Menopause Effects on Vascular Function
Condition: Cardiovascular Risk Factor
Study type: Interventional

Summary: 
      The purpose of the study is to identify the independent effect of estradiol (E2) on
      endothelin-1 (ET-1) mediated vasomotor function in women. The study is the first step in
      recognizing the impact of ovarian hormones on the mechanisms that regulate vascular function
      in women to provide a better understanding of the cardiovascular efficacy of hormone therapy.
    

Detailed description: 
      Cardiovascular disease (CVD) is the leading cause of death in women (Roger, Go, Lloyd, Adams,
      Berry, Brown, et al, 2011). Functional changes in the microvasculature occur with aging and
      precede atherosclerosis, contributing to CVD (Seals, Jablonski, & Donato, 2011). Furthermore,
      because of the decline in ovarian hormones during menopause, age-related impairments in
      endothelial function are exacerbated in postmenopausal women (PMW). However, the safety and
      efficacy of currently available hormone-based therapies remains controversial (Devi,
      Sugiguchi, Pederson, Abrassart Glodowski, & Nachtigall, 2013: Miller, Black, Brinton, Budoff,
      Cedars, Hodis, et al, 2009). Endothelin-1 (ET-1) is a potent vasoconstrictor produced and
      released by endothelial cells and implicated in the development of atherosclerosis (Best,
      McKenna, Holmes, & Lerman, 1999; Donato, Gano, Eskurza, Silver, Gates, Jablonski, et al,
      2009; Ihling, Szombathy, Bohrmann, Brockhaus, Schaefer, & Loeffler, 2009). ET-1 binds to two
      receptor subtypes, ET-A and ET-B (Yanagisawa, Kurihara, Kimura, Tomobe, Kobayashi, Mitsui, et
      al, 1988). While both receptors are located on vascular smooth muscle (VSM) and cause
      vasoconstriction, ET-B receptors are also located on the endothelium and cause vasodilation
      (Gomez-Sanchez, Cozza, Foecking, Chiou, & Ferris, 1990; Haynes, 1995; Ishikawa, Ihara,
      Noguchi, Mase, Mino Saeki, et al, 1994). In women, ET-1 preferentially binds to ET-B
      receptors compared to ET-A receptors, supporting findings of sex differences in ET-1 receptor
      responses and suggesting ET-B receptors are under hormonal control (Ergul, Shoemaker, Puett,
      & Tackett, 1998; Kellogg, Liu, & Pergola, 2001; Stauffer, Westby, Greiner, Van Guilder, &
      Desouza, 2010). In animal models, estradiol (E2) reduces ET-1 mediated vasoconstriction and
      increases ET-B receptor mRNA (Pederson, Nielsen, Mortensen, Nilas, & Ottesen, 2008). Thus,
      low levels of E2 in PMW may contribute to impaired vascular function through an ET-B receptor
      mechanism. However, the interaction between E2 and ET-1 receptor responses on regulating
      vascular function in women is currently unknown.

      The long-term goal of the laboratory is to understand the impact of ovarian hormones on the
      mechanisms that regulate vascular function in women to provide a better understanding of the
      cardiovascular efficacy of hormone therapy. The study is the first step in reaching our goal;
      the objective of the study is to identify the independent effect of E2 on ET-1 mediated
      vasomotor function in women. The investigators will measure blood flow responses to local
      heating in the cutaneous circulation during perfusion of ET-1 receptor antagonists via
      microdialysis, coupled with measures of intracellular protein and receptor expression on
      endothelial cells and skin punch biopsies (to assess VSM cells) collected from young and PMW
      while controlling ovarian hormone exposure. Young women will be tested after suppressing
      ovarian production of E2 and progesterone with a gonadotropin-releasing hormone antagonist
      (GnRHant), and again after E2 administration; PMW, who are not using hormone therapy, will be
      tested before and after E2 admin. The central hypothesis is that declines in E2 impair
      microvascular vasodilatory function due to cellular changes in ET-B receptor expression on
      endothelial and VSM cells, and that E2 administration reverses these responses.
    

Intervention name(s): No to Low Endogenous Estrogen; Estradiol
Intervention type(s): Other; Other
Intervention description(s): Ganirelix acetate (Antagon) will be used to prevent endogenous production of ovarian hormones in young women. Ganirelix is derived from native GnRH, and acts by competitively blocking GnRH receptors on the pituitary and subsequent pathways. Thus, administration of the GnRH antagonist (GnRHant) suppresses steroidogenesis, leading to low or undetectable serum estrogen and progesterone concentrations, which occurs within two days of initiation of administration (Oberye, Mannaerts, Huisman & Timmer, 1999; Oberye, Mannaerts, Kleijn, & Timmer, 1999).; Short term estradiol administration elicits changes in vascular function in women, and 0.1mg/day patch is the upper recommended limit for hormone therapy in women (Wenner, Taylor, & Stachenfeld, 2011; Moreau, Hildreth, Meditz, Deane & Kohrt, 2012).
Other intervention name(s): Vivelle dot
Intervention MeSH terms: Estradiol; Estrogens
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science