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Menopause Effects on Vascular Function

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ClinicalTrials.gov Identifier: NCT03236545
Recruitment Status : Recruiting
First Posted : August 2, 2017
Last Update Posted : October 3, 2018
Sponsor:
Collaborator:
American Heart Association
Information provided by (Responsible Party):
Megan M. Wenner, University of Delaware

Brief 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.

Condition or disease Intervention/treatment Phase
Cardiovascular Risk Factor Other: No to Low Endogenous Estrogen Other: Estradiol Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Mechanisms of Vascular Dysfunction in Women: Role of Estradiol
Actual Study Start Date : July 1, 2016
Estimated Primary Completion Date : June 30, 2019
Estimated Study Completion Date : June 30, 2019


Arm Intervention/treatment
Experimental: No to Low Endogenous Estrogen
PMW and young women (YW) will receive medical study clearance after a detailed physical examination. YW will self-administer subcutaneous injections of the gonadotropin-releasing hormone (GnRH) antagonist, ganirelix acetate (Antagon, 0.25 mg/day in 0.5 ml of normal saline, Organon, Inc., West Orange, New Jersey,) daily to suppress endogenous ovarian hormone production (16, 17, 18). This will begin following a separate medical screening at Reproductive Associates of Delaware 48 hours prior to initiating the hormone intervention to rule out other contraindications prior to beginning the treatment. YW will begin using the antagonist on days 26-28 of their menstrual cycle, and continue daily for 10-12 days. The experimental protocol will be conducted in YW after 3-4 days of using the GnRH antagonist. PMW will complete the experimental protocol prior to use of the 17β-estradiol (E2, 0.1 mg/day patch, Vivelle dot; estradiol patch).
Other: No to Low Endogenous Estrogen
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).

Experimental: Estrogen Add-Back
Estradiol (E2, 0.1 mg/day patch, Vivelle dot; estradiol patch) will be administered for 7 days to both young and PMW. Young women will use the E2 over the last 7 days of Antagon administration.
Other: No to Low Endogenous Estrogen
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).

Other: Estradiol
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 Name: Vivelle dot




Primary Outcome Measures :
  1. Vascular endothelial function [ Time Frame: 3 years ]
    The capacity of the small and large blood vessels to dilate.


Secondary Outcome Measures :
  1. Endothelin receptor expression [ Time Frame: 3 years ]
    Venous endothelial cells and skin punch biopsy will be collected and stained for ET-A and ET-B receptor expression



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Young women between 18-35 years of age with regular menstrual cycles
  • Postmenopausal women between 50-65 years of age and no more than 10 years past menopause
  • Non-smoking
  • BMI < 30 kg/m2
  • Free from known disease (heart disease, cancer, diabetes)

Exclusion Criteria:

  • Current use of hormone therapy or within the past year
  • Women using Depo-provera or an intra-uterine device (IUD)
  • Pregnant, are planning on becoming pregnant, or are breast- feeding.
  • History of stable or unstable angina
  • Diabetes
  • Neurological disease
  • Lung disease
  • Kidney or liver disease
  • Cancer
  • Hysterectomy
  • Peripheral vascular disease
  • History of blood clots
  • Heart disease
  • Fibroids
  • High blood pressure
  • Stroke

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03236545


Contacts
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Contact: Megan Wenner, PhD 302-831-7343 mwenner@udel.edu
Contact: Joshua C Hobson, MS 302-831-8137 jhobson@udel.edu

Locations
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United States, Delaware
University of Delaware Recruiting
Newark, Delaware, United States, 19716
Contact: Megan Wenner, PhD    302-831-7343    mwenner@udel.edu   
Contact: Joshua C Hobson, MS    302-831-8137    jhobson@udel.edu   
Sponsors and Collaborators
University of Delaware
American Heart Association
Investigators
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Principal Investigator: Megan Wenner, PhD University of Delaware

Publications:
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011 Feb 1;123(4):e18-e209. doi: 10.1161/CIR.0b013e3182009701. Epub 2010 Dec 15. Erratum in: Circulation. 2011 Feb 15;123(6):e240. Circulation. 2011 Oct 18;124(16):e426.

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Responsible Party: Megan M. Wenner, Assistant Professor, University of Delaware
ClinicalTrials.gov Identifier: NCT03236545     History of Changes
Other Study ID Numbers: 385453-18
First Posted: August 2, 2017    Key Record Dates
Last Update Posted: October 3, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Information will be available through clinicaltrials.gov database within one year of completion of study.
Time Frame: No later than June 30, 2020
Access Criteria: upon request

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Additional relevant MeSH terms:
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Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Estradiol
Polyestradiol phosphate
Hormones
Estrogens
Ganirelix
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Hormone Antagonists