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No. of bitstreams: 1 GleidsonBO_TESE.pdf: 11466529 bytes, checksum: bbaaa583c7710c45dac218fe4cb14279 (MD5) Previous issue date: 2016-09-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / The morphological knowledge and data about the composition of glycosaminoglycans (GAGs) in the female reproductive system and placental of agouti are essential to the understanding of reproductive events. In addition to these, the knowledge of embryonic and fetal development in the specie, provides as the basis for application of ultrasound examination and reproductive biotech, contributing directly to conservation of the specie and commercial exploitation. Therefore, the objective describe the anatomohistological characteristics of the reproductive tract of agoutis females, as well as identify the profile of glycosaminoglycans in reproductive organs and placenta during the pregnancy. Were utilized agoutis 25 adult females at different stages of the estrous cycle and pregnancy, obtained in Centre of Multiplication of Wild Animals of the Universidade Federal Rural do Semi-Árido. After eutanasiados, abdominal and pelvic cavities were opened, the reproductive organs and fetuses when gifts were photographed in situ and ex situ and analysed to morphometric. Each body fragments were fixed in 4% paraformaldehyde solution and 2.5% glutaraldehyde and submitted to histological technique of light and scanning electron microscopy. Fragments of organs were also placed in acetone to remove the lipids and then the sample subjected to agarose gel electrophoresis. Blades for light microscopy, were stained with hematoxylin-eosin, Gomori stain, Alcian-Mallory and Periodic Acid Schiff (PAS). It was observed that he ovary of the Dasyprocta leporina is coated by simple cubic to squamous epithelium that rests on the tunica albuginea, showing a cortical and medular zone. The uterine tube is organized in three layers, a mucous membrane (simple ciliated columnar epithelium), the lamina propria (loose connective) and serosa. The villus height and muscle layer thickness varying between the areas of infundibulum, isthmus and ampulla. In pregnancy this organ has profile variable, with predominance of dermatan sulfate (DS) and heparan sulfate (HS) in early gestation and DS and chondrotin sulfate (CS) in the middle and final thirds with sharp reduction at term. The uterus is classified as partial double, consisting of two horns and a cervix with two distinct ostia that communicate with the body and a single ostium that opens into the vagina. The uterine horn presented throughout pregnancy a predominance of CS and DS, with small amount of HS. The vagina has three layers, the outer adventitia (connective tissue), muscular and mucous membrane composed of epithelium that varies from little pavimentoso storied without keratinization (luteal phase) the storied pavimentoso keratinized and cornified (follicular phase) enough frilled and with leukocytes cells. In the vagina, the main GAG found was the DS, with small concentration of HS analyzed throughout of the pregnancy. The vulva is located between the anus (dorsal) and the ostium and the vestibule urethral absent in the species. The clitoris is external to vagina, in which in its peak protrude sideways two spicules corneas and the urethra centered, in the absence of a common part between the urinary and genital tracts. Embryos at 30 days after copulation had form of "C" with limb buds paddle-shaped, Crown-Rump (CR) of 10.75 ± 0.11 mm and weight of 0.17 ± 0.03 g; 40 days the skin was smooth and transparent and liver boss and curvature of reduced body, CR 19.5 ± 0,007 mm and weight 1.34 ± 0.01 g; after 65 days, the genital tubercle was already differentiated and CR was 83 ± 0.08 mm and weight of 29.22 ± 0.46 g; 85 days, presence of stubble throughout the body, eyes partly open, CR of 127.7 ±0.6 mm and weight of 96.56 ± 7.37 g; 100 days, mature fetus with long hair and the whole body, fully formed tooth and nail and open auditory meatus, CR was 164.3 ± 10.4 mm and weight of 166.5 ± 7.79 g; the infants had the open eyes and bristling at birth, with CR 179.1 ± 0.5 and weight of 201.88 ± 1.89 g. Concluded that the profile and concentration of GAGs varies as to the organ and gestation period and that the age of the embryo/fetus can be evaluated during pregnancy, allowing to estimate gestational age and the data can be used as parameters to ultrasound examinations, helping in the identification of diseases throughout development / O conhecimento morfológico e os dados sobre a composição dos glicosaminoglicanos (GAGs) no sistema reprodutor feminino e tecido placentário de cutia são essenciais para a compreensão dos eventos reprodutivos. Soma-se a estes, o conhecimento sobre o desenvolvimento embrionário/fetal na espécie, que serve como base para aplicação do exame ultrassonográfico e biotécnicas reprodutivas, contribuindo diretamente para conservação da espécie e exploração comercial. Portanto, objetivou-se descrever as características anatomohistológicas do sistema reprodutor de cutias fêmeas, bem como identificar o perfil dos GAGs presentes nos órgãos reprodutivos e placenta ao longo da gestação. Para tanto, foram utilizadas 25 cutias, adultas em diferentes fases do ciclo estral e gestação, obtidas no Centro de Multiplicação de Animais Silvestres da Universidade Federal Rural do Semi-Árido (CEMAS/UFERSA). Após eutanasiados, as cavidades abdominal e pélvica foram abertas, os órgãos do sistema reprodutor e fetos quando presentes foram fotografados in situ e ex situ e realizado a análise morfométrica. Fragmentos de cada órgão foram fixados em solução de paraformaldeído 4% e glutaraldeído 2,5% e destinados à microscopia de luz e eletrônica de varredura. Fragmentos dos órgãos também foram colocados em acetona para realização do processo de delipidação e em seguida a amostra submetida à eletroforese em gel de agarose. Observou-se que o ovário da cutia é revestido por epitélio simples cúbico a pavimentoso que repousa sobre a túnica albugínea, evidenciando-se uma zona cortical e uma medular. A tuba uterina está organizada em três camadas, uma mucosa (epitélio colunar simples, ciliado e viloso), uma lâmina própria (conjuntivo frouxo) e uma camada serosa, estando o tamanho das vilosidades e a espessura da camada muscular variando entre as áreas de infundíbulo, ampola e istmo. Na gestação, este órgão teve perfil variável, com predomínio de DS e HS no início da gestação e DS e CS nos terços médio e final e redução acentuada a termo. O útero é classificado como duplo parcial, formado por dois cornos e uma cérvix com dois óstios distintos que se comunicam com o corpo e um único óstio que se abre na vagina. O corno uterino apresentou ao longo da gestação uma predominância de CS e DS, com pequena quantidade de HS. A vagina possui três camadas, adventícia externa (tecido conjuntivo), muscular e a mucosa composta por epitélio que varia de pavimentoso pouco estratificado sem queratinização (fase lútea) a estratificado pavimentoso queratinizado e cornificado (fase folicular) bastante pregueado e com presença de células leucocitárias. Na vagina, o principal GAG encontrado foi o DS, com pequena concentração de HS analisados ao longo da gestação. A vulva localiza-se entre o ânus (dorsal) e o óstio uretral, estando o vestíbulo ausente na espécie. O clitóris encontra-se externo a vagina, no qual em seu ápice projetam-se lateralmente duas espículas córneas e uma uretra centralizada, não existindo uma parte comum entre os tratos urinário e genital. Os embriões aos 30 dias pós cópula possuíam forma de “C”, com brotos dos membros em forma de remo, Crown-Rump de 10,75 ± 0,11 mm e peso de 0,17 ± 0,03; aos 40 dias a pele foi lisa e transparente e saliência hepática e curvatura do corpo reduzidas, CR de 19,5 ± 0,007 mm e peso 1,34 ± 0,01 g; aos 65 dias, o tubérculo genital já estava diferenciado e CR observado foi de 83 ± 0,08 mm e peso de 29,22 ± 0,46 g; aos 85 dias, presença de pelos curtos distribuídos pelo corpo, olhos parcialmente abertos, CR de 127,7 ± 0,6 mm e peso de 96,56 ± 7,37 g; aos 100 dias, feto maduro com pêlos longos e em todo o corpo, unhas e dentes completamente formados e conduto auditivo aberto, CR foi de 164,3 ± 10,4 mm e peso de 166,5 ± 7,79 g; os neonatos apresentaram pêlos eriçados e olhos abertos ao nascer, com CR de 179,1 ± 0,5 e peso de 201,88 ± 1,89 g. Conclui-se que o perfil e a concentração dos GAGs varia quanto ao órgão e período de gestação e que a idade do embrião/feto pode ser avaliada durante gestação, permitindo estimar idades gestacionais, e os dados podendo ser usados como parâmetros para exames ultrassonográficos, ajudando na identificação de patologias ao longo do desenvolvimento / 2017-04-25

Made available in DSpace on 2016-06-02T19:22:53Z (GMT). No. of bitstreams: 1 3146.pdf: 7150693 bytes, checksum: cd6c8d53b2bd8f45e723e67ca13309e2 (MD5) Previous issue date: 2010-03-12 / Financiadora de Estudos e Projetos / Tendons remodeling relies upon extracellular matrix restructuring by the matrix metalloproteinases (MMPs). The aim of this study was to investigate MMP-2 activity in different regions of the calcanear tendon after resistance training in ovariectomized rats. Wistar adult female rats were grouped into: sedentary (Sed-Intact); ovariectomized sedentary (Sed-Ovx); acute exercise (AcuteEx-Intact); ovariectomized acute exercise (AcuteEx-Ovx); resistance trained (ChronicEx-Intact) and ovariectomized resistance trained (ChronicEx-Ovx) (n= 10 each group). The resistance training protocol required the animals to climb a 1.1-m vertical ladder with weights attached to their tail was used. The sessions were performed once every 3 days with 4-9 climbs and 8-12 dynamic movements per scaling. The acute groups performed one session, and the chronic groups underwent a 12-week of resistance training. There was an increase in total MMP-2 activity in Sed- Ovx, AcuteEx-intact and ChronicExintact compared with Sed-Intact in the proximal region of calcanear tendon. AcuteEx-Ovx exhibited higher total MMP-2 than Sed-Ovx and AcuteEx-Intact in the distal region of calcanear tendon. Chronic-Ovx presented lower total MMP-2 activity than Sed-Ovx and Chronic-Intact in the distal region of tendon. The active MMP-2 was higher for the AcuteEx- Ovx than Sed-Ovx and AcuteEx-Intact in proximal region of tendon. There was higher active MMP-2 in the distal region of tendon in the Acute-Ovx than Sed-Ovx and AcuteEx-Intact. Ovariectomy and resistance exercise modulate MMP-2 activity according to specific tendon region, indicating a differentiated tissue remodeling. / O remodelamento dos tendões depende da re-estruturação da matriz extracelular realizada pelas metaloproteinases de matriz (MMPs). O objetivo deste estudo foi investigar a atividade da MMP-2 em diferentes regiões do tendão calcâneo de ratas após ovariectomia e treinamento resistido. Ratas adultas Wistar foram agrupadas em: sedentário (Sed-Intacto); sedentário ovariectomizado (Sed-Ovx); exercício agudo (AgudoEx-Intacto); exercício agudo e ovariectomizado (AgudoEx-Ovx); treinado resistido (CrônicoEx-Intacto) e ovariectomizado treinado resistido (CrônicoEx-Ovx) (n= 10 por grupo). O protocolo de treinamento resistido exigiu a escalada dos animais em uma escada vertical de 1.1 metros com pesos atados a suas caudas. A sessão foi realizada uma vez a cada três dias de 4 a 9 escaladas com 8 a 12 movimentos dinâmicos em cada escalada. Cada sessão de treinamento consistia de no mínimo quatro escalas, com 50%, 75%, 90% e 100% da capacidade máxima de carregamento do animal, determinada anteriormente. Durante as escaladas subseqüentes (máximo de cinco escaladas) eram adicionados 30g até que uma nova capacidade máxima de carregamento fosse atingida. Os grupos agudos realizaram apenas uma sessão e os animais dos grupos crônicos foram submetidos a 12 semanas de treinamento resistido. Foi observado na região proximal do tendão calcâneo aumento da atividade total da MMP-2 no Sed-Ovx, AgudoEx-Intacto, CrônicoEx-Intacto comparados com o Sed-Intacto (p≤0,05). Na região distal do tendão calcâneo, o AgudoEx-Ovx exibiu maior atividade da MMP-2 total do que Sed-Ovx e AgudoEx-Intacto (p≤0,05). O CrônicoEx-Ovx apresentou na região distal do tendão calcâneo menor atividade total da MMP-2 em relação ao Sed-Ovx e CrônicoEx-Intacto (p≤0,05). O AgudoEx-Ovx apresentou na região proximal e distal do tendão calcâneo maiores valores na forma ativa da MMP-2 comparado ao Sed-Ovx e AgudoEx-Intacto (p≤0,05). Ovariectomia e treinamento resistido modulam a atividade da MMP-2 de acordo com a região específica do tendão calcâneo.

Orientador: José de Anchieta de Castro e Horta Júnior / Resumo: O reflexo auditivo de sobressalto (ASR) é uma contração rápida e intensa da musculatura estriada esquelética da face e do corpo frente a um estímulo sonoro inesperado e de alta intensidade. O ASR pode ser modificado em diversas condições, como na inibição por estímulo prévio (PPI), que se caracteriza pela diminuição da amplitude do ASR quando o estímulo sonoro de alta intensidade é precedido por um estímulo de menor intensidade. As respostas de ASR e PPI são avaliadas de forma não invasiva no homem e em roedores com grande homologia e têm sido utilizadas na pesquisa básica e clínica. Além disso, se encontram alteradas em diversas afecções neurológicas e psiquiátricas que apresentam déficits no processamento sensório-motor. No homem, existem diferenças na PPI relacionadas ao gênero, que refletem as variações hormonais ao longo do ciclo menstrual. Entretanto, estudos em roedores se mostram conflitantes em relação às diferenças no ASR e na PPI entre machos e fêmeas, raramente mencionando as possíveis variações ao longo do ciclo estral, o que dificulta a interpretação de resultados experimentais em fêmeas e a sua translação para os resultados obtidos no homem. Para avaliar a influência do gênero e das fases do ciclo estral no ASR, foram estudados 10 machos e 28 fêmeas de ratos Wistar adultos. O ciclo estral das fêmeas foi acompanhado diariamente e todos os animais foram submetidos a sessões de avaliação do ASR e PPI. Nas fêmeas, as concentrações plasmáticas de estr... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: The acoustic startle reflex (ASR) is a fast and intense motor reaction that promotes skeletal striated muscles contraction of face and body, in response to an unexpected and high-intensity sound stimulus. The ASR has many modulations such as prepulse inhibition (PPI) which is characterized by reduced amplitude of ASR when the triggering sound stimulus is preceded by a lower-intensity stimulus. The ASR and PPI responses can be measured non-invasively in humans and rodents with high homology and have been used for basic and clinical research. Additionally, they are disrupted in many neurological and psychiatric conditions that show deficits in sensorimotor processing. In humans, it is known that there are gender-related differences in PPI, which reflect hormonal changes that occur during the menstrual cycle. However, studies in rodents are conflicting regarding the differences in ASR and PPI between males and females, rarely mentioning the possible variations during the estrous cycle. This fact makes it difficult to interpret experimental results in females and their translation to results obtained in humans. To assess the influence of gender and estrous cycle in ASR, 10 males and 28 females adult Wistar rats were studied. Females’ estrous cycle was monitored daily and all animals were subjected to sessions of ASR and PPI evaluation. In females, estradiol and progesterone plasmatic concentrations were determinated. The brains of 3 males and 3 females in each phas... (Complete abstract click electronic access below) / Mestre

Fluctuating ovarian hormones have been shown to affect decision-making processes in women. While emerging evidence suggests effects of endogenous ovarian hormones such as estradiol and progesterone on value-based decision-making in women, the impact of exogenous synthetic hormones, as in most oral contraceptives, is not clear. In a between-subjects design, we assessed measures of value-based decision-making in three groups of women aged 18 to 29 years, during (1) active oral contraceptive intake (N = 22), (2) the early follicular phase of the natural menstrual cycle (N = 20), and (3) the periovulatory phase of the natural menstrual cycle (N = 20). Estradiol, progesterone, testosterone, and sex-hormone binding globulin levels were assessed in all groups via blood samples. We used a test battery which measured different facets of value-based decision-making: delay discounting, risk-aversion, risk-seeking, and loss aversion. While hormonal levels did show the expected patterns for the three groups, there were no differences in value-based decision-making parameters. Consequently, Bayes factors showed conclusive evidence in support of the null hypothesis. We conclude that women on oral contraceptives show no differences in value-based decision-making compared to the early follicular and periovulatory natural menstrual cycle phases.

No description available.

Contrairement à d’autres groupes animaux, chez les primates, la hiérarchie de dominance ne détermine pas systématiquement le succès reproductif des mâles. Afin de comprendre pourquoi, j’ai étudié les stratégies de reproduction des mâles et des femelles dans un groupe de macaques rhésus de la population semi-libre de Cayo Santiago (Porto Rico), collectant des données comportementales, hormonales et génétiques pendant deux saisons de reproduction. Les résultats se résument en cinq points. 1. Les nouveaux mâles qui ont immigré dans le groupe d’étude occupaient tous les rangs les plus subordonnés de la hiérarchie de dominance et ont monté en rang suite au départ de mâles plus dominants. Ainsi, l’acquisition d’un rang supérieur s’est faite passivement, en absence de conflits. Par conséquent, les mâles dominants étaient généralement d’âge mature et avaient résidé plus longtemps dans le groupe que les mâles subordonnés. 2. L’accès des mâles aux femelles est en accord avec le « modèle de la priorité d’accès » selon lequel le nombre de femelles simultanément en œstrus détermine le rang de dominance du mâle le plus subordonné qui peut avoir accès à une femelle (p. ex. le mâle de rang 4 s’il y a quatre femelles en œstrus). Bien que les mâles dominants aient eu plus de partenaires et aient monopolisé les femelles de qualité supérieure (dominance, parité, âge) pendant leur période ovulatoire (identifiée grâce au profil hormonal de la progestérone), le rang de dominance n’a pas déterminé le succès reproductif, les mâles intermédiaires ayant engendré significativement plus de rejetons que prédit. Il est possible que ces jeunes adultes aient produit un éjaculat de meilleure qualité que les mâles dominants d’âge mature, leur donnant un avantage au niveau de la compétition spermatique. 3. Les mâles dominants préféraient les femelles dominantes, mais cette préférence n’était pas réciproque, ces femelles coopérant plutôt avec les mâles intermédiaires, plus jeunes et moins familiers (c.-à-d. courte durée de résidence). Au contraire, les femelles subordonnées ont coopéré avec les mâles dominants. La préférence des femelles pour les mâles non familiers pourrait être liée à l’attrait pour un nouveau bagage génétique. 4. L’intensité de la couleur de la peau du visage des femelles pendant le cycle ovarien était corrélée au moment de la phase ovulatoire, une information susceptible d’être utilisée par les mâles pour maximiser leur probabilité de fécondation. 5. Les femelles retiraient des bénéfices directs de leurs liaisons sexuelles. En effet, les femelles en liaison sexuelle bénéficiaient d’un niveau de tolérance plus élevé de la part de leur partenaire mâle lorsqu’elles étaient à proximité d’une source de nourriture défendable, comparativement aux autres femelles. En somme, bien que les mâles dominants aient bénéficié d’une priorité d’accès aux femelles fertiles, cela s’est avéré insuffisant pour leur garantir la fécondation de ces femelles parce que celles-ci avaient plusieurs partenaires sexuels. Il semble que l’âge et la durée de résidence des mâles, corrélats de leur mode d’acquisition du rang, aient confondu l’effet du rang de dominance. / In contrast to most animal groups, dominance hierarchy does not systematically determine male reproductive success in primates. In order to investigate why, I studied male and female reproductive strategies in a group of free-ranging rhesus macaques on Cayo Santiago, Puerto Rico. I collected behavioural, genetic, and hormonal data during two consecutive mating seasons. My results are summarized below. 1. All new males who immigrated into the study group occupied the lowest-ranking position in the dominance hierarchy and rose in rank as the higher-ranking males left the group. Achieving a higher dominance rank occurred passively, without physical conflict. Thus, dominant males were mature individuals who resided longest in the group. 2. Male access to oestrus females followed the predictions of the ‘priority of access’ model, in which the number of females in oestrus determines the rank of the lowest-ranking male who can access a female (e.g. the fourth ranking male if four females are in oestrus). Even though dominant males obtained more mating partners and monopolised higher quality females (dominance, parity, age) during the ovulation window (as identified using progesterone profiles), dominance rank did not determine reproductive success, as intermediate-ranking males sired significantly more infants than predicted. It is likely that those young, intermediate-ranking adult males produced high quality ejaculate, giving them an advantage in sperm competition. 3. Dominant males preferred high-ranking females, but this preference was not reciprocal; high-ranking females cooperated with younger and less familiar intermediate-ranking males. Conversely, subordinate females cooperated with dominant males. Female preference for non-familiar males (i.e. short residency in the group) may be explained by an attraction to a novel genetic pool. 4. Female facial color intensity during the ovarian cycle was correlated with the timing of the ovulation window. This information may be used by males in order to maximize their fertilisation probability. 5. Consort females enjoyed a higher level of tolerance from their male partner when they were in proximity to a monopolisable food source, compared to other, non-consort females. This suggests that females obtained direct benefits from their sexual consorts. In conclusion, even though dominant males had priority access to ovulating females in the group, this was insufficient to guarantee fertilisation when females had several sexual partners. It appears that males’ age and length of residency, both correlates of their rank acquisition mode, may have been confounding factors in dominance rank.

Contrairement à d’autres groupes animaux, chez les primates, la hiérarchie de dominance ne détermine pas systématiquement le succès reproductif des mâles. Afin de comprendre pourquoi, j’ai étudié les stratégies de reproduction des mâles et des femelles dans un groupe de macaques rhésus de la population semi-libre de Cayo Santiago (Porto Rico), collectant des données comportementales, hormonales et génétiques pendant deux saisons de reproduction. Les résultats se résument en cinq points. 1. Les nouveaux mâles qui ont immigré dans le groupe d’étude occupaient tous les rangs les plus subordonnés de la hiérarchie de dominance et ont monté en rang suite au départ de mâles plus dominants. Ainsi, l’acquisition d’un rang supérieur s’est faite passivement, en absence de conflits. Par conséquent, les mâles dominants étaient généralement d’âge mature et avaient résidé plus longtemps dans le groupe que les mâles subordonnés. 2. L’accès des mâles aux femelles est en accord avec le « modèle de la priorité d’accès » selon lequel le nombre de femelles simultanément en œstrus détermine le rang de dominance du mâle le plus subordonné qui peut avoir accès à une femelle (p. ex. le mâle de rang 4 s’il y a quatre femelles en œstrus). Bien que les mâles dominants aient eu plus de partenaires et aient monopolisé les femelles de qualité supérieure (dominance, parité, âge) pendant leur période ovulatoire (identifiée grâce au profil hormonal de la progestérone), le rang de dominance n’a pas déterminé le succès reproductif, les mâles intermédiaires ayant engendré significativement plus de rejetons que prédit. Il est possible que ces jeunes adultes aient produit un éjaculat de meilleure qualité que les mâles dominants d’âge mature, leur donnant un avantage au niveau de la compétition spermatique. 3. Les mâles dominants préféraient les femelles dominantes, mais cette préférence n’était pas réciproque, ces femelles coopérant plutôt avec les mâles intermédiaires, plus jeunes et moins familiers (c.-à-d. courte durée de résidence). Au contraire, les femelles subordonnées ont coopéré avec les mâles dominants. La préférence des femelles pour les mâles non familiers pourrait être liée à l’attrait pour un nouveau bagage génétique. 4. L’intensité de la couleur de la peau du visage des femelles pendant le cycle ovarien était corrélée au moment de la phase ovulatoire, une information susceptible d’être utilisée par les mâles pour maximiser leur probabilité de fécondation. 5. Les femelles retiraient des bénéfices directs de leurs liaisons sexuelles. En effet, les femelles en liaison sexuelle bénéficiaient d’un niveau de tolérance plus élevé de la part de leur partenaire mâle lorsqu’elles étaient à proximité d’une source de nourriture défendable, comparativement aux autres femelles. En somme, bien que les mâles dominants aient bénéficié d’une priorité d’accès aux femelles fertiles, cela s’est avéré insuffisant pour leur garantir la fécondation de ces femelles parce que celles-ci avaient plusieurs partenaires sexuels. Il semble que l’âge et la durée de résidence des mâles, corrélats de leur mode d’acquisition du rang, aient confondu l’effet du rang de dominance. / In contrast to most animal groups, dominance hierarchy does not systematically determine male reproductive success in primates. In order to investigate why, I studied male and female reproductive strategies in a group of free-ranging rhesus macaques on Cayo Santiago, Puerto Rico. I collected behavioural, genetic, and hormonal data during two consecutive mating seasons. My results are summarized below. 1. All new males who immigrated into the study group occupied the lowest-ranking position in the dominance hierarchy and rose in rank as the higher-ranking males left the group. Achieving a higher dominance rank occurred passively, without physical conflict. Thus, dominant males were mature individuals who resided longest in the group. 2. Male access to oestrus females followed the predictions of the ‘priority of access’ model, in which the number of females in oestrus determines the rank of the lowest-ranking male who can access a female (e.g. the fourth ranking male if four females are in oestrus). Even though dominant males obtained more mating partners and monopolised higher quality females (dominance, parity, age) during the ovulation window (as identified using progesterone profiles), dominance rank did not determine reproductive success, as intermediate-ranking males sired significantly more infants than predicted. It is likely that those young, intermediate-ranking adult males produced high quality ejaculate, giving them an advantage in sperm competition. 3. Dominant males preferred high-ranking females, but this preference was not reciprocal; high-ranking females cooperated with younger and less familiar intermediate-ranking males. Conversely, subordinate females cooperated with dominant males. Female preference for non-familiar males (i.e. short residency in the group) may be explained by an attraction to a novel genetic pool. 4. Female facial color intensity during the ovarian cycle was correlated with the timing of the ovulation window. This information may be used by males in order to maximize their fertilisation probability. 5. Consort females enjoyed a higher level of tolerance from their male partner when they were in proximity to a monopolisable food source, compared to other, non-consort females. This suggests that females obtained direct benefits from their sexual consorts. In conclusion, even though dominant males had priority access to ovulating females in the group, this was insufficient to guarantee fertilisation when females had several sexual partners. It appears that males’ age and length of residency, both correlates of their rank acquisition mode, may have been confounding factors in dominance rank.

The control of reproductive cycles in higher primates is largely dependent on negative and positive feedback mechanisms by both steroidal and non-steroidal substances of the ovaries which regulate the function of hypothalamo-pituitary system. To gain insights into the role of INH A, the non steroidal ovarian hormone in the feedback control of pituitary FSH secretion, studies were conducted to examine the interrelationships of hormones throughout the menstrual cycle of the bonnet macaque. The findings of chapter II provide a detailed description of endocrine hormone profile during the menstrual cycle of the bonnet macaques with special attention to the feedback role of INH A on pituitary FSH secretion. To characterize the endocrine profile of different hormones, both ovarian (E2, P4, INH A) and pituitary (FSH, LH) hormones were measured daily for more than 40 days. To further examine the site of secretion of INH A and its relationship with pituitary FSH dynamics, surgical lutectomy and pharmacological induction of luteolysis employing the third generation GnRH R antagonist, Cetrorelix (CET) studies were carried out in the subsequent experiments. The results obtained from these studies suggest that INH A and P4 secreted from the CL during luteal phase regulate pituitary FSH secretion. The selective rise in FSH observed during the late menstrual cycle and during menstruation (referred to as luteo-follicular transition), as has been reported previously in higher primates, considered necessary for initiation of follicular growth and recruitment of follicles for ensuing menstrual cycle was characterized in the monkey. Surgical lutectomy and induction of luteolysis by CET experiments suggested that increased GnRH secretion is essential for this selective rise in FSH following withdrawal of inhibition by P4 and INH A. In clinical cases of reproductive ageing, the shortened follicular phase in human females has been identified to be the result of occurrence of early onset of FSH rise during the luteal-follicular transition period. The cause(s) of declining fertility with age in women who still have regular menstrual cycles are not clear, but issues of relationship between dysregulation of selective FSH rise in the late luteal phase and associated infertility could be examined using bonnet monkey as a model system. INH A is secreted in significant quantities by CL in higher primates and the feto placental unit suggesting its importance during fertility and pregnancy. Apart from the negative feedback regulation of pituitary FSH secretion, the complete repertoire of actions of this hormone during pregnancy is yet to be fully understood. The data presented in this thesis is the first comprehensive report showing the endocrine hormone profile of gonadotropins and ovarian hormones including INH A throughout the menstrual cycle of the bonnet macaque. The characterization of INH A profile in bonnet monkey will be of significant value for studies examining the role of INH A in higher primates. Dimeric inhibin has been suggested to be important for regulation of fertility and reproductive functions. Also, inhibin-α (one of the subunits of the dimeric protein) knock out mice model has provided convincing evidence that it acts as a tumour suppressor. A great deal of new information has been generated in recent years regarding the potential clinical usefulness of monitoring inhibin levels in blood and biological fluids in gynaecological diseases, pathological pregnancies and other disorders. Emerging clinical roles of inhibin have made INH A an important candidate molecule to study its molecular regulation. The results presented in chapter II suggested that LH regulates luteal INH A secretion (induction of luteolysis by CET administration experiment). As a first step towards understanding molecular regulation of inhibin-α expression in the macaque CL, in silico promoter analysis of macaque inhibin-α was performed and it revealed several transcriptional factor binding sites that were conserved across species. In rats FSH up regulates while preovulatory LH surge suppresses inhibin-α mRNA expression in the ovary and this suppression has been suggested to be necessary for occurrence of secondary FSH surge during metestrus. To address differential regulation of inhibin-α by LH and FSH in rat ovary during the periovulatory period, studies employing immature rats were carried out and the results are presented in chapter III. The results suggest that immature rat ovaries respond to exogenous gonadotropins in terms of LH signaling (cAMP production), luteinization (P4 production) and as well induction of ICER expression required for repression of inhibin-α subunit expression. PDE4 inhibitor (rolipram) treatment enhanced the ovarian cAMP concentrations suggesting that PDE4 play a major role in controlling intraovarian cAMP concentrations in rat ovaries. However increased cAMP concentrations did not appear to up regulate the ICER expression at the time point examined in this study. In higher primates time course of second FSH surge and continued synthesis and secretion of INH A in the CL are different from non primate species. In the monkey, the second FSH rise occurs during the late luteal phase and experiments have been carried out to examine the regulation of inhibin-α subunit expression by ICER. Expressions of ICER (mRNA/protein) and INH A were examined during different stages of CL and the results indicated no clear inverse relationship between the ICER and inhibin-α mRNAs. With no conclusive role for the ICER in regulating luteal inhibin-α observed in the study, the role of transcriptional activators in the regulation of inhibin-α like GATA4, SF-1, β-catenin were further examined. Since luteal INH A secretion was dependent on pituitary LH as determined earlier in chapter II, expressions of transcriptional activators were examined in CL of different stages and also during induced luteolysis and the results are described in chapter IV. In conclusion, our results indicate cross talk between WNT, cAMP and P38 MAP kinase signaling pathways in the regulation of luteal INH A secretion. The pituitary gonadotropin, LH, is the primary luteotropin in primate species acting to maintain the structure and function of the CL during the menstrual cycle. However whether the actions of LH are direct or mediated by local factors such as P4 remain unknown. Moreover, P4 secretion which is dominant during luteal phase has any role in regulating CL structure and function is not clearly defined. To address these and issues concerning P4 actions, initially, experiments were performed in the rat model to study the importance of P4 in the regulation of ovarian functions. An antiprogestin, RU486, was employed as a tool to uncover the PR regulated pathways during ovulation in rats and the findings are presented in the chapter V. The results indicated that blockade of PR action by RU486 during gonadotropin-induced superovulation resulted in inhibition of follicular rupture and ovulation in immature rats. Further to understand the downstream effectors of PR action, and to identify the candidate target genes of PR activation, semi-quantitative RT-PCR and western blot analyses were performed. The results obtained indicated that betacellulin, a member of EGF family and MMP-9 a proteolytic enzyme, were markedly repressed in response to RU486 treatment in rat ovaries. Also, the down stream pathway of EGF signaling leading to activation of ERK was markedly repressed in RU486 treated ovaries. It was next examined what role the P4/PR system has in the regulation of CL structure and function. Surprisingly, PR expression is absent in CL of rats, while it is present in higher primates. Experiments were carried out to examine intracrine actions of P4 in the regulation of CL structure and function in monkeys. The recently reported model system of induced luteolysis yet capable of responsive to trophic support from the laboratory provided an ideal opportunity to examine direct effects of P4 on structure and function of CL in the monkey. A series of pilot experiments were carried out in monkeys experiencing summer amenorrhea, to determine dose and mode of administration of exogeneous P4 to simulate mid luteal phase circulating P4 concentrations in monkeys subjected to induced luteolysis. Based on the results of pilot experiments, implantation of Alzet pumps containing 97.5mg of P4 was selected for maintaining mid luteal phase P4 concentrations. The microarray data of induced luteolysis previously deposited by the laboratory in NGBI’s gene expression omnibus were mined for identification and validation of differentially expressed genes of PR and its target genes following LH depletion and LH replacement experiments. Expressions of PR, PR cofactors and expressions of PR downstream target genes through out the luteal phase and in CL from day1 of menses were also examined. Analysis of expressions of genes revealed that of the 45 genes identified to be regulated by LH treatment, 4 genes were found to be responsive to P4, and 14 were identified to be responsive to both P4 and LH. Morphology of CL tissue sections revealed that P4 treatment appeared to have reversed the induced-luteolysis changes. In another experiment, implantation of P4 during late luteal phase (i.e., the period of declining P4 concentrations) for 24h caused changes in expressions of genes associated with tissue remodeling and morphology of luteal cells. Taken together, the results suggest that induced luteolysis plus P4 replacement model is suitable for assessing the effects of P4 on CL function. The results also suggest that CL could serve as target tissue for examining the genomic and non genomic actions of P4. In summary, studies carried out in the present thesis provides a comprehensive endocrine hormone profile throughout the menstrual cycle of the bonnet monkey with special emphasis on time course of INH A and FSH secretion which is very useful for future investigations. Studies have been carried out in rats and monkeys with different experimental model systems to address molecular mechanisms underlying inhibin-α regulation in the ovary in general and CL in particular. Experimental findings in monkeys could help elucidate the underlying molecular nature of CL functionality and extrapolate to understand luteal insufficiency and infertility producing conditions in humans. Also different model systems have been validated to examine the actions of P4/PR system in rats and monkeys and more importantly to address the direct effects of P4 upon monkey CL structure and function were established. Future investigations based on findings of these studies should help clarify relative roles for LH and P4 during maintenance of CL function and luteolysis.

Germ-line mutations in the breast cancer susceptibility gene BRCA1 strongly increase the risk of developing breast and ovarian cancer in women. Different hypothesis have been proposed to explain this tissue specificity. One of the most argued hypothesis is the one that proposes a link between BRCA1 and ovarian hormones' action. Much data have been published in the last years pointing to an important role of progesterone receptor (PR) in inducing normal mammary development and also breast cancer formation. This study aimed to search for a functional relationship between BRCA1 and PR in breast cancer cells. We have found that BRCA1 inhibits the transcriptional activity of PR. We have investigated in more detail the mechanism of this effect. BRCA1 and PR interact in vivo in a ligand-independent fashion. Most importantly, BRCA1 alters the ligand-independent and dependent degradation of PR protein through its ubiquitination and this might have a direct effect on the level of PR recruitment on regulated promoters. BRCA1 is recruited to the hormone-responsive regions of PR-target genes and affects the presence of histone deacetylase activity and the level of monoubiquitinated histone H2A, linking BRCA1 action with chromatin status. These findings support a connection between BRCA1, the principal tumour suppressor responsible for familial breast cancer, and the progesterone receptor transcriptional activity. This relationship can be hypothesized to be reflected in the BRCA1-related breast tumourigenesis. / Mutaciones germinales en el gen breast cancer susceptibility gene BRCA1 aumentan altamente el riesgo de padecer cáncer de mama y ovario en mujeres. Se han propuesto diferentes hipótesis para explicar esta especificidad de tejido. Una de las hipótesis más argumentadas es la que propone una relación entre BRCA1 y la acción de las hormonas ováricas. En los últimos años se han publicado numerosos datos señalando al papel esencial del receptor de progesterona (PR) en la inducción del desarrollo normal de la mama y en la formación del cáncer de mama. Este estudio pretendía buscar una relación funcional entre BRCA1 y PR en células de cáncer de mama. Hemos demostrado que BRCA1 inhibe la actividad transcripcional de PR. Hemos investigado en más detalle el mecanismo de este efecto. BRCA1 y PR interaccionan in vivo de una manera independiente de ligando. Y lo que es más, BRCA1 altera la degradación independiente y dependiente de ligando de PR a través de su ubiquitinización y esto podría tener un efecto directo en el nivel de reclutamiento de PR en promotores regulados. BRCA1 es reclutado a las regiones de respuesta a hormona de genes diana de PR y afecta la presencia de actividad histona desacetilasa y el nivel de histona H2A monoubiquitinada, estableciendo un enlace entre la acción de BRCA1 y el estado de la cromatina. Estos hallazgos apoyan una conexión entre BRCA1, el principal supresor de tumor responsable del cáncer de mama hereditario, y la actividad transcripcional del receptor de progesterona. Se puede hipotetizar que esta relación se ve reflejada en el proceso de tumorigénesis BRCA1-dependiente.

L’accumulation de triglycérides (TG) dans les hépatocytes est caractéristique de la stéatose hépatique non-alcoolique (SHNA). Cette dernière se produit dans diverses conditions dont le facteur commun est le métabolisme anormal des lipides. Le processus conduisant à l'accumulation des lipides dans le foie n’a pas encore été totalement élucidé. Toutefois, des lipides s'accumulent dans le foie lorsque les mécanismes qui favorisent leur exportation (oxydation et sécrétion) sont insuffisants par rapport aux mécanismes qui favorisent leur importation ou leur biosynthèse. De nos jours il est admis que la carence en œstrogènes est associée au développement de la stéatose hépatique. Bien que les résultats des études récentes révèlent l'implication des hormones ovariennes dans l'accumulation de lipides dans le foie, les mécanismes qui sous-tendent ce phénomène doivent encore être étudiés. En conséquence, les trois études présentées dans cette thèse ont été menées sur des rates ovariectomizées (Ovx), comme modèle animal de femmes post-ménopausées, pour étudier les effets du retrait des œstrogènes sur le métabolisme des lipides dans le foie, en considérant l'entraînement physique comme étant un élément positif pouvant contrecarrer ces effets. Il a été démontré que l'entraînement physique peut réduire l'accumulation de graisses dans le foie chez les rates Ovx. Dans la première étude, nous avons montré que chez les rates Ovx nourries à la diète riche en lipides (HF), les contenus de TG hépatiques étaient élevées (P < 0.01) comparativement aux rates Sham, 5 semaines après la chirurgie. Le changement de la diète HF par la diète standard (SD) chez les rates Sham a diminué l’accumulation de lipides dans le foie. Toutefois, chez les rates Ovx, 8 semaines après le changement de la HF par la SD le niveau de TG dans le foie était maintenu aussi élevé que chez les rates nourries continuellement avec la diète HF. Lorsque les TG hépatiques mesurés à la 13e semaine ont été comparés aux valeurs correspondant au retrait initial de la diète HF effectué à la 5e semaine, les niveaux de TG hépatiques chez les animaux Ovx ont été maintenus, indépendamment du changement du régime alimentaire; tandis que chez les rats Sham le passage à la SD a réduit (P < 0.05) les TG dans le foie. Les mêmes comparaisons avec la concentration des TG plasmatiques ont révélé une relation inverse. Ces résultats suggèrent que la résorption des lipides au foie est contrée par l'absence des œstrogènes. Dans cette continuité, nous avons utilisé une approche physiologique dans notre seconde étude pour investiguer la façon dont la carence en œstrogènes entraîne l’accumulation de graisses dans le foie, en nous focalisant sur la voie de l'exportation des lipides du foie. Les résultats de cette étude ont révélé que le retrait des œstrogènes a entraîné une augmentation (P < 0.01) de l’accumulation de lipides dans le foie en concomitance avec la baisse (P < 0.01) de production de VLDL-TG et une réduction l'ARNm et de la teneur en protéines microsomales de transfert des triglycérides (MTP). Tous ces effets ont été corrigés par la supplémentation en œstrogènes chez les rates Ovx. En outre, l'entraînement physique chez les rates Ovx a entraîné une réduction (P < 0.01) de l’accumulation de lipides dans le foie ainsi qu’une diminution (P < 0.01) de production de VLDL-TG accompagnée de celle de l'expression des gènes MTP et DGAT-2 (diacylglycérol acyltransférase-2). Des études récentes suggèrent que le peptide natriurétique auriculaire (ANP) devrait être au centre des intérêts des recherches sur les métabolismes énergétiques et lipidiques. Le ANP est relâché dans le plasma par les cellules cardiaques lorsque stimulée par l’oxytocine et exerce ses fonctions en se liant à son récepteur, le guanylyl cyclase-A (GC-A). En conséquence, dans la troisième étude, nous avons étudié les effets du blocage du système ocytocine-peptide natriurétique auriculaire (OT-ANP) en utilisant un antagoniste de l’ocytocine (OTA), sur l'expression des gènes guanylyl cyclase-A et certains marqueurs de l’inflammation dans le foie de rates Ovx. Nous avons observé une diminution (P < 0.05) de l’ARNm de la GC-A chez les rates Ovx et Sham sédentaires traitées avec l’OTA, tandis qu’une augmentation (P < 0.05) de l'expression de l’ARNm de la protéine C-réactive (CRP) hépatique a été notée chez ces animaux. L’exercice physique n'a apporté aucun changement sur l'expression hépatique de ces gènes que ce soit chez les rates Ovx ou Sham traitées avec l’OTA. En résumé, pour expliquer l’observation selon laquelle l’accumulation et la résorption de lipides dans le foie dépendent des mécanismes associés à des niveaux d’œstrogènes, nos résultats suggèrent que la diminution de production de VLDL-TG induite par une déficience en œstrogènes, pourrait être un des mecanismes responsables de l’accumulation de lipides dans le foie. L’exercice physique quant à lui diminue l'infiltration de lipides dans le foie ainsi que la production de VLDL-TG indépendamment des niveaux d'œstrogènes. En outre, l'expression des récepteurs de l’ANP a diminué par l'OTA chez les rates Ovx et Sham suggérant une action indirecte de l’ocytocine (OT) au niveau du foie indépendamment de la présence ou non des estrogènes. L’axe ocytocine-peptide natriurétique auriculaire, dans des conditions physiologiques normales, protègerait le foie contre l'inflammation à travers la modulation de l’expression de la GC-A. / Excessive accumulation of triglycerides (TGs) in hepatocytes is the characteristic of non-alcoholic hepatic steatosis (NAHS). NAHS occurs in various conditions in which abnormal fat metabolism is a common factor. The primary processes leading to lipid accumulation in the liver are not well understood. However, lipid in the form of TG accumulates within liver cells when mechanisms that promote their removal (by oxidation or secretion) cannot keep pace with mechanisms that promote lipid import or biosynthesis. Today, it is well accepted that estrogen deficiency is associated with the development of a state of hepatic steatosis. Although recent findings indicated the implication of ovarian hormones in liver lipid accumulation, mechanisms underlying this phenomenon need to be further investigated. Therefore, the three studies presented in this thesis have been conducted in ovariectomized (Ovx) rats, as animal model of post-menopausal women, to investigate the effects of estrogen withdrawal on liver fat metabolism and considering the effects of exercise training as a positive counteractive factor. It has been shown that exercise training can reduce liver fat accumulation in Ovx rats. In the first study, we showed that in high fat (HF) fed animals, liver TG content was higher (P < 0.01) in Ovx compared to Sham rats as soon as 5-week after the surgery. Switching from the HF to a standard (SD) diet resulted in a decrease in liver fat accumulation in Sham animals. However, 8 weeks after the diet switch, liver fat accumulation was as high in Ovx rats as those maintained on the HF diet. When liver TG content measured at week 13 was compared to initial pre-switching values (week 5), liver TG levels in Ovx animals were maintained at the same level independently of the diet switch, while in Sham rats switching to a SD diet reduced liver TG accumulation (P < 0.05). The same comparisons with plasma TG levels revealed an opposite relationship. These results may be taken as evidence that indeed liver fat resorption is hampered in the absence of estrogens. To go one step further, we used a physiological approach in our second study to investigate how estrogen deficiency affects liver fat accumulation putting an emphasis on the pathway of lipid exportation from the liver. Results of this study showed that estrogen withdrawal resulted in higher (P < 0.01) liver fat accumulation concomitantly with lower (P < 0.01) very low density lipoprotein-triglyceride (VLDL-TG) production and lower mRNA and protein content of hepatic microsomal triglyceride transfer protein (MTP). All of these effects in Ovx rats were corrected with estrogen supplementation. Moreover, exercise training in Ovx rats reduced (P < 0.01) liver fat accumulation and further reduced (P < 0.01) hepatic VLDL-TG production along with gene expression of MTP and diacylglycerol acyltransferase-2 (DGAT-2). A recent growing body of literature suggests that atrial natriuretic peptide (ANP) hormone should be the interest of new investigations in the field of energy and lipid metabolism. ANP is released from the heart into plasma by oxytocin (OT) stimulation and exerts its biological action by binding to its receptor, guanylyl cyclase-A (GC-A: ANP receptor). Therefore, in the third study, we investigated the effects of blocking the oxytocin-atrial natriuretic peptide (OT-ANP) system, using an OT antagonist (OTA), on the gene expression of hepatic guanylyl cyclase-A and some inflammatory markers in the liver of Ovx rats. Hepatic GC-A mRNAs were decreased (P < 0.05) in Ovx and Sham OTA-treated rats in the sedentary state, contrary to hepatic C-reactive protein (CRP) mRNA expression that increased in these animals (P < 0.05). Exercise training had no effect on hepatic expression of these genes in both Sham and Ovx rats receiving OTA. Overall, our results point to the interpretation that hepatic fat accumulation and resorption are dependent on mechanisms associated with a normal estrogenic status; indicating that a decrease in VLDL-TG production might be a contributing factor responsible for the hepatic fat accumulation induced by estrogen deficiency. Exercise training lowers liver fat accretion and VLDL-TG production independently of the estrogen levels. Moreover, hepatic expression of ANP receptors is decreased by OTA in both Sham and Ovx rats suggesting an indirect action of the OT system on the liver independently of the estrogenic status of the animal. Oxytocin-atrial natriuretic peptide axis may contribute to the protection of hepatic tissue under normal physiological conditions such as reducing inflammatory markers within the hepatocytes by exerting its role through guanylyl cyclase-A expression.