Polycystic ovary syndrome (PCOS) is a common and complex endocrine condition with reproductive and metabolic complications, affecting up to 10% of reproductive-age women. Hyperandrogenemia, ovulatory dysfunction, and luteinising hormone hypersecretion are characteristic traits of PCOS however, it seems that the most concerning long-term key issues are metabolic problems associated with the syndrome, such as hyperinsulinemia, insulin resistance, obesity, dyslipidaemia and non-alcoholic liver disease. Despite the numerous studies on PCOS, its origin and pathophysiology are still not fully understood. However, there is increasing evidence that the adult PCOS phenotype is programmed in fetal life by androgen excess. Exposure to increased levels of testosterone in utero in rodents, sheep and monkeys result in adult reproductive and metabolic pathologies that parallel those seen in PCOS women. Since hyperandrogenemia is a hallmark of PCOS and daughters of PCOS mothers have elevated levels of androgens at birth, it is likely that prenatal androgenisation during early life predispose to the future development of PCOS. Animal models of PCOS provide an opportunity to examine the developmental aetiology and molecular mechanisms underlying the pathogenesis of this condition. Over last 10 years our lab has successfully utilised a well-established ovine model of PCOS, where pregnant ewes were treated with testosterone propionate (TP) through mid-gestation. From this model, we had a large sample bank of fixed and frozen tissues from the fetal, lamb and adolescent prenatally androgenised animals that allowed to carry a broad range of experiments. In addition, a new cohort of prenatally androgenised adult sheep enabled additional in vivo analysis. Past research documented that prenatal androgenisation result in hyperinsulinemia with altered pancreas structure and function, and early fatty liver without difference in body weight in adolescent sheep. This thesis examines the effects and consequences of increased in utero androgen exposure on metabolic dysregulation in adolescent and adult female sheep. During puberty, but not fetal or early life, there was decreased adipogenesis in subcutaneous adipose tissue (SAT), but not visceral adipose tissue (VAT), accompanied by decreased circulating concentrations of fibroblast growth factor 21 (FGF21), leptin and adiponectin, and increased concentrations of fasting free fatty acids (FFA) in prenatally androgenised sheep. This was countered by upregulated expression of FFA transporters in liver. As adults, TP-exposed animals had increased body weight, elevated fasting insulin and FFA concentrations but normal FGF21, leptin and adiponectin levels. Histological analysis revealed that adult TP-exposed animals had SAT hypertrophy, which was associated with increased expression of inflammatory markers and correlated with increased fasting FFA. Therefore, it is likely that impaired preadipocyte differentiation in SAT during adolescence resulted in hypertrophy and inflammation of adult SAT. This consequently lowered capacity of SAT to safely store fat and potentially explains metabolic perturbations observed in PCOS-like female sheep. To further investigate potential causes of obesity in adult PCOS-like sheep postprandial thermogenesis (PPT), an important constituent of energy expenditure, was measured through implantation of datalogger thermometers into interscapular adipose tissue. Adult prenatally androgenised sheep had decreased amplitude of PPT, without difference in basal body temperature, despite receiving the same caloric intake, and independent of obesity. These findings indicate that adult PCOS-like sheep have reduced capacity for energy expenditure, which is mirrored in women with PCOS. This reduced capacity for postprandial thermogenesis was correlated with hyperinsulinemia decreased noradrenaline levels and reduced thermogenic potential of brown and/or beige adipose tissue. This suggests that women with PCOS might be prenatally programmed to become obese. In summary, findings documented in this thesis provide better understanding into the pathophysiology of PCOS from puberty to adulthood and give opportunities for early clinical intervention to ameliorate the metabolic phenotype of PCOS.

Polycystic ovary syndrome (PCOS) is a common reproductive, endocrine and metabolic disorder present in women of reproductive age. Despite the widespread prevalence and heritability of PCOS, the heterogeneous and polygenic traits have made the successful identification of candidate genes difficult. Animal models have been developed on the premise that early exposure to sex steroids can programme epigenetic changes that predispose the fetus to the adult features of PCOS. Past research has modelled ovarian dysfunction, endocrine abnormalities and metabolic perturbances in rodent, non-human primate and sheep PCOS models, through the enhanced neonatal or prenatal exposure to the male sex hormone, testosterone. The modelling of PCOS in a large domestic species such as the sheep is advantageous due to similar biological reproductive function as the human. In this regard the sheep has been extensively used to model PCOS by the treatment of pregnant ewes from early to midgestation with androgens such as testosterone propionate (TP). These experiments have demonstrated the fetal programming effects of androgens on offspring that go on to develop PCOS-like characteristics in adulthood. One of the caveats of assessing steroid effects in this way is the effect of the placenta in mediating the transfer of these hormones. TP is an aromatisable androgen and thus some of its effects in the fetus may be attributable to placental by-products such as estrogens. This thesis describes the development and assessment of a novel model of prenatal androgenisation. Two models were compared: the indirect maternal exposure to TP (the current model) and the direct fetal injection of TP. In directly treating the fetus this allowed control over the dose of TP administered and avoidance of secondary effects that androgens may exert in the mother that could be transferred to the fetus. For the maternal model, pregnant Scottish Greyface ewes were administered TP twice weekly from day (d)62-102 of a 147 day gestation. For the fetal model, fetuses were injected twice while the ewe was anaesthetised with graded doses of TP during the same period of treatment as the maternal model. The effects of prenatal androgenisation were assessed in the female fetus shortly after treatment and also in young adult sheep. Fetal ovarian and adrenal steroidogenic gene expression was monitored and found to be altered in response to elevated levels of sex steroids. At d90 the morphology of the developing ovary was not changed by prenatal androgens. In the adult a detailed ovarian and endocrine assessment was undertaken, by examination of ovarian morphology, hormone levels, ovulatory cycles, hypothalamic pituitary ovarian function and follicle steroidogenesis, during the first breeding season. In addition, the metabolic effects of prenatal androgens were monitored by measuring body fat, insulin and glucose homeostasis and liver function. Neither maternal nor fetal prenatal androgenisation during mid-gestation resulted in a perturbed hormonal milieu or polycystic ovaries in young adults. These treatments did however programme a clear ovarian phenotype demonstrated by the increased capacity of follicles to secrete androgens, independently of an abnormal endocrine environment and disordered folliculogenesis. Furthermore, animals that were exposed maternally to TP developed fatty liver and had increased insulin secretion in response to glucose load. A major outcome of this study was the finding that the fetally injected control animals were phenotypically different than the maternal control animals. In fact, some of the reproductive and metabolic features of maternal TP exposure were found in the fetal control group. This unexpected finding has raised the possibility that it is the fetal exposure to stress, that is secondary to elevated maternal androgens, rather than androgens per se that is responsible for at least some of the multitude of anomalies encountered in PCOS.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder encompassing reproductive and metabolic phenotypes. Genetic analysis, targeting candidate genes has to date proven unsuccessful in the search for a truly dominant genetic link. Another hypothesis to explain the etiology of PCOS is that of fetal programming in the context of developmental origins of health and disease. Extensive animal studies, validated by human data, support the fetal origins hypothesis of PCOS and highlight that PCOS may arise due to excess androgen exposure in fetal life. Previous reports from our laboratory found metabolic dysfunction in 11 month old prenatally androgenised females (d62-102 of fetal life), which included pancreatic and hepatic alterations. The pancreatic alterations seemed to result from gene expression changes induced in fetal life. Therefore, chapter 3 focuses on the gluconeogenic response in the day 90 fetus following maternal androgenisation from day 62 of gestation. Interestingly hepatic gluconeogenic enzymes, specifically phosphoenolpyruvate caboxykinase (PEPCK) and glucose 6 phosphatase (G6PC), were not altered. However they were decreased in the kidney, in a sex specific manner with PEPCK significantly decreased (P<0.01) and G6PC showing a strong trend toward reduction (P=0.056) in females only. This chapter progresses to explore regulatory pathways involved in gluconeogenic regulation. It seems probable that the female specific increase in circulating testosterone (P<0.001), with increased renal androgen reception (P<0.01), may be accountable for the altered expression of gluconeogenic enzymes in the kidney. Chapter 4 investigates why testosterone concentrations were not increased in the male fetus, after maternal androgenisation, by focusing on the site of testosterone production, the fetal testis. Results demonstrate that the day 90 fetus is capable of responding to prenatal androgenisation by decreasing luteinising hormone (P<0.01) and thus testicular testosterone production, such that there was a global down regulation in steroidogenic enzyme expression, in vivo testosterone production (P<0.001) and Leydig cell morphology was altered (P<0.001). As prenatal androgenisation is administered through the maternal route and placental aromatisation may occur, a novel method whereby the fetus was directly injected was utilised to assess the effects of control oil (C), testosterone (TP) or diethylstilboestrol (DES) on the fetal testis. Unlike DES, direct fetal injection with TP mimics the results found from maternal androgenisation. When the testis are examined at a later date, day 112, ten days after androgen treatment ceases, Leydig cell morphology and steroidogenic gene expression return to control values, although fascinatingly, an overshoot of in vivo testosterone production (P<0.01) was observed. When the maternal androgenisation window is extended to begin at day 30 of fetal life, further changes are noted including increased circulating testosterone (P<0.01), a strong trend toward decreased testis weight (P=0.0519) and altered expression of Sertoli and germ cell specific markers. These studies are followed up by assessing the legacy effect of testosterone on the peripubertal male testis in Chapter 5. At ten weeks of postnatal life, males, exposed to androgens from day 62-102 of fetal life had reduced testis weight (P<0.05). However, functional or cellular alterations were not observed and by 12 weeks of age, when LH had normalised, testicular weight and stimulated testosterone secretion of prenatally TP-treated males was comparable to controls. This highlights the remarkable plasticity of the testis and the unremarkable legacy of altered prenatal androgen exposure. The legacy effect of testosterone on the fetal ovary is examined in Chapter 6. Previous studies from our laboratory found minor functional alterations but no structural alterations in the fetal ovary at day 90 following androgenisation from day 62. However, as this was at a time of a highly androgenic environment we assessed the function and morphology of the ovary ten days after the removal of testosterone at day 112. In marked contrast to the normalisation of the male gonad, we observe structural changes with an increase in recruited follicles from the primordial to primary stage in the testosterone treated group (P<0.01). The chapter continues with an investigation of pathways involved in the altered follicular dynamics that may account for the change in follicular recruitment. Furthermore, the functional changes which were previously noted in the day 90 ovary were also examined in response to direct exogenous steroid treatment including, C, TP, DES and dexamethasone (DEX) and also when the window of maternal androgenisation was extended to begin at day 30. Interesting changes are observed such that the direct fetal injection treatments induce similar changes to each other, regardless of the steroid, whilst maternal androgenisation induces a different response. This highlights the complexity of the pathways involved in female gonadal development.

Made available in DSpace on 2014-06-11T19:35:39Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-08-20Bitstream added on 2014-06-13T19:24:59Z : No. of bitstreams: 1 rehme_mfb_dr_botfm.pdf: 2280081 bytes, checksum: b44989e75865f4acff4695729feffce0 (MD5) / A síndrome dos ovários policísticos (SOP) afeta 5 a 8% das mulheres no menacme e é caracterizada pela anovulação crônica e hiperandrogenismo. A obesidade central e a resistência insulínica (RI) são freqüentes na SOP e desempenham um papel fundamental na etiopatogenia da síndrome metabólica (SM). O hiperandrogenismo tem sido questionado como um fator importante no desenvolvimento da SM em mulheres com SOP. Verificar se o hiperandrogenismo influencia no desenvolvimento de síndrome metabólica em pacientes com SOP. Foram avaliados retrospectivamente os dados clínicos, bioquímicos e ultrassonográficos de 180 mulheres com SOP diagnosticadas pelos critérios de Rotterdam e de 70 mulheres com obesidade simples. As pacientes com SOP foram classificadas de acordo com o índice de massa corporal (IMC) em SOP não obesas e SOP obesas. As pacientes obesas simples não apresentaram hiperandrogenismo clínico nem bioquímico. O índice de sensibilidade à insulínica (ISI) foi avaliado pelo HOMA-IR e ISI de Matsuda e DeFronzo. A SM foi diagnosticada pelos critérios do NCEP-ATP III com modificações sugeridas pelo consenso de Rotterdam. A média de idade das pacientes foi de 27,3 + 4,7 no grupo das pacientes SOP não obesas; 28,8 + 5,0 nas SOP obesas e 27,4 + 5,2 nas obesas simples (p=0, 0773), e o IMC foi de 25,1+3,0 kg/m2; 37,0+ 5,5 kg/m2 e 36,0+ 4,2 kg/m2 respectivamente (p<0, 001). A prevalência de RI e SM não diferiu entre as pacientes obesas com e sem SOP e foi significativamente maior do que nas SOP não obesas (p<0, 001). Entretanto a prevalência de SM foi maior nas SOP obesas com hiperandrogenismo... / Polycystic ovary syndrome (PCOS) affects 5-8% of women at menacme and is characterized by chronic anovulation and hyperandrogenism. Central obesity and insulin resistance (IR) are frequent in PCOS and play a leading role in the etiopathogeny of metabolic syndrome (MS). Hyperandrogenism has been suggested as an important factor in the development of MS in women with PCOS. To determine whether hyperandrogenism influences the development of metabolic syndrome in patients with PCOS. Clinical, biochemical and ultrasonographic data on 180 women with PCOS, as diagnosed by the Rotterdam criteria, and 70 women with simple obesity were retrospectively analyzed. According to body mass index, PCOS patients were classified as nonobese with PCOS and obese with PCOS. No clinical or biochemical hyperandrogenism was observed in patients with simple obesity. Insulin sensitivity indices (ISI) were assessed as proposed by HOMA-IR and ISI (Matsuda and De Fronzo). MS was diagnosed based on NCEP-ATP III criteria with modifications suggested by the Rotterdam consensus. Mean age was 27.3 + 4.7 among non-obese patients with PCOS, 28.8 + 5.0 in obese patients with POS, and 27.4 + 5.2 in those with simple obesity (p=0.0773), while BMI was 25.1+3.0 kg/m2, 37.0+ 5.5 kg/m2 and 36.0+ 4.2 kg/m2, respectively (p<0.001). The prevalence of IR and MS did not differ between obese patients with and without PCOS, and was significantly higher in these patients than in non-obese women with PCOS (p<0.001). The prevalence of MS, however, was higher... (Complete abstract click electronic access below)

Orientador: Anaglória Pontes / Banca: Tamara Goldberg / Banca: Marcos Felipe Silva de Sá / Banca: José Alcione Macedo Almeida / Banca: Cleusa Cascaes Dias / Resumo: A síndrome dos ovários policísticos (SOP) afeta 5 a 8% das mulheres no menacme e é caracterizada pela anovulação crônica e hiperandrogenismo. A obesidade central e a resistência insulínica (RI) são freqüentes na SOP e desempenham um papel fundamental na etiopatogenia da síndrome metabólica (SM). O hiperandrogenismo tem sido questionado como um fator importante no desenvolvimento da SM em mulheres com SOP. Verificar se o hiperandrogenismo influencia no desenvolvimento de síndrome metabólica em pacientes com SOP. Foram avaliados retrospectivamente os dados clínicos, bioquímicos e ultrassonográficos de 180 mulheres com SOP diagnosticadas pelos critérios de Rotterdam e de 70 mulheres com obesidade simples. As pacientes com SOP foram classificadas de acordo com o índice de massa corporal (IMC) em SOP não obesas e SOP obesas. As pacientes obesas simples não apresentaram hiperandrogenismo clínico nem bioquímico. O índice de sensibilidade à insulínica (ISI) foi avaliado pelo HOMA-IR e ISI de Matsuda e DeFronzo. A SM foi diagnosticada pelos critérios do NCEP-ATP III com modificações sugeridas pelo consenso de Rotterdam. A média de idade das pacientes foi de 27,3 + 4,7 no grupo das pacientes SOP não obesas; 28,8 + 5,0 nas SOP obesas e 27,4 + 5,2 nas obesas simples (p=0, 0773), e o IMC foi de 25,1+3,0 kg/m2; 37,0+ 5,5 kg/m2 e 36,0+ 4,2 kg/m2 respectivamente (p<0, 001). A prevalência de RI e SM não diferiu entre as pacientes obesas com e sem SOP e foi significativamente maior do que nas SOP não obesas (p<0, 001). Entretanto a prevalência de SM foi maior nas SOP obesas com hiperandrogenismo... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Polycystic ovary syndrome (PCOS) affects 5-8% of women at menacme and is characterized by chronic anovulation and hyperandrogenism. Central obesity and insulin resistance (IR) are frequent in PCOS and play a leading role in the etiopathogeny of metabolic syndrome (MS). Hyperandrogenism has been suggested as an important factor in the development of MS in women with PCOS. To determine whether hyperandrogenism influences the development of metabolic syndrome in patients with PCOS. Clinical, biochemical and ultrasonographic data on 180 women with PCOS, as diagnosed by the Rotterdam criteria, and 70 women with simple obesity were retrospectively analyzed. According to body mass index, PCOS patients were classified as nonobese with PCOS and obese with PCOS. No clinical or biochemical hyperandrogenism was observed in patients with simple obesity. Insulin sensitivity indices (ISI) were assessed as proposed by HOMA-IR and ISI (Matsuda and De Fronzo). MS was diagnosed based on NCEP-ATP III criteria with modifications suggested by the Rotterdam consensus. Mean age was 27.3 + 4.7 among non-obese patients with PCOS, 28.8 + 5.0 in obese patients with POS, and 27.4 + 5.2 in those with simple obesity (p=0.0773), while BMI was 25.1+3.0 kg/m2, 37.0+ 5.5 kg/m2 and 36.0+ 4.2 kg/m2, respectively (p<0.001). The prevalence of IR and MS did not differ between obese patients with and without PCOS, and was significantly higher in these patients than in non-obese women with PCOS (p<0.001). The prevalence of MS, however, was higher... (Complete abstract click electronic access below) / Doutor

The purpose of this study was to investigate the relative contributions of previously identified Polycystic ovary syndrome (PCOS) manifestations (infertility, hirsutism, obesity, menstrual problems) to multiple psychological symptoms. Participants were 126 female endocrinology patient volunteers diagnosed with PCOS who completed a cross-sectional study of PCOS manifestations and psychological symptoms. Participants had significantly elevated scores on nine subscales of psychological symptoms. Menstrual problems were significantly associated with all symptom subscales as well as the global indicator, while hirsutism and obesity were significantly related to five or more subscales. After controlling for demographic factors, menstrual problems were the strongest predictor of psychological symptoms. Findings suggest features of excess body hair, obesity, and menstrual abnormalities carry unique risks for adverse psychologic symptoms, but menstrual problems may be the most salient of these features and deserve particular attention as a marker for psychological risk among women with PCOS.

Το σύνδρομο των πολυκυστικών ωοθηκών (PCOS) είναι ίσως η συχνότερη διαταραχή των γυναικών αναπαραγωγικής ηλικίας. Οι κύριες κλινικές εκδηλώσεις του συνδρόμου είναι η υπερανδρογοναιμία και η χρόνια ανωοθυλακιορρηξία, ενώ σχετίζεται σε μεγάλο βαθμό με την παχυσαρκία και την αντίσταση στην ινσουλίνη. Η αντίσταση στην ινσουλίνη έχει ένα σημαντικό ρόλο τόσο ως αίτιο όσο και ως αποτέλεσμα του συνδρόμου. Στις γυναίκες τόσο η υπερινσουλιναιμία όσο και η υπερανδρογοναιμία σχετίζεται με αυξημένο καρδιοαγγειακό κίνδυνο. Το PCOS σχετίζεται με αυξημένο καρδιοαγγειακό κίνδυνο, ενώ τόσο η αλλαγή τρόπου ζωής και η φαρμακολογική παρέμβαση έχει δειχθεί ότι βελτιώνει την υπερανδρογοναιμία και την υπογονιμότητα και ελαττώνει τον καρδιοαγγειακό κίνδυνο. Μαζί με τους κλασικούς καρδιοαγγειακούς παράγοντες κινδύνου, αιμοδυναμικές και αιματολογικές μεταβλητές παίζουν σημαντικό ρόλο στην παθογένεση της αθηρωσκλήρυνσης. Η γλοιότητα του πλάσματος είναι σημαντική αιματολογική μεταβλητή και εξαρτάται απο μακρομόρια όπως το ινωδογόνο, οι ανοσοσφαιρίνες και οι λιποπρωτεϊνες. Ο σκοπός της παρούσης μελέτης ήταν να ερευνήσει τις μεταβολές της γλοιότητας του πλάσματος σε γυναίκες με PCOS και την συσχέτιση τους με την υπερανδρογοναιμία, την παχυσαρκία και την αντίσταση στην ινσουλίνη. Η μελέτη συμπεριέλαβε 96 ασθενείς με PCOS και 72 γυναίκες με φυσιολογική έμμηνο ρύση ως ομάδα ελέγχου. Η γλοιότητα πλάσματος ήταν 1.243±0.670 mm2/s στην ομάδα ελέγχου (n=72), και 1.250±0.079 στιν γυναίκες με PCOS (n=96) (p=0.524). Η γλοιότητα του πλάσματος εμφάνισε σημαντική συσχέτιση με BMI (b=0.315, p=0.013), Ολικές Πρωτείνες (b=0.348, p=0.005), AUCIns (b=0.320, p=0.011). Στις γυναίκες με PCOS με αντίσταση στην ινσουλίνη (PCOS-IR) η γλοιότητα του πλάσματος ήταν 1.300 ± 0.055 mm2/s, ενώ στις γυναίκες με PCOS χωρίς αντίσταση στην ινσουλίνη (PCOS-ΝIR) η γλοιότητα του πλάσματος ήταν 1.231± 0.49 mm2/s (p=0.004). Στη συνέχεια χωρίσαμε όλες τις γυναίκες με PCOS σε 2 υποομάδες: αυτές με BMI<25 και αυτές με BMI>25. Η γλοιότητα πλάσματος ήταν 1.235±0.786mm2/s στις γυναίκες με PCOS και BMI<25, και 1.273±0.756mm2/s στις γυναίκες με PCOS και BMI>25 (p=0.024). Σε νέες γυναίκες με PCOS η αύξηση της γλοιότητας του πλάσματος συσχετίσθηκε με την παχυσαρκία και την αντίσταση στην ινσουλίνη. Συμπερασματικά στις νέες γυναίκες με PCOS η γλοιότητα του πλάσματος επιδεινώθηκε από την αντίσταση στην ινσουλίνη. Καθώς η αυξημένη γλοιότητα του πλάσματος είναι ένας πρώιμος παράγοντας κινδύνου για καρδιοαγγειακή νόσο, ο κλινικός χειρισμός των νέων υπέρβαρων γυναικών με PCOS θα πρέπει πάντα να περιλαμβάνει μία μείωση του σωματικού τους βάρους και τη λελογισμένη και με προσοχή χρήση των αντισυλληπτικών δισκίων ως θεραπευτική προσέγγιση. / Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. PCOS is characterized by hirsutism, anovulation, hyperandrogenemia and is also highly associated with obesity and insulin resistance. Insulin resistance plays a significant role, both as a cause and as a result of the syndrome. Both hyperinsulinemia and androgen excess in women is associated with increased cardiovascular risk. PCOS is linked to cardiovascular disease, while, altering lifestyle or pharmacological intervention has been shown to improve hyperandrogenism and infertility and reduce cardiovascular risk. Along with classic cardiovascular risk factors, hemodynamic and hemorheologic variables play an important role in the pathogenesis of atherosclerosis. Plasma viscosity is an important hemorheologic variable and is mainly determined by several macromolecules, including fibrinogen, immunoglobulins, and large lipoproteins. Our objective was to investigate plasma viscosity in women with PCOS. The acquired data were tested for association with hyperandrogenemia, obesity and insulin resistance in PCOS patients. The study included 96 young PCOS women and 72 healthy controls. Plasma viscosity was 1.243±0.670 mm2/s in the control group and 1.250±0.079 in PCOS women (p=0.524). Total protein (B=0.348, p=0.005), AUC for Insulin (B=0.320, p=0.011) and BMI (B=0.315, p=0.013) were proven to be significantly correlated to plasma viscosity. Plasma viscosity was significantly increased in PCOS women with Insulin Resistance (IR) compared to matched for age and BMI PCOS women without IR (1.300±0.055 mm2/s versus 1.231±0.049 mm2/s) (p=0.004). Then we divided all PCOS women in two separate groups, lean PCOS with BMI<25 and obese PCOS with BMI>25. Plasma viscosity was 1.235±0.786mm2/s in PCOS women with BMI<25, in the group of women was and 1.273±0.756mm2/s in PCOS women with BMI>25 (p=0.024). Young PCOS women presented a plasma viscosity which was increased by obesity and IR. In conclusion, young PCOS women presented a plasma viscosity which was deteriorated by IR. As increased plasma viscosity is an early risk factor for cardiovascular disease, clinical management of young overweight PCOS women with IR should always include a serious reduction in body weight and the use of oral contraceptive treatment with cautious.

Ziel der Untersuchungen war, zur Klärung der Ursachen einer während der letzten Jahrzehnte erhöhten Frequenz sowohl von PCOS als auch von IO beizutragen. Es war zu ermitteln, ob hormonelle Verschiebungen bei den Patienten nachweisbar und diese durch genetische und epigenetische Faktoren erklärbar sind. Ausgehend von dem Postulat, daß verminderte 21-OH- und 3beta-HSD-Aktivitäten als prädisponierende Faktoren von PCOS und IO angesehen werden, waren hormonanalytische Untersuchungen zur Ermittlung partieller 21-OH- bzw. 3beta-HSD-Defizienzen durchgeführt worden. Den eigenen Erfahrungen und Darstellungen der internationalen Literatur entsprechend befaßt sich ein Teil der Methodik mit der Entwicklung einer neuen, der üblichen 17alfa-OHP-Messung überlegenen Methode zur Ermittlung von 21-OH-Defizienzen durch 21-DOF-Bestimmung nach ACTH-Test im Blutplasma. Wir erhielten bei vier von 21 PCOS-Patientinnen und drei von acht Patienten mit IO erhöhte 21-DOF-, 21-DOF/F- bzw. 17alfa-OHP-Werte nach ACTH-Test, die auf partielle 21-OH-Defizienzen hinweisen. Zusätzlich wurden bei 12 PCOS-Patientinnen erhöhte basale DHEAS- oder DHEAS/F-Werte gefunden, die als Hinweise auf partielle 3beta-HSD-Defizienzen oder 17,20-Lyase-Hyperaktivität gedeutet wurden. In der Stichprobe der IO waren DHEAS oder DHEAS/F-Werte bei vier Patienten erhöht. Da bei vier der 12 Patientinnen mit PCOS und zwei von vier Patienten mit IO genetisch und endokrinologisch gleichzeitig eine partielle 21-OH-Defizienz nachgewiesen wurde, kann bei diesen Patienten eine partielle 3beta-HSD-Defizienz weitgehend ausgeschlossen werden. Es wurden molekulargenetische Untersuchungen für die 14 häufigsten Mutationen in CYP21 bei Cohorten mit AGS, PCOS und IO durchgeführt. Die Untersuchung der AGS-Patienten sollte dazu dienen, ein effizientes und schnelles System der Mutationssuche für diagnostische Zwecke zu etablieren. Es wurden die häufigsten, phänotypisch wirksamen Mutationen in CYP21 bei der Mehrzahl dieser Patientengruppe im homozygoten bzw. compound heterozygoten Zustand gefunden und eine deutliche Genotyp-Phänotyp-Korrelation festgestellt. Auch bei Patientinnen mit PCOS sowie bei IO, bei denen partielle 21-OH-Defizienzen nachweisbar waren, wurden Mutationen in CYP21 gefunden. Die hierbei heterozygot vorliegenden Mutationen waren dieselben, die homozygot oder compound heterozygot bei schweren Formen des AGS gefunden wurden. Es ergab sich eine Korrelation molekulargenetischer und hormonanalytischer Befunde bei AGS, PCOS sowie IO. Allerdings konnten bei der Mehrzahl der Fälle mit PCOS und mit IO weder Mutationen noch hormonelle Auffälligkeiten hinsichtlich partieller 21-OH-Defizienzen gefunden werden. Die jedoch bei vielen Patientinnen gefundenen erhöhten DHEAS- und DHEAS/F-Werte stimmen mit Untersuchungen überein, die parallel starke Zunahmen der Häufigkeit der Hemmung des Enzyms 3ß-HSD bzw. der Aktivierung der 17,20-Lyase bei PCOS-Patientinnen und der Prävalenz des PCOS selbst bei nach 1955 geborenen Frauen und von Spermatogenesestörungen bei nach 1960 geborenen Männern fanden. Die Ursache hierfür wird in der Beeinflussung der adrenalen und gonadalen Steroidhormonsynthese vor allem durch das Umweltteratogen DDT und seine Metaboliten gesehen. Weiterhin wurde der Umweltfaktor Streß diskutiert. Für die Ätiopathogenese der untersuchten Fertilitätsstörungen werden materno-fetale Mechanismen postuliert, worauf unsere sowohl molekulargenetischen als auch hormonanalytischen Befunde hinweisen. Insgesamt bestätigen die Ergebnisse unserer Arbeit die These, daß Leben auf der Interaktion von Genen und Umweltfaktoren beruht und daß Hormone dabei als Mediatoren wirken. In gen- oder umweltbedingten unphysiologischen Konzentrationen können sie während kritischer Entwicklungsphasen des neuroendokrinen Systems als Teratogene wirken und zu lebenslangen Reproduktionsstörungen führen. / This paper describes a mutational and hormonal screening in a cohort of 21 patients ultrasonically diagnosed with PCO. Our data show single heterozygous base pair CYP21 mutations in 4 patients. The four women with PCOS and CYP21 mutations also displayed clear signs of partial 21-hydroxylase deficiency through a significant rise in 21DOF or 17alfa-OHP plasma levels after ACTH stimulation. Azziz et al. have reported several heterozygous mutations in hyperandrogenic women with LO-CAH. Other studies report several heterozygous point mutations in hyperandrogenic woman who, however, were not examined for polycystic ovaries.The correlation between the hormone profiles and genetic screening results found with our patients underscores the latter s usefulness with PCOS patients. In contrast to the hormone profile, genetic screening is not influenced by external factors. The frequency of heterozygous CYP21 mutations is higher (19%) than in the normal population (5-8%), suggesting a link with PCOS in some cases. The ratio of LH/FSH was significantly raised in 43% of the cases. Most importantly, basal plasma DHEA-S levels and DHEA-S/F ratios were clearly increased, higher than the means +2SD in controls. This suggests a partial 3beta-hydroxysteroid dehydrogenase deficiency or 17,20 lyase hyperactivity. Other authors, however, were not able to find mutations in the corresponding genes. This could be explained by the fact that the DDT metabolite o,p DDD is a strong inhibitor of 3beta-HSD, and that DDT and its metabolites may be able to activate the 17,20 lyase, a cytochrome P450 enzyme. Furthermore, DDT has some oestrogen activity, and its perinatal administration can produce a PCOS-like syndrome in rats. Very significantly, there has not only been an approximately fourfold increased prevalence of PCO in women borne since 1955 in eastern Germany, following a massive prenatal exposure to DDT, but also a notable shift in the hormone profiles of those affected. A predominance of 3beta-HSD deficiencies and 17,20 lyase hyperactivity (70%) vs. 21-hydroxylase deficiency (23%) has emerged, in contrast with 21-hydroxylase deficiencies in 70% vs. 3beta-HSD deficiencies or 17,20 lyase hyperactivity in 14% for those born earlier than 1955. Similar results were obtained in this study for women with PCOS born since 1955, suggesting that the prenatal exposure of high amounts of DDT and its metabolites indeed appear to be responsible - at least in part - for the major increase in PCO and PCOS.

Σκοπός: η μελέτη της επίδρασης εξάμηνης θεραπείας με από του στόματος αντισυλληπτικό δισκίο περιέχον 35μg αιθινυλ-οιστραδιόλης και 2mg οξικής κυπροτερόνης στη γλοιότητα πλάσματος νέων γυναικών με σύνδρομο πολυκυστικών ωοθηκών. Σχεδίαση: Η γλοιότητα πλάσματος μετρήθηκε σε ασθενείς με σύνδρομο πολυκυστικών ωοθηκών πριν και 6 μήνες μετά από τη χορήγηση αντισυλληπτικού δισκίου περιέχοντος 35μg αιθινυλ-οιστραδιόλης και 2mg οξικής κυπροτερόνης. Η μέτρηση της γλοιότητας έγινε σε ιξωδόμετρο τύπου 53610/I SCHOTT-Instruments, Mainz στους 37ο C. Ασθενείς: Οι ασθενείς στρατολογήθηκαν από το τμήμα Αναπαραγωγικής Ενδοκρινολογίας της Μαιευτικής - Γυναικολογικής Κλινικής του Πανεπιστημιακού Νοσοκομείου Πατρών Ελλάδας. Στη μελέτη περιλήφθηκαν 66 νέες γυναίκες με σύνδρομο πολυκυστικών ωοθηκών. Βασικοί προσδιορισμοί: Γλοιότητα πλάσματος Αποτελέσματα: Στις ασθενείς ως σύνολο, η γλοιότητα πλάσματος ήταν 1.249±0.049 mm2/s (n=66). Μετά από 6 μήνες θεραπείας με από του στόματος αντισυλληπτικό δισκίο περιέχον 35μg αιθινυλ-οιστραδιόλης και 2mg οξικής κυπροτερόνης, η γλοιότητα πλάσματος αυξήθηκε σε 1.268±0.065 mm2/s (p=0.038). Η διαφορά στη γλοιότητα πλάσματος πριν και 6 μήνες μετά τη θεραπεία (Δ Γλοιότητας) ήταν 0,01864±,071452 mm2/s. Η Δ Γλοιότητας σχετιζόταν με τη Δ Ινωδογόνου (r=0.270, p=0.046), τη Δ Αιματοκρίτη (r=0.514, p=0.09) και τη Δ Τριγλυκεριδίων (r=0.292, p=0.021). Συμπέρασμα: Νέες γυναίκες με σύνδρομο πολυκυστικών ωοθηκών εμφάνισαν αυξημένη γλοιότητα πλάσματος μετά από θεραπεία με από του στόματος αντισυλληπτικό, το οποίο θα πρέπει για το λόγο αυτό να χρησιμοποιείται με προσοχή στον εν λόγω πληθυσμό. / Objectives: To investigate the influence of 6 months of treatment with an oral contraceptive (OC) containing 35μg ethinyl estradiol and 2mg cyproterone acetate on plasma viscosity in young women with PCOS. Design: PCOS patients were assessed for plasma viscosity before and after 6 months of treatment with an OC containing 35μg ethinyl estradiol and 2mg cyproterone acetate. Plasma viscosity was determined by a viscometer Type 53610/I SCHOTT-Instruments, Mainz at 37o C. Settings: Subjects were recruited from the Department of Obstetrics and Gynaecology, Division of Reproductive Endocrinology at the University Hospital of Patras, Greece. Patients: The study included 66 young PCOS women. Main Outcome measures: Plasma viscosity. Results: In PCOS women as a whole, plasma viscosity at baseline was 1.249±0.049 mm2/s (n=66). After 6 months of treatment with an oral contraceptive containing 35μg ethinyl estradiol and 2mg cyproterone acetate, plasma viscosity increased to 1.268±0.065 mm2/s (p=0.038). The difference between plasma viscosity before and after 6 months of treatment with an oral contraceptive containing 35μg ethinyl estradiol and 2mg cyproterone acetate (Δviscosity) was 0,01864±,071452 mm2/s. Δviscosity was related to Δfibrinogen (r=0.270, p=0.046), to Δhaematocrit (r=0.514, p=0.09) and to Δtriglycerides (r=0.292, p=0.021). Conclusion: Young PCOS women presented an increased plasma viscosity under OC treatment, which therefore should be used with caution.

Le syndrome des ovaires polykystiques (SOPK) est le désordre endocrinien le plus répandu chez la femme en âge de procréer. Ayant un impact significatif sur la qualité de vie, il est l’une des causes majeures d’infertilité et est associé à des conditions chroniques sérieuses comme le diabète de type 2, des cancers hormono-dépendants, et les maladies cardiovasculaires. Bien qu’il soit prévalent et ait des conséquences importantes, l’expérience des soins vécue par les femmes traduit des dimensions problématiques : manque de sensibilisation et d’information, délais de diagnostic, insensibilité, inattention et banalisation. Selon certaines recherches, les femmes ne sont pas satisfaites des traitements habituellement prescrits, comme la pilule contraceptive. Elles considèrent manquer d’options de traitement et seraient intéressées par d’autres modalités de soin. D’autres travaux mettent également l’accent sur l’importance du mode de vie (ex. nutrition et gestion du stress) qui peut améliorer le profil métabolique et endocrinien, ainsi que se répercuter de manière favorable sur la fonction reproductive. Le manque général d'attention à cette condition représente dès lors une étude de cas intéressante, reflétant des injustices systémiques en médecine. L’objectif de cette thèse est d’examiner les enjeux en lien avec l’autonomie des femmes affectées par le SOPK dans le cadre des soins de santé et de fertilité, et de proposer des pistes de solution visant à favoriser son expression. Ces enjeux sont analysés dans le contexte de la maladie chronique, où l’accent est surtout mis sur le traitement visant à soulager l'infertilité, mais qui néglige les approches restauratives en regard de la santé, notamment par des changements de mode de vie. L’analyse des enjeux est faite selon une approche relationnelle de l’autonomie en considérant deux modes d’expression : épisodique et programmatique. La mise en évidence de ces enjeux rend possible une réflexion sur ce que pourrait apporter une vision globale dans le soin du SOPK, s’articulant tout autant autour de la gestion de la maladie que d’une approche restaurative de la santé. Afin d’analyser les enjeux éthiques particuliers que pose le soin du SOPK, cette thèse utilise une perspective à la fois conceptuelle-normative et empirique. Ces deux perspectives permettent 6 de mieux comprendre les lacunes de l'approche médicale actuelle et de formuler des recommandations éclairées sur les meilleures façons d’y faire face. Par la reconnaissance de la nécessité d’une approche du soin intégrant tant les aspects relatifs à la prévention et à la gestion du SOPK qu’une visée restaurative à l’égard de la santé, cette thèse amène des retombées importantes pour les professionnels de la santé et les femmes affectées par le SOPK. Ce faisant elle présente des pistes permettant de soutenir tant l’autonomie épisodique que programmatique, ainsi que l’empowerment de ces femmes. / Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of childbearing age. It has a significant impact on quality of life and is one of the major causes of infertility. It is also associated with serious chronic conditions such as type 2 diabetes, hormonedependent cancers, and cardiovascular disease. While it is prevalent and has serious consequences, women's experience of care reflects problematic dimensions: lack of awareness and information, delays in diagnosis, insensitivity, inattention, and trivialization. Research shows that women are dissatisfied with commonly prescribed treatments such as the contraceptive pill. They report lacking treatment options and would be interested in other modalities of care. Research on PCOS also emphasizes the importance of lifestyle (e.g. nutrition and stress management) that can improve the metabolic and endocrine profile and have a positive impact on reproductive function. The general lack of attention to this condition is thus an interesting case study, reflecting systemic injustices in medicine. The objective of this thesis is to examine issues related to the autonomy of women affected by PCOS in the context of health care and fertility, and to propose ways to promote the expression of autonomy. The thesis analyzes these issues in the context of chronic disease, whereby treatment focuses on alleviating infertility and neglects restorative approaches to health, particularly through effective lifestyle changes. The analysis is based on the conceptual framework of relational autonomy, and considers two possible modes of autonomy expression: episodic and programmatic. Awareness of these issues makes it possible to reflect on what a holistic approach could bring to PCOS care, considering both disease management and a restorative approach to health. To consider the ethical challenges related to the care of PCOS, this thesis employs both a conceptual-normative and an empirical perspective. Both allow a better understanding of the shortcomings of the current medical approach and an informed recommendation for better ways of responding to these challenges. By recognizing the need for prevention and management of PCOS, as well as a restorative approach to health, this thesis has substantial implications for healthcare professionals and women, suggesting ways of supporting both episodic and programmatic autonomy and empowerment of affected women.