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Responses to a Saline Load in Gonadotropin-Releasing Hormone Antagonist-Pretreated Premenopausal Women Receiving Progesterone or Estradiol-Progesterone Therapy

John B. Pierce Laboratory and Departments of Epidemiology and Public Health, and Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine and Women and Infants Hospital, Brown University School of Medicine, New Haven, Connecticut 06519

Address all correspondence and requests for reprints to: Dr. Nina S. Stachenfeld, John B. Pierce Laboratory, 290 Congress Avenue, New Haven, Connecticut 06519. E-mail: nstach{at}jbpierce.org.

The effects of estradiol (E₂) and progesterone (P₄) on fluid and sodium regulation may have important clinical implications with respect to cardiovascular and renal disease as well as reproductive syndromes such as preeclampsia and ovarian hyperstimulation syndrome. We tested the hypothesis that sodium excretion is reduced in response to a sodium load during combined P₄-E₂ treatment, but P₄ administration alone has little effect on sodium regulation. Fifteen women (22 ± 2 yr) used a GnRH antagonist to suppress endogenous E₂ and P₄ for 9 d; for d 4–9, eight subjects used P₄ (200 mg/d), and seven subjects used P₄ with E₂ (two E₂ patches, 0.1 mg/d each). On d 3 and 9, isotonic saline (0.9% NaCl) was infused [120 min at 0.1 ml/kg body weight (BW)·min], followed by 120 min of rest. Compared with GnRH antagonist alone, P_[P4] increased from 1.6 ± 0.8 to 9.4 ± 2.3 ng/ml (5.1 ± 2.5 to 29.9 ± 7.3 nmol/liter, P < 0.05) in the P₄ treated group, with no change in P_[E2]. In the P₄-E₂ treated group P_[P4] increased from 1.6 ± 0.5 to 6.7 ± 0.6 ng/ml (5.1 ± 1.6 to 21.3 ± 1.6 nmol/liter, P < 0.05 and P_[E2] increased from 17.9 ± 6.3 to 200 ± 41 pg/ml (65.7 ± 23 to 734.6 ± 150.0 pmol/liter, P < 0.05). Before isotonic saline infusion, renal sodium and water excretion were similar under all conditions, but during isotonic saline infusion, cumulative sodium excretion was lower in the P₄-E₂ treated women (34.1 ± 5.1 mEq) compared with GnRH antagonist (50.2 ± 11.4 mEq). Sodium excretion was unaffected by P₄ treatment (48.0 ± 8.2 and 41.2 ± 5.1 mEq, for GnRH antagonist and P₄). Compared with GnRH antagonist alone, P₄-E₂ treatment increased distal sodium reabsorption and transiently decreased proximal sodium reabsorption, whereas P₄ treatment did not alter either distal or proximal sodium reabsorption. Before isotonic saline infusion, the plasma aldosterone (Ald) concentration was greater during P₄ treatment (153 ± 25 pg/ml; 3883 ± 1102 pmol/liter) and P₄-E₂ treatment (242 ± 47 pg/ml; 6373 ± 1390 pmol/liter) than during their respective GnRH antagonist alone treatments [96 ± 13 and 148 ± 47 pg/ml (2598 ± 475 and 3284 ± 973 pmol/liter) for P₄ and combined P₄-E₂, respectively]. Compared with GnRH antagonist alone treatments, preisotonic saline infusion plasma renin activity was greater only with P₄-E₂ treatment, whereas the plasma atrial natriuretic peptide concentration was lower only with P₄ treatment. Isotonic saline infusion suppressed plasma Ald under all conditions, but decreased plasma renin activity only with P₄-E₂ treatment (average decrease, 1.3 ± 0.5 ng/ml angiotensin I·h; P < 0.05). In summary, we found that P₄-E₂ treatment decreased sodium excretion via either renin-angiotensin-Ald system stimulation or direct effects on kidney tubules. P₄ treatment at these plasma concentrations had no independent effect on the renal response to acute sodium loading. These data suggest that E₂ is the more powerful reproductive hormone involved in sodium retention relative to P₄, and that estrogen-induced up-regulation of P₄ receptors is required for the effects of P₄ on sodium regulation.

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