Class of 2008 Abstract / Objectives: To assess the effect of metformin usage and lifestyle modifications in women with polycystic ovary syndrome (PCOS) in achieving conception and live birth. Methods: A retrospective chart review of patients at a southwest reproductive health center was performed. Patients given a diagnosis of PCOS, treated with metformin alone, with at least 12 weeks of outcome data were enrolled. Diagnostic, reproductive history, and baseline endocrine and metabolic data were collected. All available metformin use, menstrual cyclycity, ovulation, pregnancy, pregnancy outcome, and alternative treatment data were captured. Results: A total of 1250 charts were reviewed and 103 patients were enrolled. Pre-treatment, a significant relationship between BMI and HDL, triglycerides/HDL, and fasting glucose (P <0.001, 0.018, 0.016) was noted with leaner patients having better metabolic profiles. The pregnancy, miscarriage, and live birth rates with metformin treatment were 55.3 %, 18.2 %, and 35.0 % respectively. Patients (40/103) that did not conceive with metformin attempted alternative fertility treatment; 55% became pregnant and 30% had a live birth. One third of all patients experienced minor adverse events, primarily gastrointestinal in nature. Logistic regression analyses comparing responders to nonresponders did not identify any baseline patient characteristics useful as significant predictors of success with metformin treatment. Conclusions: For the population under study, metformin use and lifestyle modifications resulted in conception and live birth for as many as 35 % of patients. Contrary to recent publications, it appears that this method of fertility treatment remains a viable option to treat infertility in patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome is the most common endocrine disorder affecting reproductive-aged women. It is diagnosed using a combination of menstrual irregularity, clinical and/or biochemical hyperandrogenism and polycystic ovary morphology upon ultrasound. Hyperandrogenism in females may clinically manifest as hirsutism, acne, alopecia, or other masculinization of features. Assessing total/free testosterone, dehydroepiandrosterone sulfate, and 17-hydroxyprogesterone provides biochemical evidence of hyperandrogenism. OBJECTIVE: To determine self-reported clinical signs of androgen excess using data from the Ovulation and Menstruation Health (OM) Study, a diverse, multi-ethnic cohort study being conducted at Boston University School of Medicine. METHODS: Data was collected from participants enrolled in the Ovulation and Menstruation Health Study pilot cohort. This epidemiologic survey captured demographics, menstrual cycle patterns, PCOS histories, reproductive histories and manifestations of androgen excess in a diverse patient population. Participants were women ages 18-45 who had the capacity to ovulate/menstruate at the time of the study, had no history of chemotherapy, radiation, or surgical menopause, and were not pregnant at the time of the study. To assess androgen excess, participants were asked to self-report hair growth in nine body areas, acne on the face and back and hair loss on the scalp. The nine body areas were scored using the modified Ferriman-Gallwey (mFG) scoring system. Reference images created by a medical illustrator were used for hirsutism and alopecia grading while clear descriptions were provided for grading acne severity. Clinical hirsutism was defined as total mFG score of ≥ 8, or ethnic specific cutoff for East Asian (≥ 2) and Southeast Asian (≥ 3) women. Alopecia was defined as scalp hair loss ≥ 2. For participants that consented to medical record validation total, free and bioavailable testosterone lab levels were assessed for biochemical hyperandrogenism evaluation. RESULTS: Beginning August 9, the day the study opened to the public, 249 participants completed the pilot survey questionnaire. These participants were 66.8% white (n=165), 6.5% Hispanic or Spanish origin (n=16), 10.5% Black or African-American (n=26), 1.6% East Asian (n=4), 2.0% Southeast Asian (n=5), 2.4% South Asian (n=6), and 10.9% were of mixed ethnic backgrounds (n=27). 22.5% (55/245) of these women had clinical hirsutism by total mFG score. Mean total mFG scores were highest in women who were South Asian at 13.8±9.1 (n=6) and Hispanic at 8.6±8.7 (n=16). Moderate-severe acne was reported in 23.6% (58/246) of respondents, 24.8% (41/165) of white women, 26.7% (4/15) of Hispanic women, 15.4% (4/26) of Black women, 0.0% (0/4) of East Asian women, 20.0% (1/5) of Southeast Asian women, 50% of South Asian women (3/6) and 20% (5/25) of women of mixed ethnicities. 9.4% (23/246) of all pilot women reported alopecia, highest in Black (26.9%, 7/26) and East Asian women (25%, 1/4). Among women that had a PCOS diagnosis there was a higher presence of clinical hirsutism, higher acne severity, and higher prevalence of alopecia when compared to non-PCOS women. In addition, 33%(4/12) of the 44 women that consented to medical record validation had total testosterone levels above the normal range. CONCLUSIONS: This pilot population demonstrated an ethnic dependent pattern of development for hirsutism, acne and alopecia. Additionally, women who had a PCOS diagnosis were more likely to report having the clinical signs of androgen excess than those without a diagnosis. / 2020-06-14T00:00:00Z

The phenomenon of platelet hyperaggregability and decreased platelet responsiveness to nitric oxide (also termed as nitric oxide resistance), documented in several cardiovascular disease states, is associated with adverse cardiovascular outcomes. The series of experiments described in this thesis address primarily some aspects of the pathophysiology, epidemiology and therapy of the phenomenon of end-organ resistance to nitric oxide (NO) in two important conditions, that are closely associated with cardiovascular risk factors and disease states:- Polycystic ovary syndrome, which is closely linked with the metabolic syndrome and premature subclinical atherosclerosis. The renin-angiotensin system, which is recognized as a significant mediator in the pathophysiology of a number of cardiovascular disease states. The first study examined the epidemiology/pathophysiology of putative platelet/endothelial dysfunction in young individuals with PCOS. The subsequent studies focused on the potential impact of the renin-angiotensin system on platelet and endothelial function. This mechanistic review is set in the context of a number of recent major clinical studies which have demonstrated surprising efficacy of certain angiotensin-converting enzyme (ACE) inhibitors (ramipril and perindopril) in the prevention of thrombotic processes. Thus we tested the hypothesis whether ACE inhibitor ramipril sensitizes platelets to NO (as a potential mechanism for improved cardiovascular outcomes) in a high risk patient cohort. In addition, particular attention will be given to the emerging role of the heptapeptide Angiotensin- (1-7), a possible physiological antagonist to Angiotensin II in the vasculature and the limitation of the current literature concerning potential effects of the renin-angiotensin system on thrombotic mechanisms. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1348615 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2009

Between 10-15% of women suffer from polycystic ovary syndrome (PCOS), making it the most common cause of female infertility. Clinical features of PCOS include high circulating levels of ovarian androgens (T and A4), anovulation and obesity. The aetiology of this reproductive endocrinopathy is likely to be multifactorial, through the interplay of genetics, epigenetics and environmental factors. Primate research into sexual behaviour development noted that fetally androgenised monkeys developed symptoms like those of PCOS. There are now multiple animal models of PCOS using primates, sheep, rats and transgenic mice. The investigations described in this thesis use rodent models to examine the role of androgens in the pathogenesis of female infertility. An attempt to generate a granulosa cell specific androgen receptor knockout mouse model will first be described, followed by several studies into the developmental programming of female Wistar rat infertility and metabolism by steroid hormones. Initial investigations showed that testosterone proprionate (TP) administered to female rats during different windows of fetal and neonatal life alters the reproductive and metabolic axes of the adult animals. Fetal plus neonatal TP exposure led to complete ovarian dysgenesis, while postnatal exposure produced a PCOS-like phenotype. Animals which received TP postnatally were heavier and had an increased proportion of primordial follicles in their ovaries by postnatal day (pnd) 90 of life. Evaluation of this PCOS model showed that neonatally androgenised rats had ovarian follicles with larger antra and a greater ovarian stromal compartment. In addition, these animals were heavier when compared to controls. However, unlike human studies, neonatally androgenised rats showed no differences in circulating gonadotrophin or ovarian androgen levels. Nor did they show any programming effect of neonatal TP upon the theca interna by pnd 90. Further investigations to narrow the windows and dose of TP required to produce a PCOS phenotype showed that TP administered in an early window of neonatal life, between postnatal days (pnd) 1-6 not only led to anovulation, but potentially reprogrammed the hypothalamic-pituitary axis, as there was minimal gonadotrophin response to reduced ovarian negative feedback (inhibin B and estradiol) in these rats. Neonatal TP also affected the rat metabolic axis with adult animals becoming heavier after weaning without any change in food intake. Animals developed mesenteric and retroperitoneal obesity along with insulin resistance (IR). Increased hepatic glucocorticoid turnover and altered adipokine expression were also noted in neonatally androgenised females, possibly contributing to the pathogenesis of obesity. No effect of TP dose upon the severity of infertility or metabolic abnormalities in adult animals was observed. To delineate which features of the rat PCOS model resulted from androgenic, estrogenic or corticosteroid action, a final study used administration of different steroids during the early window of postnatal life: TP, estradiol valerate (EV), dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA) and dexamethasone (DEX). The anovulatory PCO-like phenotype observed with TP was also seen in animals which received EV, but not those which received DHT, DHEA or DEX. TP and EV treatment also resulted in a reduction of ovarian follicle numbers and activated follicle proportions, with an increase in primordial follicle proportions. Although glucose tolerant, animals treated with TP and EV were highly IR. Unlike dexamethasone, DHT and DHEA also produced IR in adult animals, to a lesser extent than TP and EV. Taken collectively, the results described in this thesis demonstrate that the PCOS-like phenotype observed in the neonatally androgenised female rat is likely to be due to the estrogenic actions of testosterone, potentially through as yet unknown epigenetic mechanisms. The programming of the metabolic components described may additionally be due to the actions of androgens. Furthermore, these studies demonstrate a novel estrogenic effect of neonatal steroids upon primordial follicle populations and show that the neonatally androgenised rat may be a rational PCOS model in a poly-ovulatory species.

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 the most common endocrinopathy disorder in reproductive age women. The symptoms of this disorder are the androgen excess seen with anovulation/oligoovulation or morphologically ovarian cysts. The aim of the study was to assess the efficacy of public health nutrition intervention designed to enhance healthy eating and lifestyle modification among PCOS patients attended the obstetrics and gynecology clinic at the American University of Beirut Medical Centre (AUB-MC) in Beirut, Lebanon. A prospective hospital based public health nutrition intervention was proposed in which 76 women with PCOS were recruited in the pilot study and 588 women were recruited in the scale-up intervention divided between PCOS and non-PCOS. During the scale up phase non-PCOS women were recruited to study the effect of the nutritional counseling on them as a way to compare the outcome with PCOS women. Recruited population were divided into 8 groups; group A: overweight/obese PCOS patient’s intervention (received weight management program with nutritional guidelines). Group B: overweight/ obese PCOS controls (received the usual heath care by the gynecologist), Group C: lean PCOS controls (received the usual heath care by the gynecologist), Group D: lean PCOS intervention (received weight maintenance program with nutritional guidelines ), Group E: overweight/obese non-PCOS patient’s intervention (received weight management program with nutritional guidelines) ,Group F: overweight/ obese non-PCOS controls, Group G: lean non- PCOS intervention (received weight maintenance program with nutritional guidelines), Group H: lean non-PCOS controls. Data were collected using a pre-validated questionnaire to capture sociodemographic variables, nutritional status, and physical activity, psychological and medical status. Blood analysis was carried out to determine biochemical indices. Assessment of study indicators were carried out at baseline, after 3 and 6 months from inception of intervention (pilot as well scale up). Patients in intervention groups attended a 6 month tailored nutrition counseling/education program (2 sessions per month), to enhance their understanding of their dietary intake and assist them with weight management, physical activity, healthy cooking, lifestyle, and food shopping. Following a six months pilot study intervention results have shown that 7% weight loss was achieved in overweight/ obese intervention groups and weight maintenance in lean intervention groups( Group A,B,C and D). There was a significant reduction in waist (-4.2 cm (±5.6)) and hip circumference (-3.1cm (±3.5)) with P < 0.001. There was no significant biochemical markers change (fasting blood sugar, CRP, LDL-C,HDL-C,TG,total cholesterol, fasting insulin, total testosterone,Vit D), however there was an increase in physical activity (3.1 hours/week (±1.5)) , and decrease in anxiety and depression score ( BDI-II and BAD-7); -0.8 (±0.8) and -0.7 (±0.7) with P < 0,001 compared to interventions. Following six months scale up intervention, the results have shown a weight reduction among overweight/obese PCOS women (group A) who lost, on average, 8.2 kg (P=0.001). Whilst non-PCOS women lost, on average 11.6 kg (P < 0.001)(Group E). Controls gained weight (Group B, D F and H). The biochemical, psychological and reproductive profile showed significant improvements among PCOS women (P < 0.001). Pregnancy rate increased to 70% among women trying to conceive. The results of this study have shown this intervention to be effective in Lebanese women with PCOS, decreasing their initial body weight by 5%- 10% and improving their reproductive, metabolic and endocrine profiles. This suggests the need for a nutritional intervention (nutritional guidelines) for women diagnosed with PCOS patients as a first line treatment. The study results support the effectiveness of lifestyle modification diet for PCOS women.

Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility and the most common endocrinopathy of women of reproductive age. Genome-wide association studies (GWAS) identified a number of loci associated PCOS in different ethnic populations, including women with Asian and European ancestry. Replication studies have confirmed some of these associations. Among the loci identified are those located near the LH receptor gene (LHCGR), a clathrin-binding protein gene (DENND1A) that also functions as a guanine nucleotide exchange factor, and the gene encoding RAB5B, a GTPase and protein involved in vesicular trafficking. The functional significance of one of these GWAS candidates (DENND1A) was supported by our discovery that a truncated protein splice variant of DENND1A termed DENND1A.V2, is elevated in PCOS theca cells, and that forced expression of DENND1A.V2 in normal theca cells increased CYP11A1 and CYP17A1 expression and androgen synthesis, a hallmark of PCOS. We previously proposed that the PCOS GWAS loci could be assembled into a functional network that contributes to altered gene expression in ovarian theca cells, resulting in increased androgen synthesis. Here we demonstrate the localization of LHCGR, DENND1AV.2 and RAB5B proteins in various cellular compartments in normal and PCOS theca cells. hCG and forskolin stimulation affects the distribution and co-localization of DENND1A.V2 and RAB5B in various cellular compartments This cytological evidence supports our PCOS gene network concept, and raises the intriguing possibility that LHCGR activation, via a cAMP-mediated process, promotes the translocation of DENND1A.V2 and RAB5B-containing vesicles from the PCOS theca cell cytoplasm into the nucleus, resulting in increased transcription of genes involved in androgen synthesis.

Aim: To describe the lived experience of women with polycystic ovary syndrome (PCOS). Method: Eight scientific articles of appropriate quality were found, analyzed, condensed and synthesized. Different experiences by women with PCOS were found and ordered into themes. The findings were then anchored in associated literature and discussed. Results: Four different themes were found: Feeling different; Disturbing symptoms; Searching for answers; Care treatment. Each of these themes offered areas of improvement in regard to nursing care. Conclusions: Extra attention to the psychosocial aspects of health for women with PCOS should be taken to improve nursing care. The exchange of information between nursing staff and patients needs to be better adapted to the individual informational needs of women with PCOS.

Bakgrund: Runt 5-10 % av kvinnor i fertil ålder har en diagnos av polycystiskt ovariesyndrom men ännu fler lider av syndromet utan en diagnos. Polycystiskt ovariesyndrom innebär att en kvinnas ena eller båda äggstockar är fyllda med cystor och att hon har en hormonstörning. Kosthållning har en betydande effekt på hur syndromet visar sig. Syfte: Se vad olika kostmetoder har för effekter på kvinnor med polycystiskt ovariesyndrom och vilken metod som är bäst. Metod: En litteraturstudie som analyserar tio vetenskapliga artiklar i fyra olika teman. Resultat: En hög-proteinkost, en kosthållning med lågt GI och ökad fysisk aktivitet ger alla tre positiva effekter på syndromet. En fettsnål kost ger mer negativa effekter än vad en fettrik kost ger. Studien visar att viktminskning också förbättrar syndromet. Slutsats: Mer forskning behövs om olika kostmetoders effekter på kvinnor med polycystiskt ovariesyndrom i större studiepopulationer och olika kostmetoder har olika effekter på hur polycystiskt ovariesyndrom visar sig. / Background: About 5-10 % of women in fertile age have been diagnosed with polycystic ovary syndrome diagnosis with many other women also having polycystic ovary syndrome without diagnoses. Polycystic ovary syndrome is a disease where a woman’s ovaries are filled with cysts, along with related hormonal disorders. Diets can help reduce the symptoms of this syndrome. Aim: See how various dietary approaches impacts on women with polycystic ovary syndrome and to see which approach is the best. Method: A literature review that analyzes ten different scientific articles. Four major themes were extracted from this review. Results: A high-protein diet, a diet with low GI and increased physical activity are three different approaches that are show to provide positive effects in people who suffer from this syndrome. Low-fat diets did not show positive effects. The study shows that the syndrome also becomes better with a weight loss. Conclusion: More research is needed on the various dietary approaches effects on women with polycystic ovary syndrome in larger study populations to identify the effects of different dietary approaches.

Background: The progesterone metabolite allopregnanolone is involved in several clinical conditions in women, e.g. premenstrual dysphoric disorder. It is a very potent GABA-steroid with GABA-A receptor effects similar to other GABA-agonists, e.g. benzodiazepines, and it causes sedation. An objective way to examine effects on the GABA-A receptor in humans is to measure saccadic eye velocity (SEV), which is reduced by GABA-agonists, e.g. allopregnanolone. Animal studies suggest that allopregnanolone is involved in the regulation of gonadotropin secretion via the GABA-A receptor, but this has not been studied in humans. Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance among women of fertile age (5–10%), characterized by polycystic ovaries, menstrual dysfunction, hyperandrogenity, and 50% have obesity. Studies have shown higher allopregnanolone levels in overweight people. PCOS women have increased levels of androstanediol, an androgen metabolite which is an GABA-A receptor agonist. Tolerance often occurs when persons are exposed to high levels of GABAergic modulators. It has not been studied whether GABA-A receptor sensitivity in PCOS women is changed. Another progesterone metabolite, isoallopregnanolone, is the stereoisomere of allopregnanolone but has not been shown to have any GABA-A receptor effect of its own. Instead it has often been used to control steroid specificity to allopregnanolone. Aims: To compare the effects of allopregnanolone and isoallopregnanolone on gonadotropin secretion. To compare allopregnanolone levels, GABA-A receptor sensitivity to allopregnanolone and effects on gonadotropin secretion in both cycle phases and PCOS conditions. To examine pharmacokinetics and pharmacodynamic properties for isoallopregnanolone. Method: In the follicular phase healthy women were examined for the effect of allopregnanolone or isoallopregnanolone on gonadotropin secretion. PCOS women and healthy women in both cycle phases were given allopregnanolone and the differences in effects on SEV were examined, as well as changes in serum levels of gonadotropins and allopregnanolone at baseline and during the test day. Pharmacokinetics and GABA-A receptor sensitivity using SEV were explored for isoallopregnanolone in healthy women. Results: Allopregnanolone decreases gonadotropin serum levels in healthy controls in both cycle phases, but has no effect on gonadotropin secretion in women with PCOS. PCOS women have higher baseline serum levels of allopregnanolone than follicular phase controls, but lower levels than luteal phase controls. PCOS women show greater reduction in SEV to allopregnanolone than controls. Isoallopregnanolone has no effect on gonadotropin secretion. There is an effect of isoallopregnanolone on SEV, explained by a metabolism of isoallopregnanolone into allopregnanolone. Conclusion: There are significant differences in the GABA-A receptor response to a GABA-steroid in different endocrine conditions in women of fertile age examined with saccadic eye velocity. The GABA-steroid allopregnanolone decreases gonadotropin serum levels in healthy women but not in PCOS women. The lack of effect on gonadotropins by isoallopregnanolone suggests an involvement of the GABA-A receptor.