Blood Pressure; Environment and Public Health; Gynecology; Physiology; Polycystic Ovary Syndrome; Reproductive Medicine; Orthostatic Intolerance
Cardiovascular disease is the biggest killer of women. It is clear that hormones involved primarily in reproductive function, including estrogens, progesterone and androgens have important effects on the cardiovascular function and health in women.
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. We have used medications to temporarily suppress the menstrual cycle in young women while adding back estrogen, progesterone or testosterone to study the effects of these hormones on body fluid regulation under more controlled conditions. We also examine the impact of these hormones on cardiovascular health and function in women with Polycystic Ovary Syndrome, endometriosis and in transgenders.
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 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.
More 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. Recently, a new drug, elagolix has become available that accomplishes the same goal.
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, progesterone or testosterone effects 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 studies now address more directly hormonal effects on cardiovascular function in women, including those of estrogens, progesterone and androgens on endothelial function in women with PCOS, endometriosis and in transgender men.
Our research continues to examine the effects of reproductive hormones (now including testosterone) on cardiovascular regulation, thermoregulation and fluid regulation in young, healthy women and in women with Polycystic Ovary Syndrome (PCOS), endometriosis and transgenders.
My current grant addresses the impact of testosterone on blood pressure regulation in women PCOS, who present with mild hypertension. Our studies will determine the roles of both the autonomic and renal systems in the regulation of blood pressure in women with PCOS in this syndrome, and will also explore the peripheral mechanisms involved. We will also determine the extent to which testosterone contributes to their mild hypertension. To study mechanisms related to blood pressure regulation in PCOS we use drug infusions, lower body negative pressure and microneurography to examine the extent to which sympathetic nervous system activity mediates sex hormone effects on blood pressure regulation.
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
R01 HL135089 Mechanisms of hypertension in women with polycystic ovary syndrome Co-P.I. Nina Stachenfeld; Co- P.i. Jane Reckelhoff (U. of Mississippi)
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. 2014
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. 2014
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. 2013
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. 2013
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. 2010
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. 2011
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. 2010
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. 2009
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. 2003
Full List of PubMed Publications
- Stachenfeld NS: Independent effect of high aerobic capacity to protect against diet induced insulin resistance in male rats. Endocrinology. 2019 May 2; 2019 May 2. PMID: 31046086
- Flores VA, Leone C, Taylor HS, Stachenfeld NS: Effects of bazedoxifene/conjugated estrogens on reproductive endocrinology and reproductive tract ultrasonographic appearance in premenopausal women: a preliminary study. Gynecol Endocrinol. 2019 May; 2019 Jan 22. PMID: 30668182
- Usselman CW, Yarovinsky TO, Steele FE, Leone CA, Taylor HS, Bender JR, Stachenfeld NS: Androgens drive microvascular endothelial dysfunction in women with polycystic ovary syndrome: role of the endothelin B receptor. J Physiol. 2019 Mar 7; 2019 Mar 7. PMID: 30847930
- Stanhewicz AE, Wenner MM, Stachenfeld NS: Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan. Am J Physiol Heart Circ Physiol. 2018 Dec 1; 2018 Sep 14. PMID: 30216121
- 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 Oct 1; 2018 Jun 15. PMID: 29906227
- 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
- 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, Feingold KR, Anawalt B, Boyce A, Chrousos G, Dungan K, Grossman A, Hershman JM, Kaltsas G, Koch C, Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Perreault L, Purnell J, Rebar R, Singer F, Trence DL, Vinik A, Wilson DP: 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