Blood Pressure; Environment and Public Health; Gynecology; Physiology; Polycystic Ovary Syndrome; Reproductive Medicine; Orthostatic Intolerance
WHRY Pilot Project Program Investigators
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
Challenges and methodology for testing young healthy women in physiological studies.
Stachenfeld NS, Taylor HS. Challenges and methodology for testing young healthy women in physiological studies. American Journal Of Physiology. Endocrinology And Metabolism 2014, 306:E849-53.
Hormonal changes during menopause and the impact on fluid regulation.
Stachenfeld NS. Hormonal changes during menopause and the impact on fluid regulation. Reproductive Sciences (Thousand Oaks, Calif.) 2014, 21:555-61.
Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors.
Wenner MM, Taylor HS, Stachenfeld NS. Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors. American Journal Of Physiology. Endocrinology And Metabolism 2013, 305:E818-25.
Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol.
Wenner MM, Haddadin AS, Taylor HS, Stachenfeld NS. Mechanisms contributing to low orthostatic tolerance in women: the influence of oestradiol. The Journal Of Physiology 2013, 591:2345-55.
Greater exercise sweating in obese women with polycystic ovary syndrome compared with obese controls.
Stachenfeld NS, Yeckel CW, Taylor HS. Greater exercise sweating in obese women with polycystic ovary syndrome compared with obese controls. Medicine And Science In Sports And Exercise 2010, 42:1660-8.
Pharmacological curve fitting to analyze cutaneous adrenergic responses.
Wenner MM, Wilson TE, Davis SL, Stachenfeld NS. Pharmacological curve fitting to analyze cutaneous adrenergic responses. Journal Of Applied Physiology (Bethesda, Md. : 1985) 2011, 111:1703-9.
Greater orthostatic tolerance in young black compared with white women.
Hinds K, Stachenfeld NS. Greater orthostatic tolerance in young black compared with white women. Hypertension 2010, 56:75-81.
Sex hormone effects on body fluid and sodium regulation in women with and without exercise-associated hyponatremia.
Stachenfeld NS, Taylor HS. Sex hormone effects on body fluid and sodium regulation in women with and without exercise-associated hyponatremia. Journal Of Applied Physiology (Bethesda, Md. : 1985) 2009, 107:864-72.
Oestrogen effects on urine concentrating response in young women.
Stachenfeld NS, Taylor HS, Leone CA, Keefe DL. Oestrogen effects on urine concentrating response in young women. The Journal Of Physiology 2003, 552:869-80.
Full List of PubMed Publications
- Flores VA, Stachenfeld NS, Taylor HS: Bazedoxifene-Conjugated Estrogens for Treating Endometriosis. Obstet Gynecol. 2018 Aug. PMID: 29995747
- Wenner MM, Hinds KA, Howard JT, Nawn CD, Stachenfeld NS, Convertino VA: Measurement of compensatory reserve predicts racial differences in tolerance to simulated hemorrhage in women. J Trauma Acute Care Surg. 2018 Jul. PMID: 29443858
- Adler TE, Usselman CW, Takamata A, Stachenfeld NS: BLOOD PRESSURE PREDICTS ENDOTHELIAL FUNCTION AND THE EFFECTS OF ETHINYL ESTRADIOL EXPOSURE IN YOUNG WOMEN. Am J Physiol Heart Circ Physiol. 2018 Jun 15; 2018 Jun 15. PMID: 29906227
- Stachenfeld NS, Leone CA, Mitchell ES, Freese E, Harkness L: Water intake reverses dehydration associated impaired executive function in healthy young women. Physiol Behav. 2018 Mar 1; 2017 Dec 23. PMID: 29277553
- Turner JM, Marsteller DA, Luxkaranayagam AT, Fletcher JM, Stachenfeld NS: Mild exercise in female subjects impairs complex learning independent of hydration status and emotion. Physiol Behav. 2017 Oct 15; 2017 Aug 23. PMID: 28842190
- DiPietro L, Stachenfeld NS, De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F, Vinik A: Exercise Treatment of Obesity 2000. PMID: 25905196
- Usselman CW, Stachenfeld NS: Contribution of Increased Angiotensin II Sensitivity to Microvascular Dysfunction in Women With a History of Preeclampsia. Hypertension. 2017 Aug; 2017 Jun 26. PMID: 28652470
- Usselman CW, Stachenfeld NS, Bender JR: The molecular actions of oestrogen in the regulation of vascular health. Exp Physiol. 2016 Mar. PMID: 26778523
- Sladek CD, Michelini LC, Stachenfeld NS, Stern JE, Urban JH: Endocrine-Autonomic Linkages. Compr Physiol. 2015 Jul 1. PMID: 26140719
- Wenner MM, Taylor HS, Stachenfeld NS: Peripheral Microvascular Vasodilatory Response to Estradiol and Genistein in Women with Insulin Resistance. Microcirculation. 2015 Jul. PMID: 25996650
- Alian AA, Galante NJ, Stachenfeld NS, Silverman DG, Shelley KH: Impact of lower body negative pressure induced hypovolemia on peripheral venous pressure waveform parameters in healthy volunteers. Physiol Meas. 2014 Jul; 2014 Jun 5. PMID: 24901895
- Horvath TL, Stachenfeld NS, Diano S: A temperature hypothesis of hypothalamus-driven obesity. Yale J Biol Med. 2014 Jun; 2014 Jun 6. PMID: 24910560
- Stachenfeld NS: The interrelationship of research in the laboratory and the field to assess hydration status and determine mechanisms involved in water regulation during physical activity. Sports Med. 2014 May. PMID: 24791921
- Alian AA, Galante NJ, Stachenfeld NS, Silverman DG, Shelley KH: Impact of central hypovolemia on photoplethysmographic waveform parameters in healthy volunteers part 2: frequency domain analysis. J Clin Monit Comput. 2011 Dec; 2011 Nov 6. PMID: 22057245
- Alian AA, Galante NJ, Stachenfeld NS, Silverman DG, Shelley KH: Impact of central hypovolemia on photoplethysmographic waveform parameters in healthy volunteers. Part 1: time domain analysis. J Clin Monit Comput. 2011 Dec; 2011 Nov 4. PMID: 22051898
- Wenner MM, Taylor HS, Stachenfeld NS: Endothelin B receptor contribution to peripheral microvascular function in women with polycystic ovary syndrome. J Physiol. 2011 Oct 1; 2011 Aug 8. PMID: 21825025
- Hinds K, Stachenfeld NS: Greater orthostatic tolerance in young black compared with white women. Hypertension. 2010 Jul; 2010 May 10. PMID: 20458005
- Stachenfeld NS, Taylor HS: Sex hormone effects on body fluid and sodium regulation in women with and without exercise-associated hyponatremia. J Appl Physiol (1985). 2009 Sep; 2009 Jun 25. PMID: 19556454
- Stachenfeld NS, Taylor H: Role of polycystic ovary syndrome in menstrual dysfunction in female athletes. Med Sci Sports Exerc. 2009 Jun. PMID: 19461543
- Stachenfeld NS: Acute effects of sodium ingestion on thirst and cardiovascular function. Curr Sports Med Rep. 2008 Jul-Aug. PMID: 18843231
- Stachenfeld NS: Sex hormone effects on body fluid regulation. Exerc Sport Sci Rev. 2008 Jul. PMID: 18580296
- Stachenfeld NS, Taylor HS: Exogenous oestradiol and progesterone administration does not cause oedema in healthy young women. Clin Endocrinol (Oxf). 2007 Mar. PMID: 17302877
- Stachenfeld NS, Taylor HS: Progesterone increases plasma volume independent of estradiol. J Appl Physiol (1985). 2005 Jun; 2005 Feb 17. PMID: 15718411
- Stachenfeld NS, Keefe DL, Taylor HS: Responses to a saline load in gonadotropin-releasing hormone antagonist-pretreated premenopausal women receiving progesterone or estradiol-progesterone therapy. J Clin Endocrinol Metab. 2005 Jan; 2004 Oct 14. PMID: 15486051
- Stachenfeld NS, Taylor HS: Effects of estrogen and progesterone administration on extracellular fluid. J Appl Physiol (1985). 2004 Mar; 2003 Dec 5. PMID: 14660504
- Stachenfeld NS, Keefe DL: Estrogen effects on osmotic regulation of AVP and fluid balance. Am J Physiol Endocrinol Metab. 2002 Oct. PMID: 12217888