Bakgrund: Polycystiskt ovarialsyndrom (PCOS) innebär en hormonell obalans och drabbar cirka 10% av världens kvinnor. Obalansen ger upphov till symtom såsom oregelbunden mens, polycystiska äggstockar, överrepresentation av androgent hormon, övervikt, hirsutism och ger också förhöjd risk för andra allvarliga följdsjukdomar. Globalt sett har en enhetlig diagnostisering varit utmanande att uppnå då syndromet ter sig mångsidigt och komplext. Sjuksköterskan har ett etiskt ansvar i att vårda efter begreppet personcentrerad vård samt kunna förse patienter med välbehövlig och relevant information om sin hälsa. Syfte: Syftet var att beskriva kvinnors erfarenheter av att leva med PCOS. Metod: En litteraturöversikt utifrån tio vetenskapliga originalartiklar hämtade från databaserna PubMed och Cinahl Complete. Resultat: Följande teman och underteman framkom: Erfarenheter och påverkan av symtom, upplevelse av kvinnlig identitet med underrubriken kulturell påverkan samt erfarenheter av mötet med vården med underrubriken stöttning. Slutsats: PCOS är ett komplext syndrom som påverkar kvinnor fysiskt, psykiskt och socialt negativt. Syndromet påverkar kvinnornas självbild och hur de ser på sin kvinnliga identitet. Vården behöver mer förståelse och utbildning i hur de på bästa sätt kan bemöta och främja hälsan hos kvinnor med PCOS. / Background: Polycystic ovary syndrome (PCOS) is a hormonal imbalance and affects approximately 10 % of women worldwide. This imbalance leads to symptoms such as irregular menstruation, polycystic ovaries, overrepresentation of androgen hormone, obesity, hirsutism and also increases the risk of other serious sequelae. Achieving a unified diagnosis has globally been challenging due to the syndrome’s multifaceted and complex nature. Nurses have an ethical responsibility to provide care, based on the concept of person-Centered care and to also be able to provide essential and relevant information to patients concerning their health. Aim: The aim was to describe women's experiences living with PCOS Method: A literature review was made based on ten scientific original articles collected from the databases PubMed and Cinahl Complete. Results: The following themes and subthemes emerged for the result: Experiences and impact of symptoms, experience of female identity with subheading cultural influence, and experiences and encounters with healthcare with subheading support. Conclusions: PCOS is a complex syndrome that negatively impacts women physically, mentally and socially. The syndrome affects women's self image and how they perceive their feminine identity. Healthcare professionals require further understanding and education on how to address and promote the health of women with PCOS, in the best way.

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.

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.

Bakgrund: Infertilitet är ett sjukdomstillstånd som innebär att ett par inte kan uppnå en klinisk graviditet under mer än ett år av försök. Det är mellan 10-15 % av alla par i fertil ålder som drabbas av tillståndet i varje land. Orsaken som hittas i 90 procent av fallen är antingen manliga, kvinnliga eller gemensamma faktorer. När ingen orsak hittas kallas det för oförklarlig-, eller idiopatisk infertilitet. Innan diagnostisering och eventuell behandling utförs därför noga utredningar med analyser på både kvinnan och mannen. Behandlingen bestäms därefter utifrån orsak. Vid kvinnlig infertilitet är in vitro-fertilisering (IVF) den mest vanliga icke-farmakologiska proceduren som används framför allt vid oförklarlig infertilitet och åldersfaktorer. Antiöstrogenet klomifencitrat har i många decennier varit farmakologiska förstahandsbehandlingen vid anovulatorisk infertilitet men vid de senaste 10 åren har den ersätts med aromatashämmaren letrozol som med en liknande mekanism kunnat ge upphov till ovulationsstimulering. Syfte: Syftet med examensarbetet var att utvärdera och jämföra effekterna av antiöstrogenet klomifencitrat med aromatashämmaren letrozol vid infertilitetsbehandling hos kvinnor. Metod: För att uppnå syftet utfördes litteratursökningar av relaterade vetenskapliga studier i den medicinska databasen PubMed. Nyckelorden som användes vid sökning var “female infertility”, “clomiphene” och “letrozole” och därefter hämtades fem randomiserade kontrollerade vetenskapliga artiklar (RCT) som granskades i resultatdelen av arbetet. Resultat: Samtliga studier, utom studie 5, visade att aromatashämmaren letrozol hade bättre effekt på ovulationstimuleringen och därmed också att uppnå klinisk graviditet än vad klomifencitrat hade. Administrering av letrozol ledde också till större tjocklek av endometrium och fler antalet mogna folliklar. Å andra sidan visade sig letrozol ge högre sannolikhet till multipla graviditet i studie 5. Det förekom ett par fall av allvarliga biverkningar under administrering av samtliga läkemedel, dock var majoriteten av biverkningarna milda och förekom i form utav huvudvärk, illamående, gastrointestinala besvär, trötthet och värmevallningar. Slutsats: Resultaten tyder på att letrozol är ett mer effektivt alternativ till infertilitetsbehandling av kvinnor. Eftersom den dessutom har mycket lägre halveringstid än klomifencitrat gör den mer säker att använda då det låg östrogennivå är ej optimal hos kvinnor i fertil ålder. / Background: Infertility is a condition that is based on a couple not being able to achieve a clinical pregnancy for more than a year of trying. Between 10-15 % of all heterosexual couples of childbearing age are affected by the condition in each country. The cause that is found in 90 percent of cases is either male-, female- or common factors. When no cause is found, it is called unexplained or idiopathic infertility. Before diagnosis and possible treatment, careful investigations are therefore performed with analysis on both the woman and the man. The treatment is then determined based on the cause. In female infertility, in vitro fertilization (IVF) is the most common non-pharmacological procedure used primarily for unexplained infertility and age factors. The antiestrogen clomiphene citrate has for many decades been the first-line parmacological treatment for anovulatory infertility, but in the last 10 years it has been replaced by the aromatase inhibitor letrozole, which with a similar mechanism have effect on ovulation stimulation. Aim: The aim of this thesis was to evaluate and compare the treatment effects of the antiestrogen clomiphene citrate with the aromatase inhibitor letrozole in female infertility. Method: A literature search of related scientific studies was implemented in the medical database PubMed. The keywords used in the searchfield were ”female infertility”, ”clomiphene” and ”letrozole” and then five randomized controlled trial articles (RCT) were selected to be reviewed in the results part of the thesis. Results: All studies, except for study 5, showed that the aromatase inhibitor letrozole had a better effect than clomiphene citrate on ovulation stimulation and thus also to achieve a clinical pregnancy. Administration of letrozole also led to greater endometrial thickness and increased numer of mature follicles. In study 5 on the other hand, letrozole was shown to increase the likelihood of multiple pregnancies. There were a couple of cases of serious side effects during the administration of these drugs, however, the majority of the side effects were mild and occured in the form of headaches, nausea, gastrointestinal disorders, fattigue, and hot flashes. Conclusion: In conclusion, the results suggest that letrozole is a more effective alternative to infertility treatment for women. In addition, since it has a much lower half-life than clomiphene citrate, it is safer to use as low estrogen levels are not optimal in women of childbearing potential.

Polycystic ovary syndrome is an endocrine disorder with symptoms of hyperandrogenism, insulin-resistance and anovulation in women which creates a disposition for other disorders, like Type 2 Diabetes. Drosophila Melanogaster flies have short generation, low cost-management and share several signaling pathways with humans and are therefore an excellent tools to study disease aetiology – yet no such model exists for PCOS. This thesis aimed to create such PCOS-like disease model through treatment of Drosophila Melanogaster adults and larvae with 5-α Dihydrotestosterone and/or high sugar diet. The samples were studied by measuring weight, fecundity, total glycerol concentration and Real-Time quantitative Polymerase Chain Reaction (RT qPCR) using PCOS-related orthologue genes. While previous studies have frequently studied the effects of high sugar diets on Drosophila Melanogaster – there are no previous studies that have studied the effects of 5-α Dihydrotestosterone, with or without high sugar diet, on the weight, fecundity and gene expression of Drosophila Melanogaster. Results showed that larva raised on high sugar diet had traits resembling an insulin-resistant phenotype while the fecundity of flies treated with high sugar diet was significantly lower than those treated with standard sugar diet and DHT. RT qPCR showed overexpression of the standard sugar diet and DHT groups in the investigated genes EcR, Med, TOLL, THADA and FOXO. The conclusion, based on the results, is that insulin-resistance was produced but that more studies are required before a complete PCOS-like disease model is possible in Drosophila Melanogaster.

A síndrome dos ovários policísticos (SOP) constituia causa mais freqüente de infertilidade, anovulação e hiperandrogenismo atualmente. Sua fisiopatogenia é em parte obscura. O hormônio anti-mülleriano (HAM),uma glicoproteína produzida pelas células da granulosa dos folículos pré-antrais e folículos antrais pequenos, parece exercer papel fundamental para seu surgimento, exacerbando o hiperandrogenismo intra-folicular e interferindo no mecanismo de seleção do folículo dominante. Além das alterações ovulatórias, há repercussões metabólicas decorrentes da síndrome, como a resistência à insulina (RI), que afeta entre 45 a 70% das mulheres com SOP em idade reprodutiva. Estratégias para aumentar a sensibilidade à insulina poderiam reduzir o impacto reprodutivo e metabólico da RI. Entre elas, destaca-se a metformina, uma droga anti-diabética oral, cuja utilização levaria a uma melhora dos padrões metabólicos e restabelecimento da ovulação. No presente estudo, foram avaliados a relação entre os níveis séricos de HAM e resistência insulínica antes e após o tratamento com metformina, comparados os níveis séricos de HAM na fase folicular precoce entre pacientes com e sem SOP e correlacionados os níveis de HAM com os níveis séricos de insulina, gonadotrofinas e androgênios. Foram realizadas dosagens séricas de HAM, androgênios e gonadotrofinas em 36 pacientes (16 com SOP e resistência insulínica e 20 eumenorreicas, sendo grupos pareados quanto à idade e índice de massa corpórea). No grupo SOP, foram avaliados níveis de HAM, insulina, glicemia e QUICKI (quantitative insulin check index) antes e depois do tratamento com metformina 1500 mg/dia por oito semanas. Foram encontrados níveis de HAM mais elevados no grupo SOP do que no grupo controle (49,9 ± 6,1 pmol/L versus 4,5 ± 2,1 pmol/L, p < 0,0001), assim como os níveis de hormônio luteinizante (LH) (10,3± 1,5 mUI/L versus 3,5 ±0,5 mUI/L, p=0,0004), testosterona (64,9 ± 5 ng/mL versus 41,1 ±4,7 ng/mL, p=0,0017) e 17-hidroxiprogesterona (17OHP) ( 90 ±16,8ng/ml versus 49,1 ±6,6 ng/ml; p= 0,03). Nas pacientes com SOP, houve correlação positiva forte entre os níveis de HAM pré-tratamento e testosterona (coeficiente r dePearson - R - de 0,83; p<0,0001). Também foi encontrada correlação positiva e significativa entre HAM e LH (R = 0,51; p = 0,04). As demais variáveis não apresentaram correlação significativa com o HAM pré-tratamento. Após o tratamento, houve redução significativa dos níveis de insulina (16,4 ± 2,6 mUI/ml versus 12 ± 1,9 mUI/ml; p=0,0132). Os níveis de HAM tiveram redução, porém sem diferença estatística (49,9 ± 6,1 versus 41,5 ± 5,6 pmol/L; p=0,06). Houve redução significativa nos níveis de testosterona (64,9 ± 5 ng/mL versus 49,3 ± 14 ng/mL). A correlação do HAM com os níveis de testosterona não persistiu após o tratamento com a metformina (R=0,08 e p=0,76). Assim, a manutenção dos níveis séricos de HAM após o uso da metformina, mesmo com a comprovada melhora metabólica e redução dos níveis de gonadototrofinas sugere que o papel do HAM na SOP baseia-se num mecanismo intrínseco ovariano, independente do eixo hipotálmo-hipófise-ovário e não influenciado pela resistência insulínica. / Polycystic ovary syndrome (PCOS) is the most frequent cause of infertility, anovulatory disordes and hyperandrogenism in young women. Its pathophisiology remains unclear and anti-mullerian hormone (AMH), a glycoprotein produced by the granulose cells of early developing follicles, seems to be fundamental to its development, by enhancing the intra-follicular hyperandrogenism and interfering in the selection of a dominant follicle. PCOS also causes metabolic disorders, such as insulin resistance (IR), that affects 45 to 70% of women with PCOS. Strategies to improve insulin sensitivity could reduce the reproductive and metabolic impact of IR.Metformin, a insulin-sensitizing agent, appears to improve the metabolicparameters and reestablish ovulatory cycles. In this study, we evaluated the relationship between anti-mullerian hormone serum levels and IR before and after protracted treatment with meformin; we also compared the anti-mullerian hormone levels in PCOS in the early follicular phase to normo-ovulatory women. The correlation of anti-mullerian hormone levels to insulin, gonatotropins and androgen serum levels was also evaluated. The study included 36 pacients (20 with PCOS and IR and 16 with ovulatory cycles). Anti-mullerian hormone serum levels, insulin, glucose and QUICKI (quantitative insulin check index) were evaluated in patients with PCOS before and after treatment with metformina 1500 mg/day during eight weeks. Anti-mullerian hormone serum levels were higher in PCOS (49,9 ± 6,1 pmol/L versus 4,5 ± 2,1 pmol/L, p < 0,0001), as well as luteinizing hormone (LH) levels (10,3± 1,5 mUI/L versus 3,5 ±0,5 mUI/L, p=0,0004), testosterone (64,9 ± 5 ng/mL versus 41,1 ±4,7 ng/mL, p=0,0017) and 17-ydroxyprogesterone (17OHP) ( 90 ±16,8ng/ml versus 49,1 ±6,6 ng/ml; p= 0,03). In PCOS, there is a positive correlation between anti-mullerian hormoneserum levels and testosterone (R= 0,83; p<0,0001) before treatment; this correlation did not persisted after treatment (R=0,08 e p=0,76). There is also a positive correlation between anti-mullerian hormone serum levels before metformin treatment and LH (R= 0,83; p<0,0001). No correlations were found between anti-mullerian hormone serum levels before treatment and other parameters. After treatment, insulin serum levels reduced (16,4 ± 2,6 mUI/ml versus 12 ± 1,9 mUI/ml; p=0,0132). AMH serum levels also reduced, but therewas no statically significant difference (49,9 ± 6,1 versus 41,5 ± 5,6 pmol/L; p=0,06). Testosterone serum levels decreased significantly (64,9 ± 5 ng/mL versus 49,3 ± 14 ng/mL). No correlation between AMH and testosterone levels was found after treatment (r=0, 08 e p=0, 76). The maintenance of AMH serum levels after treatment with metformin, despite the enhance of metabolic parameters and reduction of the gonadrotopins levels, suggests that AMH acts in the pathophisiology of PCOS by a intra-ovarian mechanism, that does not depend on the neuroendrocine axis and that is not influenced by IR.

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.

OBJECTIVE: To examine the likelihood of self-reporting a diagnosis for PCOS with the presentation of menstrual irregularity in a diverse, multiethnic population, based on data collected between August 9th, 2017 and October 24th, 2017 for the pilot of the Ovulation and Menstruation (OM) Study at Boston University School of Medicine. BACKGROUND: Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder among reproductive age women. It is typically diagnosed by variable combinations of menstrual irregularity, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasound. An alternative is its diagnosis as one of exclusion due to similarities in presentation to other endocrine disorders. As a result, PCOS may often be misdiagnosed and mismanaged in the course of a patient’s care, further exacerbated by a poor understanding of the syndrome, a lack of easily available resources, and patient frustration with clinician interactions. The early identification of key hallmarks of the disorder, such as menstrual irregularity, and awareness of its linkage to PCOS, could lead to early diagnosis and intervention. METHODS: 248 participants enrolled and participated in the Ovulation and Menstruation (OM) Health Study’s as members of its pilot cohort. Inclusion criteria were women ages 18-45 currently experiencing menstrual periods without a history of chemotherapy, radiation, or surgical menopause. Participants completed the relevant sections of the OM Study survey related to demographics, menstrual cycle patterns, and history of PCOS. Demographic questions pertained to the age, race/ethnicity, country of birth, and education levels of the participants. The menstrual cycle questions provided information regarding the age of menarche, length and pattern of menses and the menstrual cycle overall. The questions regarding history of PCOS ascertained the presence of an official or self-diagnosis for PCOS for the participant, and the age at which this was determined. The descriptive measures were presented for comparison before determining the concurrence of the presence of menstrual irregularity and the diagnosis of PCOS across demographic categories and calculating an associated prevalence ratio. RESULTS: Among women reporting a history of menstrual irregularity for 3 months or greater, PCOS was the second-highest self-reported cause for menstrual irregularity, with 20.7% of participants endorsing it as the cause for their irregularity. The presence of menstrual irregularity for 3 or more months was also more likely to be present in concurrence with a clinician diagnosis, or to a lesser extent, a self-diagnosis, for PCOS. Participants were also far more likely to have a clinician diagnosis for PCOS if they were White, US-born, young, or educated. The same applied for the likelihood of a self-diagnosis with the exception of age. CONCLUSIONS: The association between menstrual cycle irregularities and likelihood of being diagnosed with PCOS is supported by the data and appears to be influenced by demographic factors such as race/ethnicity, age, and education.

Introdução: Irisina é uma adipocina / miocina, descrita pela primeira vez em 2012 e parece estar envolvida na termogênese do tecido adiposo e na homeostase metabólica. A síndrome dos ovários policísticos (PCOS) é reconhecida como um distúrbio endocrinológico prevalente em mulheres com idade reprodutiva, e está frequentemente associado à obesidade abdominal, resistência à insulina, dislipidemia e hipertensão arterial. Objetivos: Determinar os níveis circulantes de irisina numa amostra de mulheres com PCOS e controles ovulatórias não hirsutas e verificar se os níveis séricos de irisina estão associados com variáveis hormonais, metabólicas e de composição corporal nestas participantes. Métodos: Neste estudo caso-controle foram incluídas 49 mulheres com PCOS e 33 mulheres controles ovulatórias não-hirsutas com idade e índice de massa corporal (IMC) semelhantes. Variáveis demográficas, antropométricas, hormonais e metabólicas foram obtidas através de dados da história médica, exame físico e dosagens bioquímicas e hormonais convencionais. A composição corporal foi avaliada por absorciometria de raios-X de dupla energia (DXA). Os níveis séricos de irisina foram mensurados por um kit ELISA humano. Resultados: A pressão arterial sistólica, HOMA, testosterona total e índice de androgênios livres (IAL) foram significativamente maiores e a SHBG foi menor nas PCOS. Após a estratificação por IMC, massa gorda e razão massa gorda / massa magra foram menores em mulheres com peso normal do que em mulheres com sobrepeso / obesidade. O grupo PCOS com peso normal apresentou menos massa magra total do que o grupo PCOS com sobrepeso / obesidade e subgrupos controles. A proporção de massa magra apendicular / IMC foi significativamente maior nas controles de peso normal que em controles com sobrepeso / obesidade, mas os subgrupos de PCOS foram semelhantes entre si e com as controles de peso normal e obesas. Os níveis séricos de irisina foram significativamente maiores nas pacientes 8 PCOS com sobrepeso / obesidade em comparação com as controles de peso normal. A irisina circulante correlacionou-se positivamente com o HOMA. Observou-se também correlação positiva da irisina com massa magra total e razão massa gorda /massa magra em mulheres com PCOS, mesmo após ajuste para IAL. Conclusão: Os dados do presente estudo sugerem uma associação de irisina com variáveis de composição corporal. / Introduction: Irisin is an adipokine / myokine, first described in 2012 and appears to be involved in adipose tissue thermogenesis and metabolic homeostasis. The polycystic ovary syndrome (PCOS) is recognized as a frequent endocrine disorder in women of reproductive age, and is often associated with abdominal obesity, insulin resistance, dyslipidemia, and hypertension. Objectives: To determine the circulating levels of irisin in women with PCOS and non-hirsute ovulatory control women, and to evaluate whether serum irisin levels are associated with hormone, metabolic and body composition variables in these participants. Methods: In this case-control study, 49 women with PCOS and 33 nonhirsute ovulatory controls women with similar age and body mass index (BMI) were enrolled. Demographic, anthropometric, hormone and metabolic variables were assessed by medical history, physical examination and conventional biochemical and hormon determinations. Body composition was assessed by double-energy X-ray absorptiometry (DXA). Serum irisin levels were measured by a human ELISA kit. Results: Systolic blood pressure, HOMA, total testosterone and FAI were higher and SHBG was lower in PCOS. After stratification by BMI, fat mass and fat mass / lean mass ratio were lower in women of normal weight in overweight / obese women. The PCOS group at normal weight had less total lean mass than the overweight / obese PCOS group and control subgroups. The lean appendicular mass / BMI ratio was significantly higher in normal weight controls than in overweight / obese controls, but PCOS subgroups were similar between them and with normal and obese weight controls. Serum irisin levels were significantly higher in overweight / obese PCOS patients than in normal weight controls. Circulating irisin was positively correlated with HOMA. A positive correlation was also observed between irisin 10 and total lean mass and fat mass / lean mass ratio in women with PCOS, even when adjusted for FAI. Conclusion: Our data suggest an association of irisin and body composition variables.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders among women of childbearing age and is associated with a number of metabolic disturbances. It has been hypothesised these women carry an increased risk of developing cardiovascular diseases (CVD) with advancing age. The first aim of this thesis was to establish the prevalence of PCOS-related symptoms in Northern Sweden. The Northern part of the WHO MONICA project was used for this purpose. Based on self-reported menstrual disturbances and hirsutism together with biochemical analyses of free androgen index, the estimated prevalence of PCOS in Northern Sweden was 4.8%, which corresponded with previous prevalence studies. Disturbances in the fibrinolytic system are predictors of future cardiovascular events and measurements of plasminogen activator inhibitor 1 (PAI-1) activity and tissue plasminogen activator (tPA) mass concentration may be used to assess fibrinolytic activity in women with PCOS. From the findings, over-weight women with PCOS had impaired fibrinolysis, especially if they displayed objective biochemical markers of hyperandrogenism. Conversely, lean women with PCOS, displayed no signs of disturbed fibrinolysis. The adipose tissue is an active endocrine organ that produces and releases hormones, pro- and anti-inflammatory cytokines, and chemoattractant cytokines. Proinflammatory molecules produced by adipose tissue can be active participants in the development of insulin resistance and the increased risk of cardiovascular disease associated with obesity. The findings suggested being overweight, rather than the PCOS diagnosis per se, was the main explanatory variable for elevated adipose tissue inflammation in PCOS patients. Weight reduction is the primary target for intervention in overweight and obese women with PCOS. When this thesis was planned, no placebo-controlled trials on anti-obesity drugs in women with PCOS had been conducted. Sibutramine in combination with lifestyle intervention resulted in significant weight reduction in overweight women with PCOS. In addition to the weight loss, sibutramine appeared to have a beneficial effect on metabolic and cardiovascular risk factors.