Estrogen and progesterone modulate body water and sodium at rest, and during perturbations of normal body fluid homeostasis, such as dehydration, hyponatremia and sodium loading. The mechanisms for these effects have been difficult to determine because estrogen and progesterone have opposing effects on body water and sodium regulation and increase concurrently in women of reproductive age. In the research design, the investigators temporarily inhibit sex steroid hormone secretion in young women with the gondotropin releasing-hormone analog, leuprolide acetate, and then isolate the effects of estrogen and progesterone on body water and sodium regulation by adding back each of these hormones. Leuprolide acetate down-regulates the hypothalamic-pituitary-ovarian axis with internalization of the GnRH receptors at the pituitary level. Following an initial stimulation, chronic administration of leuprolide acetate suppresses steroidogenes. After steroid hormone suppression, the investigators will """"""""add back"""""""" natural estrogen and/or progesterone, in order to accomplish the following Specific Aims: 1) To determine effects of estrogen on the osmotic sensitivity of arginine vasopressin, and renal sensitivity to arginine vasopressin. Osmotically stimulated arginine vasopressin (AVP) increases during estrogen administration and during the phases of the menstrual cycle when estrogen and progesterone levels are higher. These protocols will examine sex hormone-effects on the osmotic stimulation of AVP and the dose-response relationship between AVP and renal water regulation. The investigators hypothesize that estrogen alone and in combination with progesterone will increase overall body water retention by increasing the AVP response to increases in plasma osmolality. In earlier studies, AVP increases during elevations in female sex hormones were not always associated with commensurate body water retention increases, so the investigators further hypothesize that estrogen interferes with AVP actions in the kidney tubule. 2) To determine effects of progesterone on renal sodium regulation. Elevations in progesterone cause a transient natriuresis, which is soon counteracted by stimulation of the renin-angiotensin-aldosterone system, as well as inhibition of atrial natriuretic peptide release from cardiac myocytes. The investigators hypothesize that progesterone will enhance sodium retention during sodium loading by attenuating the inhibition of the renin angiotensin-aldosterone system and inhibiting ANP release. These studies are important because they help clarify the effects of sex hormones on the cardiovascular system, and because symptoms related to water retention are a primary reason why 80 percent of women halt hormone therapy and fail to take advantage of its protective effects on heart, bone and brain.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL062240-01A1
Application #
6126736
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Scherbenske, M James
Project Start
2000-05-01
Project End
2004-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
1
Fiscal Year
2000
Total Cost
$291,104
Indirect Cost
Name
John B. Pierce Laboratory, Inc.
Department
Type
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06519
Stachenfeld, Nina S (2014) Hormonal changes during menopause and the impact on fluid regulation. Reprod Sci 21:555-61
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
Stachenfeld, Nina S; Keefe, David L; Taylor, Hugh S (2005) Responses to a saline load in gonadotropin-releasing hormone antagonist-pretreated premenopausal women receiving progesterone or estradiol-progesterone therapy. J Clin Endocrinol Metab 90:386-94
Stachenfeld, Nina S; Taylor, Hugh S (2004) Effects of estrogen and progesterone administration on extracellular fluid. J Appl Physiol 96:1011-8
Stachenfeld, Nina S; Taylor, Hugh S; Leone, Cheryl A et al. (2003) Oestrogen effects on urine concentrating response in young women. J Physiol 552:869-80
Stachenfeld, Nina S; Keefe, David L (2002) Estrogen effects on osmotic regulation of AVP and fluid balance. Am J Physiol Endocrinol Metab 283:E711-21