Study Results
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Basic Information
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COMPLETED
NA
48 participants
INTERVENTIONAL
2016-07-01
2022-11-01
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NON_RANDOMIZED
PARALLEL
BASIC_SCIENCE
NONE
Study Groups
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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).
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).
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.
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).
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).
Interventions
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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).
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 Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
65 Years
FEMALE
Yes
Sponsors
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American Heart Association
OTHER
University of Delaware
OTHER
Responsible Party
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Megan M. Wenner
Assistant Professor
Principal Investigators
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Megan Wenner, PhD
Role: PRINCIPAL_INVESTIGATOR
University of Delaware
Locations
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University of Delaware
Newark, Delaware, United States
Countries
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References
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Miller VM, Black DM, Brinton EA, Budoff MJ, Cedars MI, Hodis HN, Lobo RA, Manson JE, Merriam GR, Naftolin F, Santoro N, Taylor HS, Harman SM. Using basic science to design a clinical trial: baseline characteristics of women enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). J Cardiovasc Transl Res. 2009 Sep;2(3):228-39. doi: 10.1007/s12265-009-9104-y. Epub 2009 May 22.
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Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988 Mar 31;332(6163):411-5. doi: 10.1038/332411a0.
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Haynes WG. Endothelins as regulators of vascular tone in man. Clin Sci (Lond). 1995 May;88(5):509-17. doi: 10.1042/cs0880509.
Ishikawa K, Ihara M, Noguchi K, Mase T, Mino N, Saeki T, Fukuroda T, Fukami T, Ozaki S, Nagase T, et al. Biochemical and pharmacological profile of a potent and selective endothelin B-receptor antagonist, BQ-788. Proc Natl Acad Sci U S A. 1994 May 24;91(11):4892-6. doi: 10.1073/pnas.91.11.4892.
Ergul A, Shoemaker K, Puett D, Tackett RL. Gender differences in the expression of endothelin receptors in human saphenous veins in vitro. J Pharmacol Exp Ther. 1998 May;285(2):511-7.
Kellogg DL Jr, Liu Y, Pergola PE. Selected contribution: Gender differences in the endothelin-B receptor contribution to basal cutaneous vascular tone in humans. J Appl Physiol (1985). 2001 Nov;91(5):2407-11; discussion 2389-90. doi: 10.1152/jappl.2001.91.5.2407.
Stauffer BL, Westby CM, Greiner JJ, Van Guilder GP, Desouza CA. Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults. Am J Physiol Regul Integr Comp Physiol. 2010 Feb;298(2):R261-5. doi: 10.1152/ajpregu.00626.2009. Epub 2009 Nov 25.
Pedersen SH, Nielsen LB, Mortensen A, Nilas L, Ottesen B. Progestins oppose the effects of estradiol on the endothelin-1 receptor type B in coronary arteries from ovariectomized hyperlipidemic rabbits. Menopause. 2008 May-Jun;15(3):503-10. doi: 10.1097/gme.0b013e318156f803.
Wenner MM, Taylor HS, Stachenfeld NS. Progesterone enhances adrenergic control of skin blood flow in women with high but not low orthostatic tolerance. J Physiol. 2011 Feb 15;589(Pt 4):975-86. doi: 10.1113/jphysiol.2010.194563. Epub 2010 Dec 20.
Wenner MM, Haddadin AS, Taylor HS, Stachenfeld NS. Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol. J Physiol. 2013 May 1;591(9):2345-55. doi: 10.1113/jphysiol.2012.247882. Epub 2013 Feb 11.
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Oberye JJ, Mannaerts BM, Huisman JA, Timmer CJ. Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part II. Dose-proportionality and gonadotropin suppression after multiple doses of ganirelix in healthy female volunteers. Fertil Steril. 1999 Dec;72(6):1006-12. doi: 10.1016/s0015-0282(99)00414-8.
Oberye JJ, Mannaerts BM, Kleijn HJ, Timmer CJ. Pharmacokinetic and pharmacodynamic characteristics of ganirelix (Antagon/Orgalutran). Part I. Absolute bioavailability of 0.25 mg of ganirelix after a single subcutaneous injection in healthy female volunteers. Fertil Steril. 1999 Dec;72(6):1001-5. doi: 10.1016/s0015-0282(99)00413-6.
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Moreau KL, Hildreth KL, Meditz AL, Deane KD, Kohrt WM. Endothelial function is impaired across the stages of the menopause transition in healthy women. J Clin Endocrinol Metab. 2012 Dec;97(12):4692-700. doi: 10.1210/jc.2012-2244. Epub 2012 Sep 11.
Other Identifiers
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385453-18
Identifier Type: -
Identifier Source: org_study_id
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