Long-term progestin-only contraceptives (LTPOCs) are ideally suited for women with limited access to healthcare. Unfortunately, abnormal uterine bleeding causes high rates of discontinuation. Endometria of LTPOC-treated patients display over-expression of an array of angiogenic factors and cytokines which lead to aberrant angiogenesis and inflammation. LTPOC-exposed endometria also show evidence of extensive oxidative stress and reduced endometrial blood flow. Our central hypothesis is that LTPOC reduces uterine blood flow to cause hypoxia/re-perfusion which triggers the generation of reactive oxygen species (ROS). The latter induce the expression of angiogenic and inflammatory modulators that produce abnormal, fragile endometrial vessels. The resultant focal bleeding facilitates tissue factor-generated thrombin which exacerbates these angiogenic and inflammatory stimuli. Hence we propose the following Specific Aims to test this hypothesis: 1) Laser Doppler flow fluxmetry will measure endometrial perfusion before and after LTPOC administration while endometrial biopsies will be collected for measurement of ROS and angiogenic endpoints;2) molecular pathways by which ROS induce aberrant angiogenesis and inflammation will be studied in endometrial stromal cell and endothelial cell cultures and co-cultures exposed to progestins with or without hypoxia, ROS or thrombin. Putative intermediate transcription factors will be discovered by electrophoretic mobility shift assays and micorarray analyses while paracrine mediators of aberrant angiogenesis will be identified by proteomic analysis;and 3) effects of synthetic progestins on uterine artery basal tone and response to pressors will be assessed in guinea pig and human uterine artery vascular ring bioassays. Autocrine mediators of these steroid effects will be analyzed by microarray studies. These novel studies will define the precise uterine vasoconstrictive effects of LTPOCs, identify the underlying vascular regulatory mechanisms, and delineate the molecular pathways whereby hypoxia, ROS and thrombin mediate endometrial angiogenesis and inflammation. Moreover, a model will be established to test innovative LTPOC formulations that minimize uterine and endometrial vasoconstriction and ROS-generation, thus preventing abnormal bleeding to improve the acceptability of LTPOC therapies.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033937-16
Application #
8142085
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Kaufman, Steven
Project Start
1995-05-01
Project End
2011-11-30
Budget Start
2011-07-01
Budget End
2011-11-30
Support Year
16
Fiscal Year
2011
Total Cost
$97,915
Indirect Cost
Name
Yale University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Guzeloglu Kayisli, Ozlem; Kayisli, Umit A; Basar, Murat et al. (2015) Progestins Upregulate FKBP51 Expression in Human Endometrial Stromal Cells to Induce Functional Progesterone and Glucocorticoid Withdrawal: Implications for Contraceptive- Associated Abnormal Uterine Bleeding. PLoS One 10:e0137855
Guzel, Elif; Buchwalder, Lynn; Basar, Murat et al. (2015) Effects of tibolone and its metabolites on prolactin and insulin-like growth factor binding protein-1 expression in human endometrial stromal cells. Gynecol Endocrinol 31:414-8
Shapiro, John P; Basar, Murat; Kayisli, Umit A et al. (2015) Mass spectrometry identification of potential mediators of progestin-only contraceptive-induced abnormal uterine bleeding in human endometrial stromal cells. Contraception 91:253-60
Kayisli, Umit A; Basar, Murat; Guzeloglu-Kayisli, Ozlem et al. (2015) Long-acting progestin-only contraceptives impair endometrial vasculature by inhibiting uterine vascular smooth muscle cell survival. Proc Natl Acad Sci U S A 112:5153-8
Guzeloglu-Kayisli, O; Basar, M; Shapiro, J P et al. (2014) Long-acting progestin-only contraceptives enhance human endometrial stromal cell expressed neuronal pentraxin-1 and reactive oxygen species to promote endothelial cell apoptosis. J Clin Endocrinol Metab 99:E1957-66
Lockwood, Charles J; Basar, Murat; Kayisli, Umit A et al. (2014) Interferon-? protects first-trimester decidual cells against aberrant matrix metalloproteinases 1, 3, and 9 expression in preeclampsia. Am J Pathol 184:2549-59
Lockwood, Charles J; Huang, S Joseph; Chen, Chie-Pein et al. (2013) Decidual cell regulation of natural killer cell-recruiting chemokines: implications for the pathogenesis and prediction of preeclampsia. Am J Pathol 183:841-56
Lockwood, Charles J; Kayisli, Umit A; Stocco, Carlos et al. (2012) Abruption-induced preterm delivery is associated with thrombin-mediated functional progesterone withdrawal in decidual cells. Am J Pathol 181:2138-48
Krikun, Graciela; Booth, C J; Buchwalder, L et al. (2012) Effects of etonogestrel treatment in the reproductive organs and uterine arteries of nonoophorectomized guinea pigs. Reprod Sci 19:400-6
Lockwood, Charles J; Huang, S J; Krikun, Graciela et al. (2011) Decidual hemostasis, inflammation, and angiogenesis in pre-eclampsia. Semin Thromb Hemost 37:158-64

Showing the most recent 10 out of 44 publications