BACKGROUND: Polycystic ovary syndrome (PCOS), a diagnosis of exclusion, is considered the most common endocrinopathy in females of reproductive age. Current cohorts of individuals with PCOS exist but are limited, specifically in racial/ethnic diversity, due to the complexity of multiple choice survey questions and difficulty to obtain data. METHODS: After examining existing cohorts and their questionnaires, an online survey was designed specifically to assess PCOS characteristics in a diverse population. The survey was field tested for cognitive understanding and usability in a diverse population, with respect to race/ethnicity and education. After cognitive testing, the survey was launched online and participants were recruited to complete the survey. Survey completion rates by level of education, race/ethnicity, and birthplace were established by determining the proportion of participants in each subgroup to complete the entire survey. We also looked at the average percentage of the survey participants in each subgroup completed before discontinuing the survey. Univariate regression analyses were performed to evaluate these results. Question comprehension was determined by evaluating all survey questions by length and complexity. The survey question asking participants to report their typical menstrual cycle length (MCL) was selected to assess participants’ question comprehension. Responses that fell outside of the normal range for MCL were examined and those that may have been inaccurate were isolated. Level of education and birthplace reported by participants who may have responded to the MCL question inaccurately were noted and assessed collectively. RESULTS: Two-hundred and forty-eight participants, aged 18-53 years, began the survey between August 9, 2017 and October 23, 2017. Of these participants, 71.7% identified as White; 11.7% as Hispanic, Latina, or of Spanish Origin; 12.6% as Black or African American; 13.2% as other races/ethnicities; and 9.2% as more than one race/ethnicity. Of the participants with some high school education, a high school diploma, or a GED, 74% completed the entire survey; of those with some college education or a 2-year degree, 81% completed the entire survey; and of those with a 4-year college degree or more, 90% completed the entire survey. On average, participants with a high school education completed 86% of the survey before discontinuing; those with some college education completed 91% of the survey before discontinuing; and those with a college degree or more completed 95% of the survey before discontinuing. Of the participants who identified as White, 92% completed the entire survey; of those who identified as Hispanic, Latina, or of Spanish Origin, 68% completed the entire survey; and of those who identified as Black or African American, 70% completed the entire survey, with statistical significance (p = 0.002). On average, participants who identified as White completed 96% of the survey before discontinuing; those who identified as Hispanic, Latina, or of Spanish Origin completed 82% of the survey before discontinuing; and those who identified as Black or African American completed 86% of the survey before discontinuing, with statistical significance (p = 0.002). Of the participants who were born in the United States, 92% completed the entire survey, and of the participants who were not born in the United States, 66% completed the entire survey, with statistical significance (p < 0.0001). On average, participants who were born in the United States completed 96% of the survey before discontinuing and participants who were not born in the United States completed 81% of the survey before discontinuing, with statistical significance (p < 0.0001). When asked to report their typical MCL, 66 participants (28.1%) responded with irregular answers and 20 (8.5%) may have responded inaccurately. Of these 20 participants, 18 (90%) completed at least some amount of college and 16 (80%) were born in the United States. DISCUSSION: This pilot study succeeds in establishing a cohort that is more racially/ethnically diverse than existing cohorts of individuals with PCOS. In order to gather more information on the ways in which PCOS manifests across different groups, future recruitment efforts ought to be more targeted towards individuals belonging to different racial/ethnic groups and socioeconomic statuses. Additionally, the baseline survey and future modules can be made more accessible to diverse groups through language translation. Furthermore, the addition of a menstrual cycle tracker component to the survey may increase the accuracy of information on participants’ menstrual cycle patterns.

The intrauterine environment induces developmental adaptations that impact health and disease risk later in life. Reproductive abnormalities are now included in the long list of health complications seen in offspring exposed to early life adversity including poor prenatal nutrition. Previous work has shown using a rat model, that offspring born to mothers that were nutrient restricted (UN) during pregnancy are growth restricted, enter puberty early, and as adults, display characteristics of early ovarian aging with reduced follicle number. This present study aimed to investigate whether key proteins involved in ovarian follicle recruitment and growth, including the PI3K/Akt pathway, may be impaired as a result of early life nutritional adversity. Maternal UN resulted in irregular estrous cyclicity due to persistent estrus, a significant decrease in young adult ovarian antral follicles, corpora lutea, and a significant increase in atretic follicles. A decrease in growing follicles in UN offspring appears to be due to lowered expression of granulosa-cell secreted growth factor IGF-1 in antral follicles, and increased expression of pro-apoptotic factor Casp3 in secondary follicles of young adult offspring born to UN dams. Changes in follicle signalling pathways were apparent before observing altered ovarian function. In UN prepubertal offspring, expression levels of IGF1-R and FSHR were lowered in secondary and antral follicles respectively. These growth factors may contribute to a decrease in PI3K/Akt activation as immunohistochemical staining revealed a decrease in pAkt immunolocalization in prepubertal antral follicles. Moreover, neonatal ovaries of UN offspring show decreased levels of immunopositive staining for AMHRII, a regulatory receptor of the ovarian reserve. This study demonstrates that maternal UN during pregnancy impacts ovarian function in female offspring as early as P65. Findings from this study provides a model of understanding mechanisms of follicle loss and reproductive dysfunction as a result of nutrient restriction during fetal life. / Thesis / Master of Science (MSc)

Background: Polycystic ovary syndrome (PCOS) affects 6-10% of women and has a range of impacts on women’s reproductive, psychological, metabolic, and cardiovascular health. A lifelong condition, symptoms of PCOS may start in adolescence and extend into post-menopause. Despite being such a pervasive disorder, with significant burden of disease for some women, it may be underrecognized within the medical and general communities. Recent studies suggest that women with PCOS may not be diagnosed early or receive appropriate guidance and information from physicians. Little is known about women’s experiences in Canada. This thesis explores experiences with diagnosis and management in Canada and assesses the barriers and facilitators women face while seeking care for their condition. Methods: Research questions were addressed using a multi-methods approach. Participants were recruited from online PCOS groups on Facebook, Reddit, and stand-alone PCOS forums. An online questionnaire measured participants’ time to diagnosis, number of doctors seen, and satisfaction with information provided. Descriptive statistics, Chi-square tests, Fisher’s exact tests, and Spearman’s rank correlations assessed characteristics of the sample and correlations between demographic factors and satisfaction measures. Twenty-five follow-up interviews were held over the phone to elicit greater richness of experiences. Qualitative data were analyzed using thematic analysis and the interpretive description framework. Results: The e-survey was completed by 296 women aged 18-60 with a self-reported diagnosis of PCOS. Approximately a third (34%) of respondents waited for more than 2 years before attaining a diagnosis and 41% saw 3 or more doctors. Most participants were dissatisfied with the information provided to them about PCOS (66%). Many did not receive any information about lifestyle management (42%) or medical therapy (28%). Barriers to diagnosis and management included lack of knowledge and/or concern in physicians. Women received insufficient information about PCOS implications (including mental health) at the diagnosis and subsequent visits. Few participants had physicians who were involved with PCOS management. Peri- and post-menopausal women especially lacked support and medical information on how to manage symptoms. Facilitators to diagnosis and management included self-education, self-advocation, and social support. Women identified a need for greater PCOS awareness in primary care physicians and the general community. Few women had heard of PCOS prior to their diagnosis. Conclusion: This thesis found delays to diagnoses and dissatisfaction in women around the care and information they received from doctors. Perceived lack of knowledge and engagement in physicians resulted in most barriers to diagnosis and management. Few participants had physicians whom they could rely upon for information and guidance. Greater awareness of PCOS is needed in the medical community, particularly in primary care. Women and girls may benefit from greater PCOS awareness early in life in health class at the elementary and/or secondary levels.

No description available.

Infertility among women has become a growing issue in the world requiring a significant number of women to seek treatment by means of assisted reproductive technologies (ART). One suggested reason for the fertility issue is modern diet, leading to diseases such as obesity and type II diabetes. In this study, twenty gilts three weeks in age, were placed on one of five dietary treatments (n=4 gilts per treatment) containing 15% fat (FAT), 35% fructose (FRU), both fat and fructose (HFHF), or two different controls: one standard industry (IND) diet meant to result in optimal lean growth and a second diet to account for the reduced lysine (LYS) intake in the treatment diets. Two experiments were performed to assess the reproductive outcomes of pre-pubertal gilts consuming a high fat and/or high fructose diet and to demonstrate interactions between diet and infertility using pigs as a model. In the first experiment, follicular fluid was collected from these gilts and introduced into porcine in vitro maturation system to determine whether characteristics of the follicular fluid affect oocyte competence and embryo development. The follicular fluid of females consuming high fructose and fat diets did not alter nuclear maturation of oocytes (p>0.10). There were, however, detrimental effects on subsequent development of embryos, especially blastocyst formation, with the gilts having consumed the HFHF diet having reduced day 5 and 6 blastocysts formation when compared to the IVM follicular fluid free (FFF) group (p=0.03 and p=0.01, respectively). In regards to embryo quality, blastocysts from the FAT group had greater cell number when compared to all other groups. In the second experiment, the reproductive tissues; ovary, oviduct, and uterus were analyzed for genes of interest: estrogen receptor alpha (ESR1), estrogen receptor beta (ESR2), insulin like growth factor I (IGFI), insulin like growth factor I receptor (IGFIR), and growth differentiation factor 9 (GDF9). Resulting data was analyzed in three ways: 1) across all 5 treatments, 2) with gilts grouped by whether or not they consumed fat, or 3) with gilts grouped by whether or not they consumed fructose. There were no differences detected between individual treatments for ESR1 and ESR2. In the ovary samples, the fructose diets decreases ESR2 (p=0.05). Also, GDF9 ovarian expression tended to decrease with fructose consumption (p=0.07). Furthermore in the ovary, there was a positive correlation between ESR2 and GDF9 expression (r=0.92 and p<0.01). GDF9 expression was lower in the oviducts of gilts consuming fat diets when compared to non-fat diets (p=0.01). Neither IGFI nor IGFIR were altered in the reproductive tissues analyzed. Based on the results from both experiments, the consumption of fat and fructose alters both the developing embryo and gene expression in the reproductive tissues that support the growing embryo. Further investigation will provide more insight on the impact nutrition has on pre-pubertal reproductive development and subsequent fertility. / Master of Science

Diss. (sammanfattning) Umeå : Umeå universitet, 2009. / Härtill 4 uppsatser.

No description available.

The overall objective was to elucidate the mechanism of action of ovulation-inducing factor/nerve growth factor (OIF/NGF) in the reproductive function of spontaneous and induced ovulators, using cow and llama as models. In Study 1, the dynamics of trkA, the high affinity receptor for OIF/NGF, were studied during periovulatory period in cows. Unilateral ovariectomies were performed by colpotomy on Days 2, 4 and 6 of the estrous cycle (Day 0= ovulation), and before and after LH administration. Ovarian samples were processed for immunofluorescent detection of trkA. The intensity and area of immuno-positive staining, and the proportion of immuno-positive cells in both the granulosa and theca layers were higher in dominant than in subordinate follicles (P<0.05). Dominant follicles displayed a different intracellular distribution of trkA from subordinate follicles. The number of positive cells was higher in the developing CL (Day 2 and 4) than in the mature or regressing CL (Day 6, Pre-LH, and Post-LH). In Study 2, the distribution of GnRH neurons in the hypothalamus was examined in female llamas (n = 4). Hypothalamic samples were processed for immunohistochemistry for GnRH. The distribution of GnRH neurons had no evident accumulation in specific hypothalamic nuclei. The majority of GnRH neurons were detected in the anterior and medio-basal hypothalamus (P<0.05). The GnRH neuron fibers were detected primarily in the median eminence and in the medio-basal hypothalamus. In Study 3, the relationship between trkA and GnRH neurons in the llama diencephalon was examined in llama brains (n = 4) obtained in Study 2. Samples were stained using double immunofluorescence. TrkA immuno-reactivity was present in most hypothalamic areas examined; the highest density was found in the diagonal band of Broca and the periventricular nuclei. A low percentage of GnRH cells (1%) showed immuno-reactivity to trkA. Close association between immuno-reactive cells (i.e., GnRH and trkA in the same microscopic field) was detected rarely (3/160 GnRH neurons). We concluded that: 1) the high affinity receptor for OIF/NGF is expressed in greater quantities in dominant than subordinate follicles and in the developing CL; 2) GnRH neurons of llamas are concentrated in the anterior and middle hypothalamus, in close relationship to the third ventricle; and, 3) expression of trkA receptors on GnRH neurons was rare, suggesting that the ovulatory effect of OIF/NGF is not via direct interaction with GnRH neurons.

Résumé : Le syndrome des ovaires polykystiques (SOPK) affecte 6-10% des femmes en âge de procréer et est la principale cause d’infertilité anovulatoire. Cette condition est principalement caractérisée par une hyperandrogénie provenant des ovaires et des glandes surrénales. De plus en plus d’études, à la fois in vivo et in vitro, indiquent qu’une surexposition ovarienne en gras, de même que les mécanismes lipotoxiques subséquents pourraient causer l’hyperandrogénie chez ces femmes. Ainsi, cette étude vise à 1) évaluer l’implication des gras et de l’inflammation folliculaire dans la production des androgènes ovariens par une étude de corrélation; et 2) comparer les niveaux folliculaires de gras, métabolites lipidiques et marqueurs inflammatoires entre les femmes SOPK et non-SOPK. Cette étude transversale a recruté 80 femmes en cours de fécondation in vitro. Treize étaient SOPK, 58 étaient non-SOPK et 9 avaient un diagnostic incertain. Les participantes au projet avaient un âge moyen de 33 ± 4 ans. Tout groupe confondus, les niveaux folliculaires de testostérone corrélaient avec les gras (r=0,381; P=0,001; indépendamment de l’IL-6), les acylcarnitines (r≥0,255; tout P=0,008; non indépendamment des gras) et l’IL-6 (r=0,300; P=0,009; indépendamment des gras). De plus, les niveaux folliculaires de gras corrélaient avec les acylcarnitines (r≥0,594; tout P<0,001). Lorsque comparées aux femmes non-SOPK, les femmes SOPK étaient plus obèses (BMI: 31,2 vs. 25,1 kg/m2; P=0,009) et avaient des niveaux folliculaires plus élevés de testostérone (12,9 vs. 0,29 nM; P=0,001), de gras (P=0,001), d’acylcarnitines (tout P=0,001) et du marqueur inflammatoire IL-6 (13,0 vs. 8.6 pg/mL; P=0,018), le tout indépendamment de l’IMC. Les résultats suggèrent qu’une exposition intra-ovarienne en gras pourrait contribuer à une augmentation de la production des androgènes. Les mécanismes pourraient inclure une β-oxydation insuffisante, illustré par des acylcarnitines élevés, menant à l’accumulation de métabolites lipidiques toxiques, et une inflammation ovarienne, possiblement suite à une infiltration de macrophages. Ces deux mécanismes semblent être indépendants. De plus, l’environnement ovarien des femmes SOPK est caractérisé par une élévation des gras, de métabolites lipidiques et de marqueurs inflammatoires. Il peut donc être proposer que l’hyperandrogénie caractéristique du SOPK soit causée en partie par la lipotoxicité. // Abstract : Polycystic ovary syndrome (PCOS) affects 6-10% of the women of childbearing age and is the main cause of anovulatory infertility. It is mainly characterised by hyperandrogenism that can originate from the adrenal gland and the ovaries. A growing number of evidences, either in vivo or in vitro, points toward an overexposition to fat and lipotoxic mechanisms (lipid induced cellular toxicity) as the cause of PCOS hyperandrogenesis. Therefore, we aimed to: 1) evaluate the implication of follicular fluid (FF) levels of fat and inflammation markers in the ovarian production of androgens through a correlation analysis; and 2) compare FF levels of lipids, lipid metabolite levels and inflammation markers between PCOS and non-PCOS women. This cross-sectional controlled study was performed with 80 women undergoing an IVF procedure. Among them, 13 were PCOS, 58 were non-PCOS and 9 had an uncertain diagnosis. Participants were aged 33 ± 4 years old and had an average body mass index (BMI) of 25.7 ± 6.2. When analysing all women, follicular levels of testosterone correlated significantly with fat (NEFA + triglycerides) (r=0.381; P=0.001; independently of l’IL-6), acylcarnitines (r≥0.255; all P=0.008; not independently of fat) and l’IL-6 (r=0.300; P=0.009; independently of fat). Moreover, follicular levels of fat significantly correlated with acylcarnitines (r≥0.594; all P<0.001). When compared to non-PCOS women, PCOS women were significantly more obese (BMI: 31.2 vs. 25.1 kg/m2, P=0.009) and had significantly higher follicular levels of testosterone (12.9 vs. 0.29 nM, P=0.001), fat (P=0.001), acylcarnitines (all P=0.001) and inflammatory marker IL-6 (13.0 vs. 8.6 pg/mL, P=0.018), everything independently of BMI. Our results suggest that intra-ovarian exposure to fat may be responsible for the increased production of androgens. Mechanisms are likely to include an insufficient β-oxidation, leading to the accumulation of toxic lipid metabolites, and ovarian inflammation, possibly through macrophage infiltration. Both these mechanisms seem independent of one another. Also, intra-ovarian environment of PCOS women are characterized by increased levels of fat, acylcarnitines and inflammatory marker. It can thus be proposed that lipotoxic mechanisms are responsible for the increased production of androgen that is characteristic of PCOS women.

Το σύνδρομο πολυκυστικών ωοθηκών (PCOS) αποτελεί την πιο συχνή ενδοκρινολογική διαταραχή των γυναικών αναπαραγωγικής ηλικίας που χαρακτηρίζεται από κεντρικού τύπου παχυσαρκία, ακμή, υπερτρίχωση και διαταραχές των εμμηνορησιακών κύκλων που οφείλονται στην υπερανδρογοναιμία και την χρόνια ανωοθυλακιορρηξία. Οι γυναίκες με PCOS αναπτύσσουν και μεταβολικού τύπου διαταραχές όπως η υπερινσουλιναιμία λόγω αντίστασης στην ινσουλίνη, η υπέρταση, ο σακχαρώδης διαβήτης, η δυσλιπιδαιμία και το μεταβολικό σύνδρομο. Τα τελευταία χρόνια γίνονται πολλές γενετικές μελέτες προκειμένου να προσδιορισθούν οι μοριακοί γενετικοί μηχανισμοί που εμπλέκονται στην παθογένεια του ΣΠΩ. Ένας σημαντικός ρυθμιστής της ωοθυλακιογένεσης που πιθανόν να παίζει ρόλο στην παθοφυσιολογία του ΣΠΩ είναι η αντιμυλλεριανική ορμόνη (ΑΜΗ). Eντός του εξωνίου 1 του γονιδίου της ΑΜΗ εδράζεται ο πολυμορφισμός Ιle49Ser (ref SNPID:rs10407022) που συνίσταται στην αλλαγή μιας βάσης θυμίνης (T) από γουανίνη (G) δημιουργώντας τρεις γονότυπους: ομοζυγώτες GG, oμοζυγώτες TT, ετεροζυγώτες GT. Δεδομένου του ρόλου της ΑΜΗ στην παθοφυσιολογία του συνδρόμου των πολυκυστικών ωοθηκών αλλά και της ενδεχόμενης χρήσης της ως διαγνωστικό και προγνωστικό δείκτη του συνδρόμου, ο πολυμορφισμός Ιle49Ser έχει καταστεί αντικείμενο μελέτης. Στην παρούσα μελέτη προσδιορίστηκε ο πολυμορφισμός Ιle49Ser σε 111 γυναίκες με ΣΠΩ και 67 υγιείς μάρτυρες . Από τη στατιστική ανάλυση δεν προέκυψε κάποια στατιστικά σημαντική διαφορά στη συχνότητα των γονοτύπων του πολυμορφισμού Ile49Ser του γονιδίου της ΑΜΗ ανάμεσα στις γυναίκες με ΣΠΩ και του υγιούς πληθυσμού ελέγχου. Από τη στατιστική ανάλυση, επίσης, δεν προέκυψε συσχέτιση των γονοτύπων με κάποια από τις ορμονικές ή κλινικές παραμέτρους των γυναικών με ΣΠΩ. Η απουσία συσχέτισης του πολυμορφισμού Ile49Ser με αυξημένο κίνδυνο για ΣΠΩ δείχνει ότι το σηματοδοτικό μονοπάτι της ΑΜΗ εμπλέκεται στην παθογένεια του συνδρόμου με έναν έμμεσο τρόπο. Ωστόσο περισσότερες μελέτες είναι απαραίτητες προκειμένου να διαλευκανθεί ο ρόλος της ΑΜΗ στην ανθρώπινη ωοθυλακιογένεση, όπως και στην παθοφυσιολογία του συνδρόμου των πολυκυστικών ωοθηκών. / The polycystic ovary syndrome (PCOS) is the most common endocrine disorder of women of reproductive age, characterized by central obesity, acne, hirsutism and disorders of menstrual cycles due to hyperandrogonemia and chronic anovulation. Women with PCOS develop type and metabolic disorders such as hyperinsulinemia due to insulin resistance, hypertension, diabetes mellitus, dyslipidemia and metabolic syndrome. Over the last decade there are an increasing number of studies conducted in order to identify the molecular genetic mechanisms that are involved in the pathogenesis of PCOS. AMH seems to be an important regulator of follicle development and may also play a significant role in the pathogenesis of PCOS. The polymorphism Ile49Ser (ref SNPID:rs10407022) is located in exon 1 of AMH gene and results from the conversion of thymine (T) to guanine (G) giving three genotypes: homozygotes TT, GG and heterozygotes GT. Taken as granted the role of AMH in the pathophysiology of PCOS and the possible use of AMH levels as a diagnostic and prognostic marker of the syndrome, recent studies concern the involvement of IIe49Ser polymorphism. The precent study identified the polymorphism Ile49Ser in a cohort of 111 women with PCOS and 67 controls. Genotype frequencies for the AMH Ile49Ser polymorphism were similar in PCOS women and controls. In addition, AMH Ile49 Ser variant was not associated with clinical or hormonal parameters of PCOS women. The absence of an association of AMH Ile49Ser polymorphism with susceptibility to PCOS indicates that the AMH signaling pathway is not directly involved in the pathophysiology of PCOS. More studies should be carried out in order to determine the role of AMH in human ovarian physiology.