AN ABSTRACT OF THE DISSERTATION OF LAN HAI, for the Doctor of Philosophy degree in Molecular Cellular and Systemic Physiology, presented on 11th December, 2015 at Southern Illinois University Carbondale. TITLE: EFFECT OF CONSTITUTIVELY ACTIVATED LUTEINIZING HORMONE RECEPTOR ON THE MOUSE REPRODUCTIVE SYSTEM MAJOR PROFESSOR: Dr. Prema Narayan The luteinizing hormone/chorionic gonadotropin receptor (LHCGR) is crucial for fertility, and genetic mutations in LHCGR cause adverse effects in reproductive development. Among the activating mutations identified in LHCGR, replacement of aspartic acid 578 by glycine (D578G) is the most common inherited mutation. Boys with this mutation undergo puberty by 2-4 years, caused by elevated testosterone in the context of prepubertal luteinizing hormone levels and present with Leydig cell hyperplasia. Clinically, these symptoms are associated with familial male-limited precocious puberty (FMPP). Our lab has published a mouse model for FMPP (KiLHRD582G) with D582G mutation equivalent to D578G in human LHCGR. We have previously demonstrated that KiLHRD582G male mice exhibited precocious puberty, Leydig cell hyperplasia and elevated testosterone and was a good model for FMPP. However, unlike women with the D578G mutation who show no abnormal phenotype, our studies revealed that female KiLHRD582G mice were infertile. KiLHRD582G female mice exhibit precocious puberty and irregular estrous cyclicity. A temporal study from 2-24 weeks of age indicated elevated steroid levels and upregulation of steroidogenic acute regulatory protein as well as several steroidogenic enzyme genes. Ovaries of KiLHRD582G mice exhibited significant pathology with the development of large hemorrhagic cysts as early as 3 weeks of age, extensive stromal cell hyperplasia with luteinization, numerous atretic follicles and granulosa cell tumors. Anovulation could not be rescued by exogenous gonadotropins. The body weights of the KiLHRD582G mice was higher that wild type counterparts, but there were no differences in the body fat composition. Hyperandrogenism and polycystic ovary phenotype was not accompanied by impaired glucose tolerance. Blocking the androgen action and estrogen synthesis indicated that reproductive phenotype was primarily due to excess estradiol. These studies demonstrate that activating LHCGR mutations do not produce the same phenotype in humans and mice and clearly illustrates species differences in the expression and regulation of LHCGR in the ovary. As we use male KiLHRD582G mice as breeders, we observed that the KiLHRD582G mice became progressive infertile, and only 8% of KiLHRD582G were fertile at 6 months of age despite normal sperm production. The infertile KiLHRD582G males were not able to form copulatory plugs in WT females, and mating studies suggested that the KiLHRD582G males were not capable of mating and/or ejaculating. Sexual behavioral testing revealed that the infertile KiLHRD582G males were capable of mounting the receptive WT females but were unable to achieve ejaculation indicating a problem with erectile and/or ejaculatory function. To address the reason for the ejaculatory dysfunction, we performed histopathological analysis of the accessory glands and penis. Hematoxylin and eosin staining showed that the normal columnar epithelium was replaced by pseudostratified columnar epithelium in the ampulla and several aggregates of chondrocyte metaplasia were apparent in the penile body of KiLHRD582G male mice. A temporal study indicated the histopathological changes in ampulla and penile body initiated at 7-8 and 12 weeks of age, respectively. Immunohistochemistry indicated that the chondrocytes stained positive for collagen type II, SOX9 and androgen receptor in the nucleus and for LHCGR in the cytoplasm. Penile fibrosis is a major cause of erectile dysfunction and is characterized by an increased collagen/smooth muscle ratio. However, our Image J analysis, hydroxyproline assay and western blot showed that KiLHRD582G penile body exhibited reduced levels of smooth muscle actin but similar total collagen content compared to WT mice. Thus, penile fibrosis was not responsible for the progressive infertility of adult KiLHRD582G mice. We also observed Leydig cell adenoma and disruption of spermatogenesis at 1 year of age. Our results suggest FMPP patients may be susceptible to infertility and testicular tumors later in their life and a follow-up study of FMPP patients is recommended.

Made available in DSpace on 2014-06-11T19:29:14Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-18Bitstream added on 2014-06-13T19:59:04Z : No. of bitstreams: 1 monteiro_cd_me_botfmvz.pdf: 382798 bytes, checksum: 2e0cae2e6c2e5b07f272096a269d9e6b (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Objetivou-se avaliar a resposta de fêmeas ovinas à administração exógena de acetato de medroxiprogesterona ou progesterona de longa ação associados à bioestimulação na pré-puberdade. Foram utilizados dois machos adultos Pool Dorset e 75 borregas sem raça definida com idade entre 154 e 218 dias, (média de 179 e erro padrão ± 1,20 dias) e peso entre 25,8 e 36,9kg (média de 30,0kg e erro padrão ± 0,124kg) no início do experimento que foram divididas equitativamente quanto ao peso, escore de condição corporal e índice de massa corpórea, em três grupos (grupo Bioestimulado, MAPesp e P4LA) de 25 animais. No grupo bioestimulado as fêmeas foram submetidas à bioestimulação por oito semanas, no grupo MAPesp as fêmeas foram submetidas por 12 dias a esponjas intravaginais impregnadas de medroxiprogesterona (60mg) e bioestimulação por oito semanas e no grupo P4LA as fêmeas foram submetidas à única aplicação de progesterona de longa ação (225mg) e bioestimulação por oito semanas. O experimento foi composto por 10 observações ao longo de 82 dias. Em 3 momentos experimentais foram realizadas coletas de sangue pareadas em sete dias para dosagem plasmática de progesterona. Em nove observações foram realizadas biometrias envolvendo aferições de peso, índice de massa corpórea e escore de condição corporal. Conclui-se que 93,3% das fêmeas dos três grupos iniciaram a ciclicidade no momento experimental 1 e a maioria, 92% das borregas, permaneceu ciclando após 63 dias da administração exógena de acetato de medroxiprogesterona ou progesterona de longa ação e bioestimulação pelos efeitos macho e fêmea. / The aim of this study was to evaluate the answer of ewe lambs to exogenous administration of either medroxyprogesterone acetate or long action progesterone associated to bioestimulation in prepuberty. Two Pool Dorset adult males and 75 mixed-breed ewe lambs were used with the average age of 179 days and average weight of 30.0kg in the beginning of the experiment. The females were divided into three different groups (Group MAP, LAP4 and Bioestimulated) according to their bodyweight, body condition score (BCS) and body mass index (BMI). There were 25 animals in each group. In the MAP group the females were submitted to intravaginal sponges containing medroxyprogesterone acetate-MAP (60mg) for 12 days and were bioestimulated for eight weeks.In the LAP4 group the females were submitted to a single application of long action progesterone (225mg) and bioestimulation for eight weeks. And in the Bioestimulated group the females were submitted to bioestimulation for eight weeks. Animals were considered cycling when progesterone concentration reached ≥1.0ng/mL in two consecutive samples taken 7days distant from one another in 3 experimental moments. After the treatments, 93.3% of the females disregarding their group began the cyclicit and most of them ( 92.0%),continued cyclic after 63 days of either MAP or long action progesterone and bioestimulation under both male and female effect.

Orientador: Ivone Panhoca / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-06T19:21:56Z (GMT). No. of bitstreams: 1 Guimaraes_MichelleFerreira_M.pdf: 3257210 bytes, checksum: b0cb64faae1ee6b05d701f96bebce7c0 (MD5) Previous issue date: 2006 / Resumo: A voz e a habilidade vocal são diferentes em cada indivíduo. Devido aos escassos estudos sobre a qualidade vocal de adolescentes durante a puberdade, o presente estudo tem como objetivo identificar os seguintes parâmetros da análise acústica da voz: freqüência fundamental, seus índices de perturbação a curto prazo {jitter e shimmer), proporção GNE (glottal noise excitation), ruído, semitons e intensidade; correlacioná-los entre e si e também com o grau do desenvolvimento puberal de adolescentes do sexo masculino. Métodos: Foram sujeitos desse estudo 46 adolescentes do sexo masculino, com idade entre ] 3 e 15 anos, estudantes de uma escola estadual de Campinas, onde foi feita a coleta dos dados. Os adolescentes foram submetidos à gravação da voz, em gravador digital. Solicitou-se emissão sustentada da vogal /s/ e fala encadeada: contagem de 1 a 10, emissão dos meses do ano e leitura de um trecho pré-estabelecido. Em seguida foram avaliados por uma médica pediátrica para caracterização do grau do desenvolvimento puberal de acordo com os estágios descritos por Tanner (G1 a G5). A análise vocal foi realizada com o programa acústico Voz Metria®. Resultados: A maioria dos adolescentes está entre G3 e GA, a freqüência fundamental média é de 261,5Hz e todos apresentaram freqüência fundamental acima de 200Hz. Jitter manteve-se com média de 0,26% (dentro dos padrões de normalidade). Shimmer mostrou-se alterado em 38 dos 46 indivíduos, apresentando média de 8,41%, considerado acima do limite de normalidade. A proporção GNE e ruído estão dentro dos limites de normalidade para todos os adolescentes, porém todos apresentaram quantidade de semitons acima do esperado. A freqüência fundamental é mais aguda em G4 e G5 (p=0,003), shimmer é alterado em freqüências mais agudas (p=0,008). Conclusão: Os adolescentes estudados possuem freqüência fundamental de característica infantil e feminina, apesar de estarem no início do desenvolvimento puberal adulto, além disso, a maioria deles apresentou shimmer alterado. A maturação da voz provavelmente ocorre após a maturação do desenvolvimento puberal / Abstract: Voice and voice ability are different in each person. Due to scarce studies about adolescents' voice, this study purpose to correlate voice fundamental frequency and its quotients of perturbation at short terra (jitter and shimmer), GNE (glottal noise excitation) values, half-tone, present noise, intensity and the degree of puberty development in male teenagers. Methods: It is a transversal study with 46 boys, with age varying from 13 to 15 years, students from a public school in Campinas (Brazil), where the study was performed. The adolescent's voices were recorded in digital recorder and the speech samples consisted of the vowel /e/ in sustained phonation, counting (from 1 to 10), saying the months of the year and reading. Afterwards, the pediatrician evaluated and characterized the puberty development according to the Tanner stages. The vocal analysis was made in Vox Metria® acoustic programmer. Results: Most of the boys were in G3 and G4 Tanner stages, the mean of fundamental frequency was 261.5Hz and all the adolescents had FO > 200Hz. The mean of jitter was 0.26%, showing it was at normality standard. Shimmer was increased in 38 of 46 boys, which mean was 8.41%. The values of GNE and noise were in the normality limit; nevertheless the half-tones were above the standard. The fundamental frequency was high-pitched in boys with G4 e G5 (p=0,003) and shimmer was increased in high-pitched (p=0,008). Conclusion: These boys have fundamental frequency with childish and feminine characteristics although they are in the beginning of adult genitals development, most of they have alteration in shimmer values. Voice maturation probably occurs after pubertal maturation / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

Orientador: Glaucia Maria Bovi Ambrosano / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-12T19:55:02Z (GMT). No. of bitstreams: 1 Aguiar_LucianaBarretoVieira_M.pdf: 652688 bytes, checksum: f2576214f5e3ce87792dcf1b7d5ec8f6 (MD5) Previous issue date: 2009 / Resumo: O objetivo neste estudo foi avaliar a aplicabilidade do método de análise da idade óssea vertebral proposta por Caldas et al (2007) em crianças de baixa renda e se for necessário desenvolver um modelo de regressão múltipla para essa população para estimar a idade em função da maturação óssea das vértebras cervicais em radiografias cefalométricas. A amostra constituiu de radiografias cefalométricas e radiografias carpais de 76 meninos e 64 meninas com idade entre 7,0 e 14,9 anos de uma região de zona rural do município de Itabaiana - Sergipe. A idade óssea carpal, calculada pelo método de Tanner & whitehouse (TW3) foi usada como padrão ouro. Os corpos das vértebras C3 e C4 foram traçadas, mensuradas e em seguida as idades ósseas foram estimadas pelo método proposto por Caldas et al (2007). Foram calculadas as médias das idades, dos erros (diferença entre vertebral e carpal) e os respectivos intervalos de confiança a 95%. A seguir foram estimados novos modelos de regressão múltipla para determinar a idade óssea vertebral das crianças em estudo. Para o gênero feminino observou uma média na idade estimada de 10,62 anos (IC95%: 10,35-10,89), diferenciando da idade carpal cuja média foi de 11,28 (IC95%: 10,89-11,67), com erro médio de 1,42 anos (IC95%: 1,20-1,64). Já para o gênero masculino, a idade média estimada foi de 10,44 anos (IC95%: 10,16-10,72), sendo a idade carpal média de 10,57 anos (IC95%: 10,21-10,93), e o erro médio estimado de 1,18 anos (IC95%: 1,00-1,36). O novo modelo de regressão múltipla estimado apresentou valores de coeficiente de determinação ajustado (R2 ajustado) de 0,6751 e 0,6209 para os gêneros feminino e masculino, respectivamente. Esses resultados sugerem que os novos modelos determinados são confiáveis e devem ser utilizadas em crianças de famílias de baixa renda. / Abstract: The purpose of this research was to evaluate the applicability of the analysis method of the vertebral age proposed by Caldas et al (2007) in low income children, as well as to develop a multiple regression model for this population in order to estimate the age based on cervical vertebral bone maturation in cephalometric radiographs. The sample comprised of cephalometric radiographs and hand-wrist radiographs of 76 boys and 64 girls aged 7.0 to 14.9 years from Itabaiana city Sergipe, rural area. The hand-wrist bone age calculate by Tanner & Whitehouse (TW3) was used as golden standard. The vertebral bodies C3 and C4 were traced and measured and afterwards the bone age were estimated by the method proposed by Caldas et al (2007). The average ages, the mean errors (difference between vertebral and hand-wrist) and the respective confidence intervals at 95% were calculated. Then, the new multiple regression models were estimated in order to determine the vertebral bone age of the children in this study. The average age estimate for the girls was 10.62 years (IC95%: 10.35-10.89), different from the 11.28 hand-wrist average age (IC95%: 10.89-11.67) with average error of 1.42 years (IC95%: 1.20-1.64). The average age estimate for the boys was 10.44 years (IC95%: 10.16-10.72), the average hand-wrist age was 10.57 years (IC95%: 10.21-10.93) and the estimate average error was 1.18 years (IC95%: 1.00-1.36). The new estimate regression model presented adjusted coefficients of determination values (adjusted R2) of 0.6751 and 0.6209 for girls and boys respectively. These results suggest that the new determined models are reliable and can be used in children from low income families. / Mestrado / Radiologia Odontologica / Mestre em Radiologia Odontológica

O objetivo deste estudo foi avaliar a influência da suplementação proteica no terço final da gestação de vacas Nelore e das bezerras em creep-feedingsobre o desempenho produtivo e reprodutivo de bezerras e novilhas. Para tanto, foi utilizado um arranjo fatorial (2X2), sendo o fator I a suplementação das vacas no terço final de gestação (n=350) e o fator II a suplementação das bezerras em creep-feeding (n=153). No terço final da gestação, as vacas foram suplementadas com 0,5 kg de farelo de soja, e as bezerras foram suplementadas em creep-feeding a partir dos 30 dias após o nascimento até a desmama, aos 6,38 meses de idade. O período experimental compreendeu do terço final da gestação até os 30 meses de idade. Não houve interação entre as estratégias de suplementação sobre o peso corporal (P=0,66) e ECC (P=0,58) das vacas, e sobre o peso corporal (P=0,62) e GMD (P=0,73) das bezerras dos 1,2 até 26,0 meses. Da mesma forma, não houve efeitoo da suplementação das vacas (P=0,98) e das bezerras em creep-feeding (P=0,78) sobre o peso das bezerras. Entretanto, a suplementação das vacas influenciou pontualmente o peso das novilhas aos 24,9 meses, sendo que as novilhas filhas de vacas suplementadas foram mais pesadas (P=0,040). A taxa de puberdade aos 12,5 (P=0,31) e 24,9 (P=0,75) meses e a taxa de prenhez aos 18,7 (P=0,86) e 26,0 (P=0,36) meses não foram influenciados por nenhuma das estratégias nutricionais. No entanto, houve interação entre a suplementação das vacas e das bezerras em creep-feeding sobre a taxa de prenhez aos 30 meses de idade, sendo que novilhas filhas de vacas suplementadas no terço final da gestação e que foram suplementadas em creep-feeding apresentaram maior taxa de prenhez (92%, P=0,019) quando comparadas com novilhas que receberam apenas um dos dois tipos de suplementação. A associação entre suplementação materna no terço final de gestação e a suplementação na fase de cria (creep-feeding) não impactaram sobre o peso corporal, GMD, taxa de puberdade das novilhas. / The objective of this study was to evaluate the influence of dam supplementation on least trimester of gestation of Nellore cows and creep-feeding supplementation on productive and reproductive performance of heifers. For this purpose, a factorial arrangement (2X2) was used, which the factor I was dam supplementation of cows in the least trimester of gestation (n = 350) and the factor II was creep-feeding supplementation (n = 153). Cows were supplemented with 0.5 kg of soybean meal by 90 days before partum, and the female calves were supplemented in creep-feeding from 30 days after birth until weaning at 6.38 months of age. The experimental period comprised the least trimester of gestation up to 30 months of age. There was no interaction between supplementations on body weight (P = 0.66) and BCS (P = 0.58) of cows, and on body weight (P = 0.62), and ADG (P = 0.73) of heifers from 1.2 to 26.0 months. In the same way, there was no effect of dam supplementation (P = 0.98), and creep-feeding (P = 0.78) on body weight of heifers. However, dam supplementation exerted punctual influence on body weight of heifers at 24.9 months of age, when heifers that dam were supplemented were heavier (P = 0.040). The reproductive parameters such puberty rate at 12.5 (P = .31) and 24.9 (P = 0.75) months and the pregnancy rate at 18.7 (P = 0.86) and 26.0 (P = 0.36) months were not influenced by any nutritional strategies. However, there was interaction between supplementations on the pregnancy rate at 30 months of age, which heifers from cows that received supplement on least trimester of gestation and were submitted to creep-feeding showed higher pregnancy rate (92%, P = 0.019) than heifers who received only one of two types of supplementation. The association between dam supplementation and creep-feeding did not affect body weight, ADG, and puberty onset in Nellore heifers.

Using data from the Third National Health and Nutrition Examination Survey, we assessed measures of puberty in U.S. girls in relation to blood lead levels to determine whether sexual maturation may be affected by current environmental lead exposure. The study sample included 1,706 girls 8-16 years old with pubic hair and breast development information; 1,235 girls 10-16 years old supplied information on menarche. Blood lead concentrations (range = 0.7-21.7 pg/dL) were categorized into three levels: 0.7-2.0, 2.1-4.9, and 5.0-21.7 μg/dL. Sexual maturation markers included self-reported attainment of menarche and physician determined Tanner stage 2 pubic hair and breast development. Girls who had not reached menarche or stage 2 pubic hair had higher blood lead levels than did girls who had. For example, among girls in the three levels of blood lead described above, the unweighted percentages of 10-year-olds who had attained Tanner stage 2 pubic hair were 60.0, 51.2, and 44.4%, respectively, and for girls 12 years old who reported reaching menarche, the values were 68.0, 44.3, and 38.5%, respectively. The negative relation of blood lead levels with attainment of menarche or stage 2 pubic hair remained significant in logistic regression even after adjustment for race/ethnicity, age, family size, residence in metropolitan area, poverty income ratio, and body mass index. In conclusion, higher blood lead levels were significantly associated with delayed attainment of menarche and pubic hair among U.S. girls, but not with breast development.

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<p dir="ltr">This dissertation sought to contribute a pair of genetically informed studies strategically designed to make potentially causal inferences about potential co-developing processes of internalizing symptoms, body mass index (BMI) and relative pubertal timing during adolescence. Paper 1 used the Early Growth and Development Study (EGDS; N=561), a prospective adopted-at-birth design which primarily accounts for passive gene environment correlation by virtue of youth having been adopted at birth and placed in non-relative adoptive families. Paper 2 used the discordant sibling design from a subsample of siblings from the Adolescent Brain Cognitive Development (ABCD) Study (N=3792), which by design accounts for all confounding of the effects of a risk factor with all shared familial influences that siblings share and all environmental differences that exist between families. The hypothesized associations were further examined in subsamples of twins and MZ twins to make increasingly strict, potentially causal inferences. Across the two studies, I hypothesized that higher internalizing symptoms and higher BMI would positively co-develop at the within person and within family level, respectively for each paper. I hypothesized that there would be unidirectional within person effects of relatively earlier pubertal development on higher internalizing symptoms, across both studies. Finally, I hypothesized that there would be positive co-development of higher BMI and earlier relative pubertal timing early on in both studies, but that only higher BMI would continue to unidirectionally predict earlier relative pubertal timing across the two studies’ ends. In paper 1, specific hypotheses were completely unsupported. In Paper 2, hypotheses were partially supported for two of out three pairs of phenotypes. Specifically, there was evidence of one within family cross-lagged effect between higher discordance in internalizing symptoms at age 10 and higher discordance in BMI at age 11. There was also evidence of one within family cross-lagged effect between higher discordance in relative pubertal timing at age 12 and higher discordance in internalizing symptoms at 13. Findings from both papers indicated that the association between BMI and relative pubertal timing is likely largely confounded by common stable between person, stable discordance, and stable family average factors. Implications and limitations are discussed.</p>

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