Orthostatic intolerance is a leading cardiovascular dysfunction in women of reproductive age. The orthostatic adjustment from seated or lying to standing posture involves the integration of central blood volume and the baroreflex response. The adequacy of the baroreflex response is a function of central baroreceptor sensitivity and peripheral vascular resistance. While a number of studies have indicated that estradiol and progesterone impact aspects of the orthostatic response, no studies have related these changes directly to orthostatic tolerance, and the individual effects of estradiol versus progesterone on orthostatic responses in humans have not been isolated. Estrogens and progesterone have opposing influences on blood pressure regulation, with estradiol tending to increase peripheral vasodilation, and with progesterone tending to increase vasoconstriction. Moreover, estradiol has important effects on progesterone receptor function;thus the interaction of these hormones may also impact the orthostatic response in women. Our experimental design permits suppression followed by controlled estradiol and progesterone administration to determine the individual and combined effects of estradiol and progesterone on baroreflex function and peripheral resistance. On the basis of lower body negative pressure tests to presyncope, we will place subjects into high and low orthostatic tolerance groups in order to test the following Specific Aims: 1) to determine the estradiol and progesterone effects on sympathetic outflow, as well as cardiovagal, sympathetic and integrated baroreflex function;2) to determine the estradiol and progesterone effects on peripheral blood flow and the mechanisms for the sex hormone effects on peripheral blood flow. We expect that these studies will not only increase our understanding of the roles estradiol and progesterone play in blood pressure regulation in women, but may also serve as a basis for interventions to improve orthostatic tolerance in women. We also expect that the data in these studies will provide a basis to study the impact of sex hormones on diseases related to compromised peripheral circulation, such as hypertension, Raynaud's phenomenon and diabetes

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Fleg, Jerome
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John B. Pierce Laboratory, Inc.
New Haven
United States
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Wenner, Megan M; Hinds, Kumba Adia; Howard, Jeffrey T et al. (2018) Measurement of compensatory reserve predicts racial differences in tolerance to simulated hemorrhage in women. J Trauma Acute Care Surg 85:S77-S83
Stachenfeld, Nina S (2014) Hormonal changes during menopause and the impact on fluid regulation. Reprod Sci 21:555-61
Wenner, Megan M; Haddadin, Ala' S; Taylor, Hugh S et al. (2013) Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol. J Physiol 591:2345-55
Wenner, Megan M; Taylor, Hugh S; Stachenfeld, Nina S (2011) Progesterone enhances adrenergic control of skin blood flow in women with high but not low orthostatic tolerance. J Physiol 589:975-86
Wenner, Megan M; Wilson, Thad E; Davis, Scott L et al. (2011) Pharmacological curve fitting to analyze cutaneous adrenergic responses. J Appl Physiol 111:1703-9
Hinds, Kumba; Stachenfeld, Nina S (2010) Greater orthostatic tolerance in young black compared with white women. Hypertension 56:75-81
Stachenfeld, Nina S (2008) Sex hormone effects on body fluid regulation. Exerc Sport Sci Rev 36:152-9
Stachenfeld, Nina S (2008) Acute effects of sodium ingestion on thirst and cardiovascular function. Curr Sports Med Rep 7:S7-13
Stachenfeld, Nina S; Taylor, Hugh S (2007) Exogenous oestradiol and progesterone administration does not cause oedema in healthy young women. Clin Endocrinol (Oxf) 66:410-8
Stachenfeld, Nina S; Taylor, Hugh S (2005) Progesterone increases plasma volume independent of estradiol. J Appl Physiol 98:1991-7

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