Das polyzystische Ovarsyndrom (PCOS) mit einer Prävalenz von 5 % – 10 % ist eine der häufigsten Endokrinopathien bei Frauen vor der Menopause. Wie bisher vermutet, handelt es sich bei PCOS um ein sogenanntes multifaktorielles Krankheitsgeschehen. Einzelne Manifestationen des Metabolischen Syndroms (MetS), wie Hyperandrogenämie, Insulinresistenz (IR) und damit verbundene Hyperinsulinämie, Dyslipidämie und ein erhöhter CRP-Spiegel, werden bereits als Risikofaktoren für Typ 2 Diabetes mellitus (DM-II) und kardiovaskulären Krankheiten (KVK) bei den Patientinnen mit PCOS verwendet. Die Konzentrationen von Leptin und Adiponektin könnten nützliche und zuverlässige Marker für das Ausmaß der metabolischen Störung bei PCOS-Patientinnen sein. In zahlreichen Studien wurde davon berichtet, dass eine additive Gabe von Metformin die IR und andere Surrogat-Parameter des MetS in gleicher Weise bei adipösen und normalgewichtigen Probandinnen verbessert. In dieser Studie wurde der Insulin-Spiegel im Rahmen eines oralen Glukose-Toleranz-Test bei der Erstdiagnose und ca. ein bis eineinhalb Jahren nach der Metformintherapie bestimmt. Die Nüchtern-Insulinwerte der Vor-Therapie-Gruppe sind im Vergleich zur Nach-Therapie-Gruppe bei 75 % der Teilnehmerinnen signifikant aus dem hyperinsulinämischen Bereich in den normoinsulinämischen Bereich abgesunken (29.7 ± 6.7 µU/ml bzw. 13.7 ± 2.7 µU/ml, P = 0.045). Vergleichbar signifikant haben sich die Werte nach ein und zwei Stunden verbessert (154.5 ± 13.6 µU/ml vs. 96.2 ± 13.9 µU/ml, P = 0.0096 bzw. 128.0 ± 19.0 µU/ml vs. 59.2 ± 13.3 µU/ml, P = 0,0104). Konsistent damit senkte sich der HOMA-Index (5.9 ± 1.4 vs. 2.8 ± 1.6, P = 0,521). Die Leptin-Konzentration sank um 50 % (39.9 ± 9.7 vs. 20.3 ± 2.9 ng/ml, P = 0.0737 bzw. (mittlere Insulinspiegel nüchtern) 29.7 ± 6.7 µU/ml vs. 13.7 ± 2.7 µU/ml, P = 0,045), und die Adiponektin-Konzentration der Nach-Therapie-Gruppe im Vergleich zur Vor-Therapie-Gruppe stieg deutlich an (5.34 ± 0.6 vs. 6.35 ± 0.8 ug/ml, P = 0.4666, ns). Somit sind die Plasmaspiegel von Leptin und Adiponektin günstige Marker zur Risikoabschätzung und Diagnostik eines PCOS, zweitens eine metabolische Frühdiagnostik, und eine frühere Erwägung und Anwendung einer Strategie zur Senkung der Insulinresistenz sind aus präventiver Sicht ratsam.

This PhD thesis focuses on improving the limit of detection (LOD) of Raman biosensors by using surface enhanced Raman scattering (SERS) and/or hollow core photonic crystal fibers (HC-PCF), in conjunction with statistical methods. Raman spectroscopy is a multivariate phenomenon that requires statistical analysis to identify the relationship between recorded spectra and the property of interest. The objective of this research is to improve the performance of Raman biosensors using SERS techniques and/or HC-PCF, by applying partial least squares (PLS) regression and principal component analysis (PCA). I began my research using Raman spectroscopy, PLS analysis and two different validation methods to monitor heparin, an important blood anti-coagulant, in serum at clinical levels. I achieved lower LOD of heparin in serum using the Test Set Validation (TSV) method. The PLS analysis allowed me to distinguish between weak Raman signals of heparin in serum and background noise. I then focused on using SERS to further improve the LOD of analytes, and accomplished simultaneous detection of GLU-GABA in serum at clinical levels using the SERS and PLS models. This work demonstrated the applicability of using SERS in conjunction with PLS to measure properties of samples in blood serum. I also used SERS with HC-PCF configuration to detect leukemia cells, one of the most recurrent types of pediatric cancers. This was achieved by applying PLS regression and PCA techniques. Improving LOD was the next objective, and I was able to achieve this by improving the PLS model to decrease errors and remove outliers or unnecessary variables. The results of the final optimized models were evaluated by comparing them with the results of previous models of Heparin and Leukemia cell detection in previous sections. Finally, as a clinical application of Raman biosensors, I applied the enhanced Raman technique to detect polycystic ovary syndrome (PCOS) disease, and to determine the role of chemerin in this disease. I used SERS in conjunction with PCA to differentiate between PCOS and non-PCOS patients. I also confirmed the role of chemerin in PCOS disease, measured the level of chemerin, a chemoattractant protein, in PCOS and non-PCOS patients using PLS, and further improved LOD with the PLS regression model, as proposed in previous section.

INTRODUCTION: Polycystic Ovary Syndrome (PCOS) is the most common endocrinopathy causing infertility in women of reproductive age. According to the Rotterdam criteria, a PCOS diagnosis should be given if at least two of the following are met: 1) hyperandrogenism; 2) oligo-anovulation; and 3) polycystic ovarian morphology. Previous studies analyzing the prevalence of PCOS have done so in unselected and clinical populations but few studies have attempted to characterize the syndrome and its long-term outcomes within Electronic Health Records using International Classification of Disease (ICD) codes. OBJECTIVES: With a hospital-based electronic health record dataset, this thesis seeks to: (1) characterize PCOS in reproductively aged women (18-34) using the diagnostic codes (ICD-9 and ICD-10) versus the Rotterdam criteria, (2) determine the prevalence of metabolic syndrome (MetS), Type 2 Diabetes, and cardiac events in women above age 35, (3) determine age of diagnosis for MetS and time to diagnosis of MetS. METHODS: The following 3 cohorts were queried on the Research Patient Data Registry (RPDR): 1) patients aged 18-34 with classic PCOS (phenotype A and B) but without an ICD diagnosis for PCOS, 2) patients aged 18-34 with a PCOS ICD-9/10 diagnosis and 3) patients above age 35 with a history or current diagnosis of PCOS. Their electronic health records (between January 1 , 2003 and December 31 , 2020) were ascertained from 9 Mass General Brigham institutions after IRB approval and analyzed on Software for Statistics and Data Science (STATA). RESULTS: Overall, RPDR identified 12,669 patients aged 18-34 who fit the Rotterdam criteria (under multiple phenotypes), 4646 of which had classic PCOS but lacked an ICD- 9/10 code for PCOS. RPDR also identified 9341 women aged 35 and above with a past or current diagnosis of PCOS. Hispanics/Latinas (18-34) were two times more likely to be undiagnosed when compared to Non-Hispanic Whites (OR: 2.25, 95% CI: 1.98-2.56). The prevalence of MetS, specified by a diagnostic code (277.7 or E88.81), and other cardiac conditions in women above age 35 were considerably lower than those found in the current literature. CONCLUSION: Databases such as RPDR allow for a detailed analysis of patient demographics, labs, procedures and diagnoses. Additionally, it allows for larger cohorts of patients matching more specific criteria to be ascertained. Future studies should compare the prevalence of individual features of MetS by ICD codes and analyze the cardiology reports to determine if the events are being reported but not codified. / 2023-11-30

Introduktion: Polycystisk ovarial syndrom (PCOS) är ett vanligt förekommande endokrinsjukdom som oftast drabbar kvinnor i fertil ålder. För att bli bekräftad diagnosen PCOS så måstetre kritetrier gällande kvinnans hälsåtillstånd uppfyllas; ovulationsstörningar, hyperandrogenism och polycystiska ovarial morfologi. Förutom de nämnda kriterierna såverkar insulinresistens (IR) ha en viktig roll för PCOS patofysiologi. Därför har ämnen sompåverkar insulinkänsligheten såsom myo-inositol (MI) hamnat i större fokus som potentiellbehandling av PCOS. Därav har syftet med detta arbete varit att undersöka om MI förbättrarovulation och fertilitet för kvinnor med diagnosen PCOS. Metod: För att genomföra detta litteraturstudie har vetenskapliga artiklar sökts via databasen PuBMED med sökorden ”PCOS and myoinositol on infertility” och ”myoinositol for PCOS”. Totalt valdes fem originalstudier vilka svarade mot utvalda urvalskriterier, därefteranalyserades och sammanställdes de fem valda studierna vidare för att undersöka hur MItillskott påverkar ovulationsstörningar och infertilitet hos kvinnor med PCOS. Resultat: Majoriteten av de valda studierna visade en statistisk signifikant förbättring påkvinnans ovulationsstörning, vilket ledde till förbättrad fertilitet och därmed uppnåddesgraviditet hos många deltagare i studierna. Slutsats: Sammanfattningsvis visar MI tillskaott vara en bra behandling motovulationsstörningar och infertilitet hos kvinnor med PCOS. Dock bör fler studier genomförasdär hänsyn till hur MI tillskott påverkar androgennivåer för att förbättra ovulationsstörning ochinfertilitet vid PCOS tas in.

OBJECTIVE: After comparing the top 10 menstrual tracking applications, there are no applications that address symptoms specific to Polycystic Ovary Syndrome (PCOS). This thesis demonstrates the need for a comprehensive menstrual tracking application that caters toward all populations, including patients with PCOS. METHODS: Mobile application usage was evaluated through data from the Ovulation and Menstruation (OM) Health Study to view relationships between PCOS/demographic groups and preference for tracking methods. The top 10 most popular mobile menstrual tracking applications were compiled through a search on the iOS operating system. Mobile menstrual tracking applications were then evaluated through an adapted APPLICATIONS system, which includes categories to score for PCOS-specific symptoms. RESULTS: PCOS groups showed clear preference for tracking methods overall, and are more likely to view their own health as fair/poor. P values for tests between other demographic variables in the OM Health study were insignificant, but there are observable trends in education, income, and age and usage of tracking methods. Evaluation of the top 10 mobile menstrual applications resulted in Clue scoring the highest, but no applications scored a complete PCOS-specific score. CONCLUSIONS: With continual variance in menstrual cycles, there needs to be development of a mobile menstrual application that is effective for all populations. Mobile menstrual applications have proven their popularity through PCOS groups and the rising usage within younger age groups. However, through the adapted APPLICATIONS system, major features are still missing, and are necessary to cater towards unique groups such as people with menstrual irregularities and PCOS.

Objective: To evaluate the influence of obesity, fertility status, and androgenism scores on health-related quality of life in women with polycystic ovary syndrome (PCOS). Design: Cross-sectional, correlational. Setting: Private reproductive endocrinology practice in two southeast U.S. cities. Participants: Convenience sample of 128 women with PCOS, half of whom were attempting to conceive in addition to being treated for PCOS. Most were White (97%), married (78%), with a mean age of 30.4 years (SD ± 5.5). Main Outcome Measures: The Health-Related Quality of Life Questionnaire (PCOSQ) for women with polycystic ovary syndrome. A laboratory panel and clinical measures, including body mass index, waist-to-hip ratio, and degree of hirsutism. Results: The most common health-related quality of life concern reported by women with PCOS was weight, followed in descending order by menstrual problems, infertility, emotions, and body hair. Conclusions: The psychological implications of PCOS are easily underestimated and have been largely ignored. Nursing has a pivotal role in recognizing these concerns and implementing therapy to improve quality of life in women with PCOS.

Introduction: Overweight and obesity are among the most serious public health problems in the world. Today, about half of adult men, one third of adult women and one in five children are estimated to be overweight or obese. Being overweight is not considered as a disease, but it can lead to obesity, which puts the individual at high risk of suffering from several diseases such as diabetes type 2, high blood pressure. To define whether an individual is overweight, normal weight, obese or underweight, BMI value is used. Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects women in fertitlity age. The syndrome is associated with several of risk factors such as insulin resistance, obesity, cardiovascular problems, and infertility. Imbalances in the hormones produced by ovaries can be a cause of PCOS.Currently, there are three prescription drugs in Sweden to treat obesity such as liraglutide (Saxenda®), bupropion/naltrexone (Mysimba®) and orlistat (Xenical®).Objectives: The purpose of this study was to investigate the effectiveness of using liraglutide as monotherapy or in combination with metformin to treat women who were overweight or obese and affected by polycystic ovarian syndrome.Method: This study is based on four randomized controlled clinical trials studies, which are taken from the PubMed database. Using these keywords “liraglutide, obesity, weight loss, BMI, treatment, metformin, PCOS”.Results: The greatest weight loss was observed in study 4 in obese women with PCOS, whichwere treated with the combination of both liraglutide 1.2 mg/day and metformin 1000 BID/day. A weight reduction of -9.23 ±1.23 after 12 weeks of treatment was observed. While less weight loss of -3.0 ± 0.6 kg was observed in study two, where obese women with PCOS were treated with liraglutide 1.2 mg/day and metformin 1000 mg BID/day as a monotherapy. In study 1, obese women with PCOS treated with the combination of both liraglutide 1.2-± mg/day and metformin 1000 BID/day had a weight loss of -6.5 ± 2.8 kg. The obese women with PCOS in study 3 were treated with liraglutide 3 mg/day and had a weight loss of -6.3 ± 3.7 kg butexperienced more severe GI adverse events.Conclusion: The four studies showed that short-term treatment with liraglutide, which is a GLP-1 receptor agonist, 1.2 mg/day together with metformin 1000 mg BID/day as a combination therapy is associated with significantly greater weight loss, BMI changes and with changes in waist circumference compared to when treated with liraglutide or metformin as a monotherapy

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting up to 18% of all women, yet only 1.5% have been formally diagnosed. Untreated, PCOS is associated with the early onset of diabetes mellitus type II, heart disease, and cancer. One of the most common clinical symptoms of PCOS is mental health illness. The estimated lifetime prevalence of mental illness in women with PCOS is 80%. Therefore, mental health professionals may be especially poised to screen, refer, and address PCOS in their practices. This study was used to develop a survey tool as well as a brief educational intervention using framing theory to boost PCOS knowledge of diagnostic criteria and clinical symptoms, screening practices, and referrals for PCOS evaluation. The survey assessed mental health providers' knowledge about PCOS, estimates of PCOS prevalence in their practices, and evaluated attitudes about screening for PCOS in order to identify other potential barriers and facilitators to screening. This study was conducted using a randomized, two-group (experimental vs. attention control) design with three measurement periods: pre-intervention, 4-weeks, and 12-weeks. Participants were stratified by whether or not they had medical degrees. One-hundred and sixty three (N=163) participants completed the first survey and were randomized and completed one of the two educational interventions (PCOS related or attention control). Knowledge outcomes included number of correctly identified PCOS diagnostic criteria and clinical symptoms. Behavior outcomes included whether or not participants screened or referred clients for PCOS in the last 3 months. Fourteen attitude measures and two confidence measures were also separately evaluated as potential influencing factors of knowledge and behavior. The study resulted in no change in PCOS knowledge of diagnostic criteria or clinical symptoms or behavior based on intervention assignment in medical professionals; however, baseline knowledge in this group was high. Confidence in PCOS knowledge was associated with screening behavior. The PCOS educational intervention appears to have potential efficacy at increasing non-medical professional clinical symptom knowledge of PCOS (Chi-square(1)=5.341, p=0.021) but did not improve screening or referring behavior. The PCOS intervention resulted in greater confidence in PCOS knowledge in the PCOS intervention group than in the attention control group (p=.003). Framing theory appears to be a promising framework for messaging designed to increase knowledge about PCOS only in non-medical mental health practitioners. Results of this study should be interpreted with caution because sample size goals were not met and there was high attrition among medical mental health practitioners. Future intervention strategies should consider the inherent differences in the type of professional that are targeted (i.e. medical vs. non-medical) and the presence of specific barriers to screening and referral behavior. These strategies should improve upon the intensity of the intervention and the timing of the intervention to occur during provider training (i.e. during residency or early internships) in order to increase screening and referring behaviors for PCOS. / Public Health

Abstrakt Bakgrund: Polycystiskt ovarialsyndrom är en endokrin sjukdom som drabbar 5-10% av kvinnor i fertil ålder. Orsaken till diagnosen är ännu inte fastställd men kan ha en viss anknytning till ärftlighet. I samband med diagnosen förekommer ett flertal symtom som medför lidande. Syftet: Var att beskriva kvinnors upplevelser av att leva med Polycystiskt ovarialsyndrom. Metod: Fjorton vetenskapliga studier analyserades med en kvalitativ innehållsanalys med manifest induktiv ansats. Resultat: Fem slutliga kategorier framkom i resultatet: Att leva med bristande förmåga att bli gravid, Att känna skam och dölja sitt utseende, Att påverkas av diagnosen inifrån och utifrån, Att leva med en diagnos som förändrar relationer och Att känna sig missnöjd i mötet med sjukvårdspersonal. Slutsats: Att leva med kronisk sjukdom innebär förändringar i vardagen. En djupare förståelse av kvinnors upplevelser av PCOS kan bidra till förbättrad omvårdnad utifrån ett helhetsperspektiv.

OBJETIVO: avaliação da expressão gênicado receptor do fator de crescimento semelhante à insulina de (Insulin-Like Growth Factor- IGF) 1 em células da granulosa luteinizadas do cumulusde mulheres não obesas, com sensibilidade à insulina normal, com síndrome dos ovários policísticos (SOP) tratadas e não tratadas com metformina. MODELO DO ESTUDO: prospectivo, longitudinal, randomizado. PACIENTES E MÉTODOS: avaliamos 12 mulheres com ciclosovulatórios, 9 mulheres com SOP e 8 mulheres com SOP e tratadas com metformina, ao menos 8 semanas na dose de 1.700 mg/dia. Todos os grupos foram similares com relação ao peso, ao índice de massa corporal (IMC), à circunferência da cintura e com sensibilidade à insulina normal. Todas as mulheres foram submetidas à estimulação ovariana controlada com uso de agonista de GnRH em protocolo longo e gonadotrofinas para ciclos de FIV/ICSI. As células da granulosa do cumulusforam obtidas por microdissecção dos cinco maiores folículos pré-ovulatórios. A expressão gênica do receptor de IGF-1 foi determinada com técnica da Reação da Polimerase em Cadeia a partir da Transcrição Reversa (Reverse transcriptase - Polymerase Chain ReactionRT-PCR) emiquantitativa. Foram avaliadas as concentrações séricas e foliculares de estradiol, progesterona, testosterona, hormônio folículo estimulante (Follicle-Stimulating Hormone- FSH), hormônio luteinizante (Luteinizing Hormone - LH), Sex Hormone-Binding Globulin(SHBG), glicose, insulina e IGF-1. Para análise estatística, foram utilizados os testes: ANOVA, Newman-Keuls, coeficiente de Pearsone regressão linear múltipla, sendo considerado nível de significância de 5%. RESULTADOS: não foram observadas diferenças com relação à expressão gênica do receptor de IGF-1 nos três grupos analisados (P>0,05). O número de oócitos (20,4 vs. 13,1 vs.11,5, P= 0,009), os níveis séricos de estradiol (1.896,00 pcg/mL vs. 985,20 pcg/mL vs.908,10 pcg/mL,P = 0,03) e testosterona (1,43 ng/mL vs.0,89 ng/mL vs. 0,82 ng/mL pcg/mL,P = 0,02) foram maiores no grupo de mulheres com SOP não tratadas com metformina em comparação com as mulheres com ciclos ovulatórios e tratadas com metformina, respectivamente. As mulheres com ciclos ovulatórios (50.710±42.520 ng/mL) apresentaram maiores concentrações foliculares de progesterona quando comparados com as mulheres com SOP tratadas (13.660±5.212 ng/mL) e não tratadas com metformina (17.680±6.644 ng/mL) (P=0,01). Na avaliação da regressão múltipla, a testosterona sérica não sofreu influência da expressão gênica do receptor de IGF-1 ou do IMC. CONCLUSÕES: as altas concentrações séricas de estradiol e testosterona, maior número de oócitos no grupo de mulheres com SOP não tratadas com metformina nos levam a concluir que mulheres com SOP provavelmente têm uma maior sensibilidade à estimulação da esteroidogênese ovariana quando comparadas com mulheres sem essa doença, embora não tenhasido encontrada diferença na expressão do receptor de IGF-1 nos trêsgrupos analisados. A similaridade dos resultados deste estudo entre mulheres com SOP tratadas com metformina e com ciclos ovulatórios nos levam a \"hipotetizar\" que um dos possíveis mecanismos de ação da metformina no sistema IGF-1 nas células da granulosa do cumulus poderia ser por mecanismos pós-receptores. / OBJECTIVE: evaluation of the gene expression of the IGF-I receptor in luteinized cumulus granulosa cells from non-obese women with normal insulin sensitivity and with polycystic ovarian syndrome (PCOS)treated or nor with metformin. STUDY MODEL: prospective,longitudinal, randomized. PATIENTS AND METHODS: we evaluated 12 women withovulatory cycles and 9 women with PCOS who had been treated for at least 8 weeks with a metformin dose of 1700 mg/day. All groups were similar interms of weight, body mass index (BMI), and waist circumference and all had normal insulin sensitivity. All women were submitted to controlled ovarian stimulation with a GnRH agonist in a long protocol and with gonadotropins for IVF/ICSI cycles. Cumulus granulosa cells were obtained by microdissection of the five largest pre-ovulatory follicles. Gene expression of the IGF-1 receptor was determined by semiquantitative RT-PCR. Serum and follicular concentrations of estradiol, progesterone, testosterone, FSH, LH, insulin, SHBG, and IGF-1 were determined. Data were analyzed statistically by ANOVA and by the Newman-Keuls test and the Pearson coefficient and linear multiple regression were calculated, with the level of significance set at 5%. RESULTS: no difference in geneexpression of the IGF-I receptor were observed between the three groups studied (P>0.05). The number of oocytes (20.4 vs. 13.1 vs. 11.5, P= 0.009) and the serum levels of estradiol (1,896.00 pcg/mL vs. 985.20 pcg/mL vs.908.10 pcg/mL,P = 0.03) and testosterone (1.43 ng/mL vs.0.89 ng/mL vs. 0.82 ng/mL pcg/mL,P = 0.02) were higher in the group of women with PCOS not treated with metformin than in women with ovulatory cycles and in women treated with metformin, respectively. The women with ovulatory cycles (50.710±42.520 ng/mL) presented higher follicular concentrations of progesterone compared with women with PCOS treated (13.660±5.212 ng/mL) or not with metformin (17.680±6.644 ng/mL) (P=0.01). Multiple regression revealed that serum testosterone was not affected by the gene expression of the IGF-1 receptor or by BMI. CONCLUSIONS: the high serum concentrations of estradiol and testosterone and the larger number of oocytes in the group ofwomen with PCOS not treated with metformin lead us to conclude that women with PCOS probably have greater sensitivity to stimulation ofovarian steroidogenesis than women without the disease, although no difference was detected in the expression of the IGF-I receptor between the three groups studied. The similarity ofthe present results for the women with PCOS treated with metformin and for the women with ovulatory cycles leads us to hypothesize that one of the possible mechanisms of action of metformin on the IGF-1 system in cumulus granulosa cells may be of the post-receptor type.