Student Name: Alexis Oldfield

Student Concentration: Translational Medicine

Committee Member 1: Ned Place

Committee Member 2: Bethany Cummings

Committee Member 3: Kimberly O'Brien

Abstract: Obesity affects more than one-third of reproductive aged women and is associated with many adverse reproductive health outcomes. These include an increased likelihood of anovulatory cycles, longer time to pregnancy, infertility, a decreased efficacy of contraceptive methods, an increased risk of late menopause, endometrial hyperplasia, and gynecological cancers. Some women with obesity, however, maintain regular menstrual cycles. Of those that do, altered ovarian hormone production has been documented, including decreased luteal progesterone concentrations, and reduced luteinizing hormone pulse amplitude in addition to lower follicle stimulating hormone (FSH) and anti-Mullerian hormone (AMH) production, albeit controversial. These endocrine aberrations likely reflect alterations in antral ovarian follicle development, but this has never been systematically evaluated in this population. An understanding of antral follicle development in obesity may be necessary to develop effective care for the reproductive dysfunction commonly seen in this population particularly in light of our increasingly obesogenic demographic. The central objective of this dissertation was to characterize antral follicle and endocrine dynamics in women with obesity and regular ovulatory cycles. In Chapter 1, we use serial ultrasonography and venipuncture to characterize antral follicle development and ovarian hormone production during an inter-ovulatory interval (IOI) in women with obesity and regular ovulatory cycles and determine any differences in follicle and endocrine dynamics between obese and non-obese groups. We observed that women with obesity display fewer selectable (6-9mm) follicles across the IOI, as well as fewer recruitment events, smaller ovulatory follicle diameters at selection, and less anovulatory dominant follicles. These alterations in follicle dynamics were accompanied by decreased progesterone and AMH concentrations in women with obesity. In Chapter 2, we demonstrate the impact of a 6-month hypocaloric dietary intervention on follicle and endocrine dynamics in women with obesity and regular ovulatory cycles. We showed that weight loss was accompanied by an increased ovulatory follicle diameter at selection, increased number anovulatory dominant follicles, as well as a decreased total antral follicle count driven by fewer recruitable (2-5mm) follicles across the IOI. We also observed increased luteal progesterone production following weight loss. Lastly, in Chapter 3, we investigate the impact of obesity on endometrial development across the IOI, and report on any impact of a 6-month hypocaloric dietary intervention on endometrial thickness with weight loss. We discovered that women with obesity and regular ovulatory cycles show a thicker endometrium across the IOI, with a lesser degree of change in endometrial thickness at the secretory-proliferative phase transition compared to their non-obese counterparts. These differences in endometrial development were not improved with weight loss in the short-term, despite increased progesterone production. Collectively, this dissertation provides new knowledge related to the impact of obesity on suppressed antral follicle development and ovarian hormone production, and further improvements in antral follicle development and luteinization following weight loss, albeit these changes are insufficient to improve increased endometrial thickness in the short term.

Publications: Impact of Obesity on Anti-Mullerian Hormone (AMH) Levels in Women of Reproductive Age. Oldfield AL, Kazemi M, Lujan ME. J Clin Med. 2021 Jul 20;10(14):3192. doi: 10.3390/jcm10143192. PMID: 34300357 Macrocyclic Control in Helix Mimetics. Guarracino DA, Riordan JA, Barreto GM, Oldfield AL, Kouba CM, Agrinsoni D. Chem Rev. 2019 Sep 11;119(17):9915-9949. doi: 10.1021/acs.chemrev.8b00623. Epub 2019 May 2. PMID: 31045350 Head-to-Tail Cyclic Peptide Inhibitors of the Interaction between Human von Willebrand Factor and Collagen. Guarracino DA, Oldfield A, Gentile K, Martin S, Nguyen D, Barreto G, Kouba C. ChemMedChem. 2017 Dec 7;12(23):1985-1993. doi: 10.1002/cmdc.201700522. Epub 2017 Nov 14. PMID: 29059501 Ultrasound Characterization of Disordered Antral Follicle Development in Women with Polycystic Ovary Syndrome. Jarrett BY, Vanden Brink H, Oldfield AL, Lujan ME. J Clin Endocrinol Metab. 2020 Nov 1;105(11):e3847-61. doi: 10.1210/clinem/dgaa515. PMID: 32785651