Blood Pressure; Environment and Public Health; Gynecology; Physiology; Polycystic Ovary Syndrome; Reproductive Medicine; Orthostatic Intolerance
Status of Women in Medicine Commitee (SWIM)
The regulation of body fluid and sodium content involves the integration of several physiological systems. One important system controls water and sodium output and/or reabsorption by the kidneys. A number of investigations have found that hormones involved primarily in reproductive function, specifically estrogen and progesterone, have important effects on the systems that regulate body fluid balance.
Estrogen, for example, can alter the "set point" around which the thirst mechanism and kidney water reabsorptive functions regulate body fluid content. Progesterone appears to affect body fluid content through its impact on the hormones that regulate body sodium content. The study of these hormones is challenging in young women because estrogen and progesterone fluctuate during the menstrual cycle.
Consequently, we have examined these systems in older post-menopausal, women before and during treatment with estrogen. We have also used the birth control pill to control the levels of estrogen and progesterone in young women. Most recently we have used medications to temporarily suppress the menstrual cycle in young women while adding back estrogen and/or progesterone to study the effects of these hormones on body fluid regulation under more controlled conditions.
Specialized Environmental physiology; Reproductive hormone effects on temperature and body fluid regulation; Polycystic Ovary Syndrome; Orthostatic tolerance; Blood pressure regulation
Extensive Research Description
Adequate body fluid and cardiovascular regulation are essential to respond to environmental challenges. Over my first seven years at Yale we demonstrated that estradiol, with and without progesterone, alters the osmotic regulation of arginine vasopressnin (AVP). Moreover, my laboratory has shown under a variety conditions and within both aging and younger populations that this is a change in osmotic set point for the control of AVP. We came to this conclusion because there is little change in renal free water clearance, the primary fluid regulation variable controlled by AVP. In addition we demonstrated that estradiol and progesterone not only affect osmotic regulation of AVP, but also affect body fluid distribution across the compartments (interstitial, intra- and extra-cellular, plasma) and may have important implications for the development of edema in women.
Most importantly, in order to deal with challenges associated with studying reproductive hormone effects on physiological systems, we developed a model to study effects of reproductive hormones on physiological systems in young women. In this model we “medically oophorectomize” young women by transiently suppressing gonadotropin releasing hormone (GnRH) with an agonist (leuprolide acetate) or antagonist (ganirelix acetate). Both of these drugs suppress GnRH and therefore suppress both estrogens and progesterone.
While the women are suppressed, we add-back controlled levels of estradiol and progesterone to test the hypothesis of interest. This protocol is particularly useful because it isolates estradiol effects from those of progesterone in young women. Other methods of studying estradiol effects in young women (such as pregnancy, oral contraceptives, menstrual cycle phase) can only indirectly infer estradiol-related effects because other physiological changes are taking place simultaneously. This model provides a unique opportunity to examine the effect of the chosen sex hormone on a variety of system.
Our research continues to examine the effects of reproductive hormones (now including testosterone) on thermoregulation and fluid regulation in young, healthy women and in women with Polycystic Ovary Syndrome (PCOS). We have recently demonstrated that combined sodium loss with water retention is a characteristic of women at risk for Exercise Associated Hyponatremia (EAH). These studies have demonstrated that in women at risk for this potentially fatal syndrome, the primary cause of EAH is more closely related to overall fluid retention concomitant with sodium losses.
Our studies have also demonstrated that obese women with PCOS have compromised thermoregulation compared to their healthy obese counterparts, which may be related to their consistent elevations in testosterone.
My current grant addresses the impact of female reproductive hormones on blood pressure regulation in women at risk for orthostatic intolerance. Regularly occurring orthostatic intolerance can be debilitating and is much more common in young women relative to men, children or older women. Our studies will determine the roles of estradiol and progesterone in this syndrome, and will also explore the peripheral mechanisms involved.
To study mechanisms related to orthostatic intolerance in young women we use microneurography to examine the extent to which sympathetic nervous system activity mediates sex hormone effects on orthostatic tolerance, and laser Doppler flowmetry combined with skin microdialysis to examine mechanisms controlling the peripheral circulation.
Our recent studies have demonstrated that adrenergic responses are shifted to the right in women with low orthostatic tolerance, suggested reduced vasoconstriction in response to adrenergic stimulation compared to women with high orthostatic tolerance. Moreover our studies have demonstrated that progesterone enhances vasoconstriction in response to adrenergic stimulation only in women with high orthostatic tolerance. We are just beginning studies examining endothelial function in the skin microvasculature in women with PCOS.R01 HL71159 Title: Estrogen and progesterone effects on orthostatic intolerance
P.I. Nina Stachenfeld
R21 HL093450 Title: Compromised microcirculation in women with Polycystic Ovary Syndrome P.I. Nina Stachenfeld
Studying estrogen and progesterone effects on physiological systems in women
Stachenfeld, N.S. and Taylor, H.S. Studying estrogen and progesterone effects on physiological systems in women. Am J. Physiol. Endocrinol. Metab., 306: E849–E853, 2014. DOI:10.1152/ajpendo.00038.2014. Editor’s Pick, May 2014.
Hormonal changes during menopause and the impact on hydration.
Stachenfeld, N.S. Hormonal changes during menopause and the impact on hydration. Reprod Sci. 21: 555-561, 2014. http://rsx.sagepub.com/content/21/5/555.long DOI: 10.1177/1933719113518992
Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors Am.
Wenner M.M., Taylor, H.S., Stachenfeld, N.S. Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors Am. J. Physiol. 283 (Endocrinol. Metab.). 305: E818-25 2013. http://www.ncbi.nlm.nih.gov/pubmed/23921139.
Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol
Wenner, M.M., Haddadin, A.S., Taylor, H.S., Stachenfeld, N.S. Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol J. Physiol. 591.9: 2345–2355 2013 http://www.ncbi.nlm.nih.gov/pubmed/23401618
Greater exercise sweating in obese women with Polycystic Ovary Sydrome compared with obese controls.
Stachenfeld, N.S., Yeckel, C. W., Taylor, H.S. Greater exercise sweating in obese women with Polycystic Ovary Sydrome compared with obese controls. Med. Sci Sports Exerc. 42:16601668, 2010.
Pharmacology curve fitting to analyze cutaneous adrenergic responses
Wenner, M.M., Wilson, T.E., Davis, S, L., Stachenfeld, N.S. Pharmacology curve fitting to analyze cutaneous adrenergic responses. J. Appl. Physiol. 111: 1703–1709, 2011 http://www.ncbi.nlm.nih.gov/pubmed/21868682
Greater orthostatic tolerance in young, healthy black versus white women.
Hinds, K. A., Stachenfeld, N.S. Greater orthostatic tolerance in young, healthy black versus white women. Hypertension. Hypertension. 56: 75-81, 2010.
Sex hormone effects on body fluid and sodium regulation in women with and without Exercise-Associated Hyponatremia J
Stachenfeld, N.S., Taylor, H.S. Sex hormone effects on body fluid and sodium regulation in women with and without Exercise-Associated Hyponatremia J. Appl. Physiol. 107: 864-872, 2009.
Estrogen effects on urine concentrating response in young women.
Stachenfeld, N.S., Taylor, H.S., Leone, C.A., Keefe, D.L. Estrogen effects on urine concentrating response in young women. J. Physiol. 552.3:869-880, 2003.