed good correlation with each other. This is because the different estrogens are very similar and also due to the fact that the same sub-group in the population (the reproductively active females) is secreting these hormones. Therefore, an estradiol rapid assay was proposed as a first screening system for estrogens in samples. Even though there was a positive correlation between the estradiol rapid assay and testosterone rapid assay, separation of samples based on estradiol levels wasn’t a good predictor of testosterone levels in the samples. A testosterone rapid assay was therefore recommended as necessary to screen for androgens in samples. The positive correlation between the estradiol rapid assay and progesterone rapid assay was expected because both estradiol and progesterone are secreted and excreted by the same population sub-group (reproductively active females). This study also demonstrated a good predictability of separating samples containing progesterone using the estradiol ELISA. Progesterone is secreted by pregnant women, a sub-group of the reproductively active females. It is advised that a progesterone rapid assay be included to screen samples for progestogens The second objective of this study was to compare estradiol rapid ELISAs with a bioassay for anti-androgenicity using mouse testicular cell cultures. The mouse testicular cell testosterone synthesis bioassay to monitor anti-androgenicity of the samples showed no correlation between the ELISA data for estrogens. This study shows that anti-androgenic effects need to be monitored independently because the data for estrogenic compounds cannot be used as a predictor for anti-androgenic effects. This demonstrated the need for the inclusion of a mouse testicular cell testosterone synthesis bioassay to screen for androgenicity and anti-androgenicity of water samples. In summary, due to the different mechanisms of action of EDCs, this study recommended a battery of assays to monitor for EDCs. The battery of assays suggested is: v progesterone rapid assay was expected because both estradiol and progesterone are secreted and excreted by the same population sub-group (reproductively active females). This study also demonstrated a good predictability of separating samples containing progesterone using the estradiol ELISA. Progesterone is secreted by pregnant women, a sub-group of the reproductively active females. It is advised that a progesterone rapid assay be included to screen samples for progestogens. The second objective of this study was to compare estradiol rapid ELISAs with a bioassay for anti-androgenicity using mouse testicular cell cultures. The mouse testicular cell testosterone synthesis bioassay to monitor anti-androgenicity of the samples showed no correlation between the ELISA data for estrogens. This study shows that anti-androgenic effects need to be monitored independently because the data for estrogenic compounds cannot be used as a predictor for anti-androgenic effects. This demonstrated the need for the inclusion of a mouse testicular cell testosterone synthesis bioassay to screen for androgenicity and anti-androgenicity of water samples. In summary, due to the different mechanisms of action of EDCs, this study recommended a battery of assays to monitor for EDCs. The battery of assays suggested is: Estradiol ELISA as a rapid assay to screen for estrogens. Testosterone ELISA as a rapid assay to screen for androgens. Progesterone ELISA as a rapid assay to screen for progestogens. Mouse testicular cell testosterone synthesis bioassay to screen for androgenicity and anti-androgenicity.

Master of Science / Department of Human Nutrition / Brian Lindshield / 5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) convert testosterone into the more potent androgen, dihydrotestosterone (DHT), that is responsible for regulating prostate growth and proliferation. 5αR2 is the main isoenzyme in normal prostate tissue, however prostate tumors have increased 5αR1 and decreased or unchanged 5αR2 expression. Previously, finasteride (5αR2 inhibitor) treatment begun 3 weeks after tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 activity to produce dihydrotestosterone to stimulate its growth. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, while dutasteride (dual 5αR1 & 5αR2 inhibitor) treatment would decrease tumor growth regardless if treatment is begun before or after tumor implantation. Sixty, 8-week old male nude mice were randomized to Control, Pre-Finasteride, Post-Finasteride, Pre-Dutasteride and Post-Dutasteride diet groups (all diets contained 83.3 mg drug/kg diet). Pre groups began their treatment diets 1-2 weeks prior to tumor implantation, while post groups began their treatment diets 3 weeks after tumor implantation. Tumors were implanted by subcutaneous injection of 1 x 10⁵ WPE1-NA22 human prostate cancer cells in Matrigel™ and allowed to grow for 22 weeks. Tumor areas, body weights, and feed intakes were measured weekly. At study conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control. Dutasteride intake also significantly reduced seminal vesicle weights compared to finasteride intake. There were no significant differences in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells, and its parent line RWPE-1 prostate epithelial cells, were unaltered by treatment with testosterone, DHT, or the synthetic androgen mibolerone, suggesting that these cell lines are not androgen-sensitive. Thus, the lack of response to androgen treatment by WPE1-NA22 prostate cancer cells may explain the inadequate tumor growth observed.

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 intéressante. / Prostate 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.

Hormônios como a testosterona, a desidroepiandrosterona (DHEA), o cortisol e o hormônio do crescimento (GH) e fatores de crescimento, como o fator de crescimento semelhante à insulina (IGF-1), são agudamente liberados no sangue logo após sessões de exercício de força (EF). Esses hormônios e fatores de crescimento estão relacionados com a modulação de processos fisiológicos na célula muscular esquelética. Mais recentemente, pesquisadores evidenciaram a presença de enzimas esteroidogênicas, responsáveis por metabolizar o colesterol em diferentes hormônios esteroides, no interior da célula muscular. Isso possibilitaria às células musculares regularem a concentração hormonal intramuscular. Essa modulação intramuscular pode ser capaz de afetar diferentes processos fisiológicos nessas células, como a atividade das células satélites (CS). Contudo, o papel da modulação da concentração hormonal sérica induzida pelo EF em regular as concentrações intracelular de hormônios nas células musculares, regulando a atividade das CS ainda não é bem conhecido em humanos. Para investigar esse fenômeno, indivíduos treinados em força foram submetidos a duas diferentes sessões de EF com o objetivo de modular diferentemente as respostas hormonais séricas entre elas. Uma sessão (HH) que elevaria expressivamente as concentrações agudas séricas da testosterona total e livre, do DHEA, do cortisol, do GH, e do IGF-1, enquanto outra sessão não induziria elevações expressivas desses hormônios (LH). Indivíduos treinados foram escolhidos por apresentarem menor impacto de sessões de exercício de força na modulação de processos fisiológicos nas células musculares por serem mais acostumados às mesmas. Isso favorece relacionar os processos da modulação hormonal sistêmica e local com a possível regulação da atividade das CSs. As sessões de EF foram efetivas em modular agudamente as concentrações séricas da testosterona total, DHEA, GH e cortisol. Contudo, apenas o Cortisol foi elevado mais para sessão HH comparado com a sessão LH. Consequentemente, apenas o cortisol teve sua concentração diferentemente alterada nas células musculares, estando mais aumentado também após a sessão HH. A ausência de elevação na célula muscular de hormônios androgênicos foi suportada pela ausência de mudança na expressão gênica das enzimas esteroidogênicas como a 5&#945; redutase e a 17&#946; Hidroxiesteróide Desidrogenase. Interessantemente, a expressão gênica da miostatina e da miogenina aumentaram aproximadamente nove e quatro vezes, respectivamente, 72 horas após as sessões de EF. Por fim, possivelmente afetados pelos níveis de cortisol elevado na célula muscular, que pode ter favorecido um expressivo aumento de expressão gênica da miostatina, a quantidade de CS e consequentemente de mionúcleos não sofreram nenhum efeito das sessões de EF. Essa ausência de modulação da quantidade de CS ocorreu mesmo com o aumento da expressão da miogenina que poderia ter favorecido um processo de diferenciação das CS. Assim, é possível sugerir que quando o hormônio é elevado agudamente no sangue de forma expressiva como o cortisol, o mesmo afetará sua concentração na célula muscular. Esse aumento da concentração hormonal no músculo pode regular a atividade das CS, já que não foi observada a esperada mudança na quantidade de CS nas células musculares após as sessões de EF / Hormones such as testosterone, dehydroepiandrosterone (DHEA), cortisol and growth hormone (GH), as well as growth factors such as insulin-like growth factor (IGF-1) are acutely released into the blood after resistance exercise (RE). These hormones are related to the regulation of physiological processes in skeletal muscle cells. Recently, researchers have shown the presence of steroidogenic enzymes, responsible for metabolizing cholesterol in different steroid hormones, inside the muscle cell. This metabolization would enable muscle cells to regulate intramuscular hormone concentration. This intramuscular modulation may affect different physiological processes in these cells, such as satellite cell activity (SC). However, the role of acute RT-induced changes in serum hormone concentrations in regulating intracellular hormonal concentrations in muscle cells and, consequently, activity of SC is yet unknown in humans. To investigate this phenomenon, resistance-trained individuals underwent two different RE sessions to differently modulate serum hormonal responses. One session (HH) should significantly elevate serum concentrations of total and free testosterone, DHEA, cortisol, GH, and IGF-1, while the other session should not induce expressive elevations in these hormones (LH). Trained individuals were chosen because muscle cells are less impacted by RE as these individuals are more accustomed to RE. This design allows relating systemic and local hormonal modulation with possible modulations on SC activity. RE sessions were effective in acutely modulating the serum concentration of total testosterone, DHEA, GH, and cortisol. However, only cortisol was significantly raised for HH compared to LH. Consequently, only cortisol had its concentration differently modulated in muscle cells, being higher also after the HH session. The lack of elevations in muscle cell androgenic hormones was supported by the absence of changes in the steroidogenic enzymes gene expression such as 5&#945; reductase and 17&#946; Hydroxysteroid Dehydrogenase. Interestingly, myostatin and myogenin gene expression increased approximately nine and four times, respectively, 72 hours after the RE sessions. Finally, high cortisol levels in the muscle cell may have favored an expressive increase in myostatin gene expression, did not induce the expected changes in SC activity. This lack of modulation in the amount of SC and myionuclear content occurred regardless of the increase in myogenin expression, which could have favored the SC differentiation. Therefore, it is possible to suggest that when systemic hormones are expressively elevated like cortisol, there is a parallel increase in hormonal concentration in the muscle cell. The increase in muscle cell hormone concentration may have regulated the SC activity based as we did not observe the expected changes in the SC content after the RE sessions

Made available in DSpace on 2016-08-10T10:38:30Z (GMT). No. of bitstreams: 1 Caroline Oliveira Araujo Melo.pdf: 9819543 bytes, checksum: 9c73c3b07e3a86d2b7a6f185fa67e197 (MD5) Previous issue date: 2010-01-11 / The androgen is a generic term usually applied to describe a group of sex steroid hormones. Androgens are produced primarily by a male's testes. However, some small amounts are also produced by the ovaries in females and by the adrenal gland, in both sexes. Androgens are responsible for the male sex differentiation during embryogenesis at the 6th or 7th week of gestation , triggering the development of the testes and penis in male fetuses and is directed by the testicular determining factor, the gene SRY (sex determining region on Y chromosome), located on the short arm of chromosome Y. The differentiation of male external genitalia in penis, scrotum and penile urethra occurs between the 9th and 13th weeks of pregnancy and requires adequate concentration of testosterone and converting this to another more potent androgen dihydrotestosterone (DHT), through the action of 5&#945; reductase in target tissues. The actions of testosterone and DHT require the presence of functional androgen receptors, which, after the connection with these hormones, activate the transcription of specific genes in target tissues. The AR gene is a protein coding gene located at Xq11.2-q12. It spans over 90 kb and codes for a protein that functions as a steroid-hormone activated transcription factor. The AR, like other members of the nuclear receptor superfamily, has three major functional domains: the AR is characterized by a modular structure consisting of four functional domains: an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region, and a ligand (androgen-) binding domain (LBD). Mutations in the AR gene cause the X-linked Androgen Insensitivity Syndrome (AIS) characterized by androgen unresponsiveness, which affects the proper male sexual development both at embryogenesis and puberty. As a genetic disorder, AIS presents a problem and a burden to the affected people and their families and a major medical challenge for the health providers. This impaired response to androgen results from the incapacity or reduced capacity of the androgen receptor (AR) to transactivate androgen-responsive genes in target cells, and leads to abnormal differentiation and development of male internal and external genitalia, and thus leading to male pseudohermaphroditism. / Andrógeno é um termo genérico geralmente utilizado para descrever um grupo de hormônios esteroides sexuais. Os andrógenos são produzidos no homem primariamente pelos testículos. No entanto, algumas pequenas quantidades são também produzidas pelos ovários nas mulheres e pelas glândulas adrenais, em ambos os sexos. Os andrógenos são responsáveis pela diferenciação sexual masculina durante a embriogênese na 6ª ou 7ª semana de gestação, desencadeando o desenvolvimento dos testículos e pênis em fetos masculinos e é dirigido pelo fator determinante testicular, o gene SRY (região determinante do sexo no cromossomo Y), localizado no braço curto do cromossomo Y. A diferenciação da genitália externa masculina em pênis, escroto e uretra peniana ocorre entre a 9ª e 13ª semana de gravidez e requer concentração adequada de testosterona e a conversão para um outro andrógeno mais potente, a dihidrotestosterona (DHT), através da ação da 5 &#945;- redutase em tecidos alvos. As ações da testosterona e DHT requerem a presença dos receptores androgênicos funcionais. O gene AR é uma proteína codificada para o gene localizado no Xq11.2-q12. Ele abrange mais de 90 kb e codifica pra a proteína que funciona como um hormônio esteroide que ativa o fator de transcrição. O AR, como outros membros da superfamília de receptores nucleares, tem três domínios principais: o AR é caracterizado por uma estrutura modular consistindo de quatro domínios funcionais: o domínio N-terminal (NTD), um domínio de ligação ao DNA (DBD), a região de dobradiça, e um domínio de ligação ao ligante (LBD). Mutações no gene AR causam a Síndrome de Insensibilidade aos Andrógens ligada ao cromossomo X (AIS) caracterizada pela insensibilidade androgênica, que afeta o desenvolvimento sexual adequado tanto na embriogênese quanto na puberdade. Como uma desordem genética, o AIS apresenta um problema e um fardo para as pessoas afetadas e suas famílias e um grande desafio médico para os provedores de saúde. Essa resposta prejudicada aos andrógenos resulta na incapacidade ou redução da capacidade do receptor de andrógeno (AR) de transativar os genes responsivos aos andrógenos em células alvo, e leva à diferenciação e desenvolvimento anormais da genitália masculina interna e externa, e assim, levando ao pseudohermafroditismo masculino.