Contraceptive effectiveness and safety are public health concerns of high national and international priority. The acceptability of a specific contraceptive method impacts significantly on the success of fertility control. Parenteral progestin contraceptives provide effective, long- term, reversible protection against pregnancy, but they often are discontinued because of abnormal bleeding patterns. The goal of this proposal is to understand the molecular and cellular mechanisms that underly irregular bleeding commonly associated with depot medroxyprogesterone acetate (DMPA) injections and levonorgestrel- containing silastic capsules (Norplant). Unlike the initiation of normal menses, which is triggered by spiral artery constriction, irregular bleeding associated with parenteral progestins is thought to originate from the subepithelial capillary plexus. Regulation of the endometrial microvasculature is understood poorly, but its growth and development are coordinated by ovarian hormones. We and others have demonstrated that a specific angiogenic peptide, vascular endothelial growth factor (VEGF), is hormonally regulated in human endometrium. We hypothesize that VEGF mediates the effects of ovarian steroids on the growth and function of the endometrial microvasculature. Progestational agents alter endometrial VEGF action, disrupting normal angiogenesis and regulation of endometrial microvessels. This disruption of endometrial vasculature, glands, and stroma ultimately leads to unpredictable, irregular uterine bleeding. Modern cellular and molecular approaches will be used to elucidate the biological bases for irregular bleeding associated with parenteral contraceptives. This information will allow the rational design of improved devices, or suggest adjuvants (e.g., estrogen) to ameliorate the irregular bleeding observed with parenteral progestin therapy, leading to improved acceptance of DMPA and Norplant. All integrated, multidisciplinary team of investigators with expertise in clinical contraception and basic laboratory investigation will address the following objectives:
Specific Aims I : The ultrasonographic, hysteroscopic, microscopic and biochemical characteristics of the endometrium, including expression of VEGF and estrogen and progesterone receptors, will be examined in women using parenteral progestin contraceptives and in normal, ovulatory controls.
Specific Aim II. The in vivo regulation of VEGF by ovarian steroids and the role of VEGF in endometrial angiogenesis will be studied in human endometrium transplanted subcutaneously in immunodeficient mice.
Specific Aim III. The molecular regulation of endometrial VEGF by ovarian steroids and their receptors will be studied in isolated human endometrial epithelial and stromal cells in vitro. An understanding of the cellular expression of VEGF and the endocrine regulation of endometrial angiogenesis should provide new targets to improve the acceptability of these effective contraceptive devices.
| Ramathal, Cyril Y; Bagchi, Indrani C; Taylor, Robert N et al. (2010) Endometrial decidualization: of mice and men. Semin Reprod Med 28:17-26 |
| Taylor, Robert N; Yu, Jie; Torres, Paulo B et al. (2009) Mechanistic and therapeutic implications of angiogenesis in endometriosis. Reprod Sci 16:140-6 |
| Weiss, Gerson; Goldsmith, Laura T; Taylor, Robert N et al. (2009) Inflammation in reproductive disorders. Reprod Sci 16:216-29 |
| Laws, Mary J; Taylor, Robert N; Sidell, Neil et al. (2008) Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development 135:2659-68 |
| Tee, Meng Kian; Vigne, Jean-Louis; Taylor, Robert N (2006) All-trans retinoic acid inhibits vascular endothelial growth factor expression in a cell model of neutrophil activation. Endocrinology 147:1264-70 |
| Pritts, Elizabeth A; Ryan, Isabelle P; Mueller, Michael D et al. (2005) Angiogenic effects of norplant contraception on endometrial histology and uterine bleeding. J Clin Endocrinol Metab 90:2142-7 |
| Peeters, Louis L H; Vigne, Jean-Louis; Tee, Meng Kian et al. (2005) PPAR gamma represses VEGF expression in human endometrial cells: implications for uterine angiogenesis. Angiogenesis 8:373-9 |
| Taylor, R N; Mueller, M D (2004) Anti-angiogenic treatment of endometriosis: biochemical aspects. Gynecol Obstet Invest 57:54-6 |
| Mueller, Michael D; Pritts, Elizabeth A; Zaloudek, Charles J et al. (2003) Regulation of vascular endothelial growth factor by tamoxifen in vitro and in vivo. Gynecol Obstet Invest 55:119-24 |
| Taylor, Robert N; Lebovic, Dan I; Mueller, Michael D (2002) Angiogenic factors in endometriosis. Ann N Y Acad Sci 955:89-100; discussion 118, 396-406 |
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