A síndrome dos ovários policísticos (SOP) é um distúrbio endócrino caracterizado por anovulação crônica e hiperandrogenismo. Modelos animais em ratas são usados para estudar processos complexos da SOP. As procineticinas (PROKs) são proteínas relacionadas a apoptose, proliferação vascular e regulação do sistema reprodutor. No entanto, seu padrão de expressão e função não são bem conhecidos no ovário com SOP. Este estudo propõe-se a identificar e localizar as PROKs e seus receptores nos ovários de ratas com SOP experimental. Foram utilizadas 33 ratas Wistar divididas em 3 grupos que receberam, entre o 1º e o 3º dia de vida, uma única injeção por via subcutânea de: propionato de testosterona (1,25 mg/0,1 mL, GT, n=12); benzoato de estradiol (0,5 mg/0,1 mL, GE, n=11) e óleo de oliva (0,1 mL, GC, n=10). Aos 90-95 dias de idade, os animais foram eutanaziados e os ovários removidos para avaliação da expressão gênica e proteica das procineticinas 1 e 2 e seus receptores por qRT-PCR e imunoistoquímica. A expressão dos genes Prok1 e Prok2 nos ovários de ratas do GT foi maior quando comparado ao GC (p=0,0157 e p=0,0354). Houve maior expressão da proteína PROK2 em células da teca interna (p=0,0049) e nas células intersticiais (p=0,0068) de folículos antrais nos ovários de ratas do GT em relação ao GC. PROK2 foi mais expressa em células da granulosa dos folículos pré-antrais comparado aos folículos antrais no GT (p=0,0098). Concluímos que as procineticinas estão expressas no ovário do modelo estudado em diferentes padrões, e que a PROK2 parece exibir maior expressão no grupo testosterona. Por apresentar papéis relevantes no controle do eixo hipotálamo-hipófise-gonadal, acreditamos que esses resultados podem abrir uma linha de investigação sobre o papel dessa proteína na fisiopatologia da síndrome / Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by chronic anovulation and hyperandrogenism. Animal models have been used to study PCOS pathophysiology. Prokineticins (PROKs) are proteins with functions related to apoptosis, vascular proliferation and reproductive physiology. However, their expression patterns and functions are unknown in the PCOS ovary. The aim of this study is to identify and localize the PROKs and their receptors in PCOS rat models induced by testosterone or estradiol. Thirty-three female Wistar rats aged between 1-3 days were sorted into three groups according to the compounds injected subcutaneously: Testosterone propionate (1.25 mg / 0.1 mL, TG, n = 12); Estradiol benzoate (0.5 mg / 0.1 mL, EG, n = 11) and olive oil (0.1 mL, CG, n = 10). At 90-95 days of age, the animals were euthanized and the ovaries removed for evaluation of prokineticins 1 and 2 and their receptors by qRT-PCR and immunohistochemistry. The expression of the genes Prok1 and Prok2 in the ovaries was higher in TG compared to CG (p=0.0157 and p=0.0345). There was higher expression of PROK2 in theca interna (p=0.0049) and interstitial cells (p=0.0068) of antral follicles in the ovaries of TG vs CG; PROK2 was higher expressed in the granulosa cells of the preantral follicles compared to the antral follicles in the TG (p=0.0098). We conclude that prokineticins are expressed in the ovary of the animal model studied and they present different patterns, PROK2 seems to exhibit higher expression in the testosterone group. Due important roles in the control of the hypothalamicpituitary- gonadal axis, we believe that these results may open a line of investigation about the role of this protein in the pathophysiology of the syndrome

OBJETIVO: Avaliamos se a presença da síndrome dos ovários policísticos (SOP) altera múltiplos marcadores ultrassonográficos e laboratoriais de risco metabólico e doença cardiovascular em mulheres obesas sem outras condições que interferem com o critério de elegibilidade do contraceptivo oral combinado (COC). MÉTODOS: Estudo caso-controle avaliando 90 mulheres obesas ( 30,0 Kg/m² e < 40 Kg/m²), com idade entre 18 e 40 anos, sem outras condições de saúde que interferem com os critérios de elegibilidade de COC: 45 com SOP e 45 controles, pareadas por idade. Índice de massa corporal; circunferência da cintura e do quadril; pressão arterial sanguínea; insulina e glicemia de jejum; quantitative insulin sensitivity check index (QUICKI); HDL, LDL e colesterol total; triglicérides; testosterona; globulina carreadora de hormônios sexuais (SHBG); índice de androgênio livre (FAI); índice de rigidez da carótida e espessura íntimamédia (EIM); dilatação mediada por fluxo da artéria braquial (DMF) e doença hepática gordurosa não alcoólica (DHGNA) foram avaliados. RESULTADOS: Em mulheres obesas com SOP, observamos uma maior freqüência de DHGNA quando comparada a obesas sem SOP (73,4% vs. 46,6%, p<0,01). Embora não significativo, observamos uma tendência a aumento da insulina (10,06±6,66 UI/mL vs. 7,45±5,88 UI/mL, p=0,05), diminuição do QUICKI (0,36±0,06 vs. 0,39±0,07, p=0,05) e diminuição da DMF (7,00±3,87% vs. 8,41±3,79%, p=0,08). Nenhuma outra diferença significativa foi observada. CONCLUSÕES: DHGNA é freqüente em mulheres obesas sem outras condições que interferem com o critério de elegibilidade do COC, especialmente naquelas com SOP. Isto deveria ser considerado na escolha da melhor opção contraceptiva. / OBJECTIVE: To evaluate whether the presence of polycystic ovary syndrome (PCOS) alters multiple ultrasonographic and laboratorial markers of metabolic and cardiovascular disease risk in obese women without any other health condition that interferes with combined oral contraceptive (COC) eligibility criteria. METHOD: A case-control study evaluating 90 obese women ( 30.0kg/m² and <40kg/m²) aged between 18 and 40 years without any other health condition that interferes with COC eligibility criteria: 45 with PCOS and 45 age-matched controls. Body mass index; waist and hip circumference; arterial blood pressure; fasting insulin and glucose; quantitative insulin sensitivity check index (QUICKI); HDL, LDL and total cholesterol; triglycerides; testosterone; sex hormone-binding globulin (SHBG), free androgen index (FAI); carotid stiffness index and intima media thickness; flow-mediated dilatation of brachial artery; and nonalcoholic fatty liver disease (NAFLD) were assessed. Results: In PCOS women, we observed a higher frequency of NAFLD (73.4% vs. 46.6%, p<0.01) and higher FAI (10.43% vs. 6.84%, p<0.01). We also observe a trend of increased insulin (10.06±6.66IU/mL vs. 7.45±5.88IU/mL, p=0.05), decreased QUICKI (0.36±0.06 vs. 0.39±0.07, p = 0.05), and decreased FMD (7.00±3.87% vs. 8.41±3.79%, p=0.08). No other significant difference was observed. Conclusions: NAFLD is frequent in obese women without any other health condition that interferes with COC eligibility criteria, especially in those with PCOS. This should be considered when choosing the best contraceptive option.

A Síndrome dos Ovários Policísticos (SOP) representa um dos distúrbios endócrinos reprodutivos mais comuns em mulheres em idade reprodutiva. As mulheres com SOP normalmente respondem bem ao tratamento de reprodução assistida (TRAs), mas frequentemente apresentam oócitos de baixa qualidade e capacidade reprodutiva, a qual está correlacionado com a interação do oócito com as células do cumulus. A baixa qualidade oocitária pode estar relacionada a perda de estabilidade genômica do oócito, ou até mesmo das células do cumulus, o que pode levar a uma redução gradativa da fertilidade feminina. Os telômeros e a atividade da telomerase possuem um papel fundamental na manutenção da estabilidade genômica e são considerados importantes marcadores de viabilidade celular, podendo ser um indicativo da qualidade oocitária. O objetivo do estudo foi avaliar o comprimento do telômero e atividade da telomerase nas células do cumulus de mulheres com SOP. Neste estudo prospectivo caso-controle foram incluídas 110 voluntárias, sendo 43 mulheres com SOP e 67 controles no período de Setembro de 2015 a Junho de 2017. Foram avaliados os dados como idade, Índice de massa corporal (IMC), hormônio luteinizante (LH), hormônio folículo estimulante (FSH), globulina de ligação de hormônios sexuais (SHBG), prolactina, estradiol, insulina, testosterona total, androstenediona, índice de androgênio livre (FAI), homocisteína e proteína c-reativa. Foi avaliado o comprimento do telômero nas células do cumulus de oócitos imaturos (CCI), nas células do cumulus de oócitos maduros (CCM), nos oócitos imaturos no estágio de vesícula germinativa (VG), nos oócitos imaturos em metáfase I (MI) e nos leucócitos pelo método quantitativo da reação em cadeia da polimerase (qPCR). A atividade da telomerase das CCI, CCM, dos oócitos VG e MI foram avaliadas pelo Kit TRAPeze® XL. A análise estatística foi determinada pelo teste Mann-Whitney, regressão linear múltipla e correlação de Spearman. Os resultados foram que as variáveis IMC (p=0,001), LH (p=0,015), estradiol (p=0,004), insulina (p=0,002), testosterona (p<0,0001), androstenediona (p=0,001), FAI (p<0,0001) e proteína c-reativa (p=0,003) foram maiores no grupo SOP. FSH (p=0,0002) foi menor no grupo SOP. A prolactina e a homocisteína não diferiram entre os grupos. O comprimento do telômero nas CCI não diferiu entre os grupos SOP e controle (1,60±0,56 vs 1,58±0,33; p=0,649, respectivamente), bem como o comprimento do telômero nas CCM não diferiu entre os grupos SOP e controle (1,61±0,47 vs 1,70±0,43; p=0,378, respectivamente). Entretanto, nos leucócitos o comprimento do telômero foi menor no grupo SOP (p=0,025). A atividade da telomerase nas CCI foi maior no grupo SOP do que no grupo controle (1,62±1,49 vs 0,30±0,42; p=0,003, respectivamente) e a atividade da telomerase nas CCM também foi maior no grupo SOP do que no grupo controle (1,39±1,63 vs 0,55±0,84; p=0,022, respectivamente). O comprimento do telômero e a atividade da telomerase nos oócitos VG e MI não diferiu entre os grupos. Uma correlação positiva foi observada entre a atividade da telomerase e o comprimento do telômero nas CCI no grupo controle (p=0,051). O grupo SOP apresentou uma correlação positiva entre a atividade da telomerase e o comprimento do telômero, porém nas CCM (p=0,048). Foi observada uma correlação positiva do comprimento do telômero entre as células (leucócitos, CCI e CCM) em ambos os grupos. Os dados sugerem que a SOP parece não afetar o comprimento do telômero nas CCI e CCM, apenas nos leucócitos. Por outro lado, uma maior atividade da telomerase nas CCI e CCM pode ser necessária para a manutenção do comprimento telomérico à nível reprodutivo nas mulheres com SOP. / Polycystic Ovarian Syndrome (PCOS) represents one of the most common reproductive endocrine disorders in women of reproductive age. Women with PCOS, despite responding well to Assisted Reproduction Treatments (ART), the oocytes usually have low quality and reproductive capacity, which is correlated to oocyte interaction with cumulus cells. The low oocyte quality may be related to loss of genomic stability of oocytes, or even cumulus cells, and may lead to a reduction of female fertility. The telomere length and telomerase activity play a fundamental role in maintaining genomic stability, which is considered an important molecular marker of cell viability, whose alterations are related to apoptosis and/or senescence, maybe also an indicative of oocyte quality. The aim of the study was to evaluate the telomere length and telomerase activity in cumulus cells of women with PCOS. In this prospective case-control study, 110 volunteers were included, 43 women with PCOS and 67 controls from September 2015 to June 2017. Data were evaluated as age, body mass index (BMI), luteinizing hormone (LH), follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG), prolactin, estradiol, insulin, total testosterone, androstenedione, index of free androgen (FAI), homocysteine and c-reactive protein. Telomere length in cumulus cells from immature (ICC) and mature (MCC) oocytes, leukocytes and immature oocytes in the germinal vesicle stage (VG) and in metaphase I (MI) were evaluated by quantitative real-time polymerase chain reaction (qPCR). Telomerase activity of ICC, MCC, VG and IM oocytes were evaluated by TRAPeze® XL Kit. Statistical analyses were determined by the MannWhitney test, multiple linear regression and Spearman\'s correlation. The results were that the variables BMI (p=.001), LH (p=.015), estradiol (p=.004), insulin (p=.002), testosterone (p<.0001), androstenedione (p=.001), FAI (p<.0001) and c-reactive protein (p=.003) was increased in PCOS group. FSH (p=.0002) was smaller in PCOS group. Prolactin and homocysteine were not different between the groups. The telomeres length in ICC did not differ between PCOS and control groups (1.60±0.56 vs 1.58±0.33; p=.649, respectively). The telomeres length in MCC did not differ between PCOS and control groups (1.61±0.47 vs 1.70±0.43; p=.378, respectively). However, in leukocytes reduced telomeres were observed in the PCOS (p=.025), respectively. The telomerase activity in ICC was higher in the PCOS group than in the control group (1.62±1.49 vs 0.30±0.42; p=.003, respectively) and the telomerase activity in MCC was higher in the PCOS group than in the control group (1.39±1.63 vs 0.55±0.84; p=.022, respectively). The telomere length and telomerase activity in VG and MI oocytes did not differ between groups. A positive correlation between telomerase activity and telomere length in the ICC was observed in control group (p=.051). PCOS also presented a positive correlation between telomerase activity and telomere length in MCC (p=.048). Telomere length of leukocytes, ICC and MCC were a positive correlated in both groups. The data suggest that PCOS does not appear to affect telomere length in ICC and MCC, only in leukocytes. On the other hand, a greater activity of telomerase in CCI and CCM may be necessary for the maintenance of telomere length at the reproductive level in women with PCOS.

Introdução:A história natural da Síndrome dos Ovários Policísticos (SOP) tem início durante a fase do crescimento fetal, que é umperíodo em que ocorre a diferenciação e a maturação funcional dos órgãos e tecidos. Quando surgem condições adversas durante a vida fetal, existe predomínio do processo catabólico, que promove a restriçãode crescimento intra-útero e o nascimento de recém-nascidos (RN) pequenos para a idade gestacional (PIG). Durante esta fase de hipoxemia fetal crônica, surgem alterações na expressão gênica de proteínas nucleares (reprogramação fetal) que poderão codificar manifestações fenotípicas na vida adulta, a depender das células que foram acometidas. Este processo, associado à predisposição genética e aos fatores ambientais, pode favorecer o surgimento da SOP. Objetivo:Avaliar se os RN de termo PIG (femininos) têm maior prevalência de SOP na idade adulta quando comparados aos RN Adequados para Idade Gestacional (AIG) na população da coorte de indivíduos nascidos em Ribeirão Preto durante o período de 31.05.1978 e 01.06.1979. Casuística e Métodos:Foram convocadas 440 mulheres de novembro/2007 à outubro/2008 para avaliação de repercussões reprodutivase metabólicas no menacme. Deste total, concordaram em participar da pesquisa 355 pacientes (268 AIG e 87 PIG), sendo que 138 AIGs e 37 PIGs foram excluídas devido ao uso de anticoncepcional hormonal (97) e pela presença de gestação ou amamentação (78). Todas as mulheres foram submetidas à anamnese (com avaliação da idade, das características do ciclo menstrual, dos sinais/sintomas do hiperandrogenismo, do peso, da altura e do índice de massa corpórea). Realizamos a dosagem hormonal (FSH, LH, prolactina, testosterona, DHEAS, 17-OH progesterona, insulina), a avaliação bioquímica (lipidograma, glicemia e teste de tolerância oral com 75 gramas de glicose), a SHBG e a ultra-sonografia pélvica para definição do diagnóstico de SOP. Também avaliamos o índice de androgênios livres (FAI),a resistência insulínica (RI) (através do HOMA) e a prevalência da síndrome metabólica (SMET). A coleta foi realizada entre o terceiro e o quinto dia do ciclo menstrual, após jejum de 12 horas. Resultados:a prevalência de SOP foi mais elevada no grupo PIG (32%) do que em mulheres do grupo AIG (13,8%), com risco relativo de 2,02 (IC95%: 1,27 - 3,21, p=0,0097) . Em relação aos critérios de SOP,a irregularidade menstrual (PIG: 51% vs AIG: 25,4%, p=0,0012) e o hiperandrogenismo (PIG: 41,2% vs AIG:22,3%, p=0,01) foram mais elevados nas pacientes PIG. Já a ultrassonografia, os exames bioquímicos, o FAI, e a avaliação hormonal não apresentaram diferenças significativas entre os grupos. Também não houve diferenças entre os grupos em relação às prevalências de SMET e RI. Conclusão: Mulheres PIG ao nascimento representam um grupo de risco para o desenvolvimento da SOP durante o menacme. Estudos de seguimento destas mulheres devem ser realizados para avaliar a relação do pesoao nascer com a prevalência de doenças cardiovasculares e metabólicas ao longo da vida. / Introduction:The natural history of Polycystic Ovary Syndrome (POS) starts during fetal growth, a period during which the differentiation and functional maturation of organs and tissues occurs. When adverse conditions arise during fetal life there is a predominance of the catabolic process, which promotes intrauterine growth restriction and the birth of small for gestational age (SGA) newborns (NB). During this phase of chronic fetal hypoxemia, changes in the gene expression of nuclearproteins arise (fetal reprogramming) that might code for phenotypic manifestations during adult life depending on the affected cells. This process, together with genetic predisposition and environmental factors, may favor the onset of POS. Objective:To determine whether term female SGA NB have a higher prevalence of POS during adult age compared to women adequate for gestational age (AGA) at birth in the population of the cohort of individuals born in Ribeirão Preto during the period from 31.05.1978 to 01.06.1979. Cases and Methods:From November 2007 to October 2008, 440 women have been convoked for the assessment of reproductive and metabolic repercussions during menacme. Among them, 355 appeared (268 AGA and 87 SGA), with 137 AGAs and 38 SGAs being excluded from the study due to the use of a hormonal contraceptive (98) and to the presence of pregnancy or breast-feeding (77). The medical history of all women was taken, including age, characteristics of the menstrual cycle and of signs and symptoms of hyperandrogenism, height, and body mass index. We performed hormone determination (FSH, LH, prolactin, testosterone, DHEAS, 17-OH progesterone), biochemical evaluation (lipid profile, glycemia and 75 g oral glucose tolerance test), and pelvic ultrasound for the definition of the diagnosis of POS. Blood was collected between the third and fourth day ofthe menstrual cycle after a 12 hour fast. Results:The prevalence of POS was higher in the SGA group (32%) than in the AGA group (13.8%), with relative risk of 2,02 (IC 95%: 1,27- 3,21, p=0,0097). Regarding the criteria for a diagnosis of POS, chronic anovulation (SGA:51% vs AGA: 25,4%, p = 0.0012) and clinical hyperandrogenism (SGA: 41.2% vs AGA: 22.3%, p = 0.01) were more elevated in SGA patients. In contrast, ulrasonography and the biochemical and hormonal exams did not show significant differences between groups. Conclusion:Women who were SGA at birth represent a risk group for the development of POS during menacme. Following studies this women should be performed to assess the relation to birth weight with the prevalence of cardiovascular and metabolic diseases during of life.

Contexte : Une amélioration des habitudes de vie, avec une légère perte pondérale (5 %), augmenterait les chances de concevoir un enfant chez les femmes obèses souffrant d’infertilité. La perte de poids est considérée comme le principal déterminant de la survenue d’une grossesse, mais aucune étude n’a évalué le rôle la qualité alimentaire. Objectif principal : Évaluer l’impact de l’amélioration de la qualité alimentaire sur les chances de survenue d’une grossesse auprès de femmes obèses et infertiles. Méthodologie : Étude prospective s’insérant dans un essai randomisé contrôlé évaluant l'impact d'une intervention interdisciplinaire visant l’amélioration des habitudes de vie sur la fertilité des femmes obèses suivies à la clinique de fertilité du CHUS en comparaison à des femmes ayant accès aux soins standards en fertilité seulement (n = 102). Des visites de recherche ont lieu à l’entrée de l’étude puis aux 6 mois jusqu’à la fin du projet, soit après 18 mois ou jusqu’à l’accouchement. La collecte de données inclut un questionnaire de fréquence alimentaire, des mesures anthropométriques et un test de condition physique. Un index de qualité alimentaire, le Healthy Eating Index modifié (mHEI, 0-100 points), a été calculé. Résultats : Pour l’ensemble des participantes, l’amélioration de la qualité alimentaire n’était pas associée à de meilleures chances de grossesse. À l’aide d’un modèle de régression de Cox, il a été possible d’observer que la qualité alimentaire initiale était un prédicteur important de grossesse au sein des deux groupes confondus (HR (par 10 unités) : 1,24 [1,03 – 1,50], p = 0,027), indépendamment du niveau de condition physique et de l’anthropométrie. De façon similaire, une meilleure qualité alimentaire observée avant conception présentait une association significative indépendante avec les chances de concevoir dans le temps (HR (par 10 unités) : 1,25 [1,04 – 1,49], p = 0,017). Les variables anthropométriques, incluant le poids, n’étaient pas associées à une probabilité accrue de concevoir. Conclusion : Une meilleure qualité alimentaire en préconception augmenterait les chances de grossesse chez les femmes infertiles souffrant d’obésité. / Abstract : Background : Improvement of lifestyle habits, associated with a modest weight loss (5 %), has shown to increase odds of pregnancy in overweight and obese women diagnosed with infertility. Weight loss is considered as the main factor that explains the improvement of fertility, but no study evaluated the specific role of diet quality on fertility in this population. Objective : Evaluate the impact of improving diet quality on odds of pregnancy in obese and infertile women seeking for fertility treatments. Methods : Prospective study nested in a randomized controlled trial evaluating the impact of an interdisciplinary lifestyle intervention on fertility of obese women followed at the fertility clinic of the CHUS, in comparison to standard fertility care only. Research visits take place every 6 months until the end of the project, which is after 18 months or delivery. Data collection include a food frequency questionnaire, anthropometric measurement and a fitness evaluation. A score of diet quality, the modified Healthy Eating Index (mHEI, 0-100 units), was calculated. Results : For all the participants, improvement of diet quality was not associated with the probability of pregnancy. With Cox regression, we observed that the initial diet quality was an important predictor of pregnancy within the two confounded groups (HR (by 10 units) : 1.24 [1.03 – 1.50], p = 0.027), independently of cardiorespiratory fitness and anthropometry. Similarly, the best diet quality observed before conception presented a significant independent association with odds of pregnancy over time (HR (by 10 units) : 1.25 [1.04 – 1.49], p = 0.017). Anthropometric variables, including weight, were not associated with a higher probability of conception. Conclusion : A greater diet quality in preconception seems to increase probability of pregnancy in obese infertile women.

Abstract Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age, affecting 5–18% of them. Menstrual irregularities, hyperandrogenemia and obesity are key features in PCOS and they are suggested to be the most important metabolic risks linked to PCOS, but their respective roles are still under debate. Anti-Müllerian hormone (AMH) is involved in sexual differentiation and follicle growth and its level is increased in women with PCOS. The aims of this project were to clarify the significance of menstrual irregularities, hyperandrogenemia and serum levels of AMH in adolescence as predictive factors of the syndrome and to investigate the respective roles of obesity and hyperandrogenism as metabolic risk factors in women with PCOS from adolescence to late adulthood. The study populations were the Northern Finland Birth Cohort 1986 (N=3373 women) and a Nordic population including 1553 women with PCOS and 448 controls. At the age of 16 years, women with menstrual irregularities were more hyperandrogenic compared with women with normal menstrual cycles. Serum AMH levels correlated positively with those of testosterone at this age. They were higher in adolescents with menstrual irregularities compared with those with regular cycles and in women with hirsutism or PCOS at the age of 26 years. However, AMH was not a good marker of metabolic abnormalities in adolescence or a reliable tool to predict PCOS in later life. Androgen levels were higher in women with PCOS throughout life compared with controls. The parameters that best predicted PCOS at all ages were the free androgen index, and androstenedione. Women with PCOS exhibited increased abdominal obesity, altered insulin metabolism, worse lipid profiles and higher blood pressure from early adulthood until menopause compared with controls. The highest prevalence of metabolic syndrome was detected in obese and hyperandrogenic women with PCOS. In conclusion, irregular menstrual cycles, identified by a simple question at adolescence, represent a good marker of hyperandrogenemia, later metabolic risks and development of PCOS. Due to the persistence of hyperandrogenism and metabolic alterations, the treatment of PCOS should be focused on prevention and treatment of these problems as early as in adolescence in order to decrease future morbidity. / Tiivistelmä Monirakkulainen munasarjaoireyhtymä (polycystic ovary syndrome, PCOS) on lisääntymisikäisten naisten tavallisin (5-18%) hormonaalinen häiriö. Kuukautishäiriöt, mieshormoniylimäärä eli hyperandrogenismi ja lihavuus kuuluvat oireyhtymään oleellisesti ja niiden ajatellaan olevan tärkeimmät PCOS:aan liittyvät metaboliset riskitekijät, vaikkakin niiden tarkat roolit ovat epäselvät. Anti-Müllerian hormoni (AMH) vaikuttaa sukupuolen kehitykseen sikiöaikana sekä munarakkuloiden kypsymiseen hedelmällisessä iässä ja sen pitoisuus on suurentunut PCOS-naisilla. Tämän väitöskirjan tavoitteena oli selvittää kuukautishäiriöiden, hyperandrogenismin ja AMH-pitoisuuden ennustearvoa PCOS-oireyhtymälle, sekä arvioida lihavuuden ja hyperandrogenismin vaikutusta metabolisiin riskitekijöihin PCOS-naisilla läpi elämän. Tutkimusaineistoina olivat Pohjois-Suomen syntymäkohortti 1986 (N=3373 naista) sekä pohjoismaalainen yhteistyöaineisto, jossa oli 1553 PCOS-naista ja 448 kontrollia. 16-vuotiaiden kuukautishäiriöistä kärsivien naisten mieshormonipitoisuuksien todettiin olevan korkeammat kuin naisilla, joilla kuukautiskierto oli säännöllinen. AMH-tasot korreloituivat positiivisesti testosteronin kanssa 16-vuotiaana, ja pitoisuus oli koholla naisilla, joilla todettiin kuukautishäiriö. AMH-tasot 16-vuotiaana olivat myös korkeampia naisilla, joilla oli 26-vuotiaana PCOS tai hirsutismi. Kuitenkaan AMH-pitoisuus 16-vuotiaana ei korreloinut metabolisten riskitekijöiden kanssa eikä se ollut luotettava parametri ennustamaan PCOS:n kehittymistä. Mieshormonitasot olivat korkeammat PCOS-naisilla läpi elämän verrattuna kontrolleihin. Vapaan mieshormonin indeksit ja androstendioni olivat parhaat parametrit erottamaan PCOS-naiset kontrolleista. PCOS-naisilla todettiin olevan enemmän vyötärölihavuutta, huonompi veren rasvaprofiili ja korkeampi verenpaine varhaisaikuisuudesta menopaussiin saakka. Lihavilla hyperandrogeenisilla naisilla todettiin suurin metabolisen oireyhtymän esiintyvyys. Yksinkertaisella kysymyksellä selvitetyt kuukautishäiriöt nuoruusiässä todettiin olevan yhteydessä hyperandrogenismiin sekä myöhempiin metabolisiin riskeihin ja PCOS:n kehittymiseen. Jotta pystyttäisiin vähentämään myöhempää sairastavuutta ja kuolleisuutta PCOS-naisilla, oireyhtymän hoidon tulisi keskittyä ennaltaehkäisemään ja hoitamaan lihavuutta, hyperandrogenismia ja metabolisia riskejä jo varhaisaikuisuudessa.

La polykystose rénale autosomique dominante (ADPKD) est la maladie monogéniquehumaine la plus fréquente (prévalence 1/800). Les gènes responsables de cette maladie sont PKD1(codant pour PC1) ou PKD2 (codant pour PC2). La maladie évolue vers l’insuffisance rénale terminale.Aujourd’hui, seul un traitement symptomatique est proposé aux malades. Les mécanismes à l’originede l’ADPKD sont mal connus. Les modèles animaux permettent de mieux comprendre laphysiopathologie d’une maladie. Il n’existe pas de bon modèle de polykystose (même causemoléculaire, même mode de transmission, même signes cliniques). En utilisant la transgénose degrands fragments, nous avons créé un modèle de surexpression de PKD2 humain. Le transgène estsous le contrôle de son promoteur naturel humain. Cette souris exprime deux fois plus de PC2 queles sauvages. Elle ne présente que quelques microkystes mais une tubulopathie associant défaut deconcentration des urines et protéinurie tubulaire. La surexpression de PC2 inhibe l’expression degènes codant pour des protéines de la matrice extracellulaire. Le phénotype cellulaire de cesanimaux est remarquable : un tiers des cellules présentent un nombre élevé de centrosomes. Cephénotype cellulaire a été retrouvé chez des souris sous exprimant Pkd2 et chez des souris sousexprimant Pkd1. Ce caractère multicentrosomique est corrigé en incubant les cellules avec uninhibiteur de CaMKII ou en croisant nos souris transgéniques avec une souris KO de Camk2. Nousavons réussi à lier CaMKII, la duplication des centrosomes et les polycystines, in vitro et in vivo. Ceciamène un éclairage nouveau sur la duplication du centrosome et la physiopathologie de l’ADPKD. / Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic human disease (prevalence 1/800). Genes responsible for this disease are PKD1 (encoding PC1) or PKD2 (encoding PC2). The disease progresses to end stage renal disease. Today, only symptomatic treatment is offered to patients. The mechanisms underlying the ADPKD are unknown. Animals models allow better understand the disease’s pathophysiology. There is no good model of ADPKD (same molecular cause, same clinical signs). We created a mice model of human PKD2 overexpression. The transgène is under the control of its human natural promoter. This mouse expresses PC2 twice as much as the wild. It shows only few microcysts but tubulopathy involving lack of urine concentration and tubular proteinuria. PC2 overexpression inhibits the expression of genes encoding proteins of the extracellular matrix. The cellular phenotype of these animals is special : one third of the cells have a high number of centrosomes. This cellular phenotype was found in Pkd2 Knockout mice and in Pkd1 knockout mice. This multicentrosomic character is corrected by incubating the cells with a CaMKII inhibitor or by crossing our transgenic mice with Camk2 knockout mice. We propose a link between CaMKII, Centrosome duplication and polycystin in vitro and in vivo. This brings a new light on centrosome duplication and pathophysiology of ADPKD.

Bakgrund: Polycystisk ovarialsyndrom (PCOS) är den vanligaste hormonella rubbningen hos fertila kvinnor, ändå är den okänd för många. Det finns ett flertal symtom där dessa varierar från kvinna till kvinna. Okunskap kring PCOSförekommer både i vården liksom i samhället och diagnosen kan därför vara svåratt upptäcka. Att leva med symtomen från PCOS kan påverka negativt både kroppsligt och psykiskt. Hur kvinnor med diagnosen upplever PCOS behöverlyftas fram och förståelsen för dem behöver ökas både inom vården liksom förkvinnorna med PCOS. Med ökad förståelse kan ett bättre bemötande och vård ges.Syfte: Syftet är att beskriva kvinnors upplevelser av att leva med Polycystiskovarialsyndrom. Metod: Kvalitativ metasyntes med metaetnografisk analysmetod.16 kvalitativa artiklar är inkluderade i resultatet och samtliga artiklar hargenomgått en kvalitetsgranskning. Tre databaser användes vid insamling av data; Cinahl, Medline och PubMed. Resultat: Resultatet lyfter fram att flertalet kvinnorfick diagnos efter en lång tid och där kvinnorna ibland behövde vara påstridiga,medan i andra fall diagnosticerades PCOS som bifynd. Vissa kvinnor kände inte till att deras symtom kunde vara något avvikande och sökte sig därför inte till vården. Information om PCOS från vården mötte inte alltid patienternas behov.Fertilitetsaspekten ansågs vara det som fokuserades mest på från vårdens sida ochatt de psykologiska aspekterna glömdes bort. Symtom som övervikt och hirsutism påverkade det sociala livet negativt och psykisk ohälsa är vanligt förekommande.Slutsats: PCOS behöver uppmärksammas mer och normaliseras. En mer holistiskvård där fokus inte enbart ligger på det medicinska aspekterna, utan även ser till individens behov av stöd och information hade gynnat bemötandet och vårdandet till kvinnor med PCOS. / Background: Polycystic ovary syndrome (PCOS) is the most common hormonal condition amongst fertile women, yet it is still unknown for many. There are several symptoms that may vary from woman to woman. Ignorance of polycystic ovary syndrome occurs in healthcare and in society and can be difficult to detect.Living with the symptoms of PCOS can have a negative effect both physically andmentally. How women with the diagnosis experience PCOS needs to be highlighted and the understanding of them needs to be increased, both inhealthcare and for the women with PCOS. With increased understanding, bettertreatment and care can be provided. Aim: The purpose was to describe women’sexperiences of living with Polycystic ovary syndrome. Method: Qualitative meta synthesis with meta ethnographic analysis method. A total of 16 articles wereincluded and all passed through a quality critique checklist. The articles werecollected from three databases: Cinahl, Medline and PubMed. Findings: It couldtake a long time for a diagnosis to be made and sometimes the women had to be persistent, while others could be diagnoses as an incidental finding. Some womendid not know that their symptoms were not normal and therefore did not seekmedical care. Information about PCOS from the health care did not always meetthe patient’s needs. The fertility aspect was thought to be the main focus from the health care providers and that the phycological aspects were forgotten. Symptoms like overweight and hirsutism affected the social life in a negative way and mental illness was common. Conclusion: Polycystic ovary syndrome needs to be brought more attention to and to be normalized. A more holistic care where not only the main focus is on the medical aspects of PCOS, but instead also sees that the individuals need for support and information can be met.

Polycystic Ovarian Syndrome (PCOS) is an endocrine disorder that affects women’s menstrual cycles, androgen (male hormones) levels, and cysts on the ovaries. This endocrine disorder has various symptoms, with insulin resistance as a hallmark symptom. Approximately 65-70% of women with PCOS have insulin resistance and hyperinsulinemia, whether or not they are overweight, obese, or lean (Marshall & Dunaif, 2012). Many women with PCOS struggle to lose weight because their excess weight is related to nutrition, lifestyle factors, and imbalanced hormones. Understanding PCOS as a metabolic disorder with nutritional implications led to investigating the potential benefit of having registered dietitian nutritionists (RDN) as part of the healthcare team of women with PCOS. We developed a survey based on the literature on PCOS, diet/nutrition interventions, and the role of RDNs in the healthcare team of PCOS women of childbearing age. Only childbearing-age women (18–44) diagnosed with PCOS were eligible to complete the survey. The survey was designed as a needs assessment to determine if women with PCOS are routinely referred to RDNs for support; whether or not such support is beneficial; and what gaps in knowledge or misconceptions about nutrition and PCOS exist among participants. Most importantly, it was designed to examine if women understand how nutrition relates to managing their PCOS symptoms and future disease risks. The data from this survey shows the need for RDNs on the healthcare team of women with PCOS and gives us an understanding of nutrition education interventions that could be developed for future studies. Understanding how RDNs play a role in symptom management could lead to a better quality of life for women with PCOS.

People who are diagnosed with or suspect endometriosis or polycystic ovary syndrome (PCOS) are rarely included in the design of reproductive health applications, leading to a lack of functions useful to this user group. Non-normative user groups in general, including those experiencing endometriosis or PCOS, are also rarely mentioned in research of reproductive health applications or Human-Computer Interaction. Based on user requests, the aim of this thesis was to design new functions within the application Read Your Body aimed at their users experiencing endometriosis or PCOS. The project consisted of an iterative design process including research for design, sketching, prototyping, and user tests. It was found that this user group mainly wanted to track their symptoms and cycle to gain health insight, and a large number of tracking options and easy customisation was requested. The design process resulted in a design prototype that includes the ability to track symptoms, triggers, self-care practices and treatments as well as visualising and exporting data for personal health insight or to communicate with others. Knowledge created on the non-normative user group, their goals for tracking, and how to design reproductive health tracking applications for non-normative users could be useful in future research and design projects. The functions designed could improve understanding of self and communication with healthcare professionals, and inform diagnosis, treatment plans and self-care practices.