Abbott Research Team
Currently, there are two main areas of research focus: polycystic ovary syndrome (PCOS) afflicting up to 15% of women and female hyposexual dysfunction affecting ~10% of women. Both areas are collaborative efforts with PIs on campus and at other institutions.
In collaboration with Drs. Daniel Dumesic (UCLA), Jon Levine (Dept. of Neuroscience) and Dawn Davis (Dept. of Medicine), my lab developed two comprehensive nonhuman primate models for polycystic ovary syndrome (PCOS) that have been the vanguards for a multitude of animal and human studies aimed at determining developmental origins of this most common endocrinopathy in women. With NIH funding, we have translated insight gained from nonhuman primate models to discern pathophysiological mechanism causing discrete aspects of reproductive and metabolic dysfunction in women with PCOS, including abnormalities at the molecular level in the hypothalamus, adipose tissue, pancreas and ovary, as well as potential genetic contributions to naturally occurring PCOS.
Our most recent work identifies metabolic dysfunction and re-reprogramming of hypothalamic regulation as possibly the initial abnormalities in early developmental origins of PCOS. Most recently, we have been employing viral vector knockdown approaches to functionally identify molecular mechanisms. With regard to female hyposexual dysfunction, in collaboration with Drs. Alex Converse (Waisman Laboratory for Brain Imaging and Behavior), Yves Aubert (University of Bergen, Norway), Nicole Datson (BioMarin Nederland B.V., Netherlands) and Kelly Allers and Bernd Sommer (Boehringer Ingelheim, Germany), we have used MRI and PET neuroimaging, together with molecular neurobiology and digitized behavioral observations, to elucidate neural components contributing to female nonhuman primate social and sexual interactions with male pairmates. One of our recent studies contributed to a successful bench-to-bedside completion for flibanserin (Addyl), with the therapeutic achieving approval by the FDA for clinical use in treating hyposexuality in women, commencing October, 2015.
Neurosteroid Regulation of Adiposity, Glucose Homeostasis and Energy Expenditure in Primates
Sponsor: NIH AAH3686 PI: J Levine, PhD
We will use both pharmacological and viral vectormediated shRNA approaches to determine if adiposity, glucoregulation and energy metabolism are altered by inhibition of the CYP19A1 aromatase enzyme, or by permanent silencing of the CYP19A1 gene in the hypothalamus of female rhesus macaques. We will also analyze the synthesis of E2 in the VMN and ARC by a microdialysis approach, and determine whether VMN and ARC E2 originates from hypothalamically synthesized androgens. These studies may fundamentally change our understanding of metabolic control of adiposity, glucoregulation and energy homeostasis by sex steroids in female NHPs, and prompt exploration of new therapeutic strategies to diminish metabolic disease in women.
PCOS Investigations and Reviews
Abbott, D. H., Dumesic, D. A., & Levine, J. E. (2019). Hyperandrogenic origins of polycystic ovary syndrome - implications for pathophysiology and therapy. Expert Rev Endocrinol Metab, 14(2), 131-143. doi:10.1080/17446651.2019.1576522
Abbott, D. H., Rogers, J., Dumesic, D. A., & Levine, J. E. (2019). Naturally Occurring and Experimentally Induced Rhesus Macaque Models for Polycystic Ovary Syndrome: Translational Gateways to Clinical Application. Med Sci (Basel), 7(12). doi:10.3390/medsci7120107
Abbott, D. H. (2019). Metformin use in polycystic ovary syndrome pregnancy impacts on offspring obesity. Lancet Child Adolesc Health, 3(3), 132-134. doi:10.1016/S2352-4642(19)30001-X
Abbott, D. H., Vepraskas, S. H., Horton, T. H., Terasawa, E., & Levine, J. E. (2018). Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation. Neuroendocrinology, 107(2), 133-146. doi:10.1159/000490570
Abbott, D. H. (2017). Neuronal androgen receptor: Molecular gateway to polycystic ovary syndrome? Proc Natl Acad Sci U S A, 114(16), 4045-4047. doi:10.1073/pnas.1703436114
Abbott, D. H., Rayome, B. H., Dumesic, D. A., Lewis, K. C., Edwards, A. K., Wallen, K., . . . Levine, J. E. (2017). Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys. Hum Reprod, 32(4), 923-936. doi:10.1093/humrep/dex036
Genes, androgens and intrauterine environment in PCOS
Start Date: 8/1/2012 --- End Date: 7/31/2019
Sponsor: NIH P50HD044405, PI: A Dunaif, MD
Kraynak, M., Colman, R. J., Flowers, M. T., Abbott, D. H., & Levine, J. E. (2019). Ovarian estradiol supports sexual behavior but not energy homeostasis in female marmoset monkeys. Int J Obes (Lond), 43(5), 1034-1045. doi:10.1038/s41366-018-0156-4
Kraynak, M., Flowers, M. T., Shapiro, R. A., Kapoor, A., Levine, J. E., & Abbott, D. H. (2017). Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys. Am J Physiol Endocrinol Metab, 313(5), E507-E514. doi:10.1152/ajpendo.00058.2017