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ULTRASONOGRAPHIC IMAGING OF OVARIAN MORHPOLOGY FOR THE DIAGNOSIS AND EVALUATION OF ANOVULATORY CONDITIONS ACROSS THE ADIPOSITY SPECTRUM IN WOMEN AND ADOLESCENTS Heidi Vanden Brink, MS, RDMS Cornell University 2019 The leading cause of reproductive disturbance in women is polycystic ovary syndrome (PCOS), afflicting up to 10% of women. Hyperandrogenic anovulatory phenotypes (HA-Anov) of PCOS exhibit a heightened risk of cardiometabolic comorbidities. In contrast, normoandrogenic anovulatory (NA-Anov) phenotypes of PCOS experience less severe comorbidities. Therefore, we propose that these two conditions should be considered separately to initiate treatment and preventative measures appropriate for the risks associated with the clinical conditions. However, current limitations in the reliability of androgen assays to diagnose hyperandrogenism necessitate alternative biomarkers which accurately reflect NA- and HA-Anov conditions. Unique morphological (structural) descriptions on ultrasonography have been described in the ovaries of women with NA- and HA-Anov phenotypes. However, the degree to which they specifically capture androgen status over other concurrent comorbidities is unclear. There is growing evidence that obesity and hyperinsulinemia influence the development of hyperandrogenism, folliculogenesis, and ovarian morphology. Thus, ovarian morphology may capture the integration of reproductive and metabolic signals. The degree to which these competing influences enhance or impair the utility of ultrasonographic evaluations of ovarian morphology to guide diagnoses and treatment is an important area of consideration. In this dissertation, we tested the hypothesis that sonographic evaluations of the ovary using reproducible measures provide robust morphologic biomarkers that effectively inform the diagnosis and prognosis of reproductive and metabolic disturbances in women. In Chapter 1, we undertake a series of experiments to establish the reproducibility of several new or commonly used, two- (2D) and three-dimensional (3D) sonographic methods to evaluate ovarian morphology. We conduct a method comparison study to test the agreement of various approaches for obtaining follicle number per ovary (FNPO) versus an established, but time-consuming reproducible method generated by our group. 2D counts of FNPO made in real-time exhibit poor agreement and the data do not support continued use of this method in clinical practice or research. Other 2D and 3D methods are appropriate for the categorization of ovarian dysmorphology, however substantial over- and under-counting across 2D and 3D methods hinder their utility when a precise estimate of FNPO is needed. We subsequently tested the reliability and agreement of ovarian stromal assessments. Although we did not identify a reproducible method to evaluate the stroma, we provide evidence that increased stromal area is a consistent finding in women with anovulation. A method which obtains total stromal area by subtraction of follicular area was shown to be promising under certain imaging conditions, but ultimately there was justification to test the overarching hypothesis of this dissertation using metrics related to ovarian size and follicle number, not stromal features, which showed adequate reproducibility. In Chapter 2 we test whether reproducible methods to evaluate the ovary on ultrasound can discriminate between anovulatory conditions in lean and overweight women. We report that the ovary exhibits diagnostic potential for anovulatory conditions. We also show that thresholds to define ovulatory disorders were impacted by BMI. However, the impact of BMI on the diagnostic accuracy of ovarian features was variable and did not lead to the development of BMI-specific thresholds for ovulatory disorders. Rather, the findings point to a possibility that consideration of metabolic consequences of obesity and/or metabolic pathways impacting hyperandrogenism and ovarian morphology are relevant to improve diagnostic accuracy of ovulatory disorders. In Chapter 3, we focus on insulin resistance (IR) as a metabolic disturbance suspected to contribute to the pathogenesis of androgen excess and abnormal ovarian morphology. We show that the degree of metabolic risk perceived in women with ovulatory disorders depends on how both hyperandrogenism and IR are defined. The data also suggest that IR may influence the reproductive axis predominantly through increasing free, but not total, androgens. Whether the diagnosis and evaluation of ovulatory disturbances using ovarian morphology are possible over the life course remains an important point of consideration. In Chapter 4 we conducted a secondary analysis on data obtained from adolescents with PCOS to explore relationships between ovarian markers and aspects of reproductive and metabolic disturbance. We show that sonographic imaging using transabdominal ultrasound is possible and that features of the ovary reflect reproductive and metabolic disturbances in adolescents. The demonstration that the ovary can serve as a biomarker at such early stages of reproductive development justifies its consideration as a diagnostic feature during the adolescent reproductive transition.
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women; ultrasound; follicle; ovary; adolescents; PCOS; physiology; Health sciences; Nutrition
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Lujan, Marla E.
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Roberson, Mark Stephen
Thalacker-Mercer, Anna E.
Cummings, Bethany P.
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Ph.D., Nutrition
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Doctor of Philosophy
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dissertation or thesis
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