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Why Is Orthostatic Tolerance Lower in Women than in Men? Renal and Cardiovascular Responses to Simulated Microgravity and the Role of Midodrine
  1. Marlene S. Grenon,
  2. Xinshu Xiao,
  3. Shelley Hurwitz,
  4. Natalie Sheynberg,
  5. Christine Kim,
  6. Ellen W. Seely,
  7. Richard J. Cohen,
  8. Gordon H. Williams
  1. 1From the Division of Endocrinology, Hypertension and Diabetes (S.M.G., S.H., N.S., C.K., E.W.S., G.H.W.), Brigham and Women's Hospital, Boston, MA; NASA Center for Quantitative Cardiovascular Physiology, Modeling and Data Analysis (S.M.G., X.X., R.J.C.), Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA; and the Department of Cardio-Thoracic Surgery (S.M.G.), McGill University, Montreal, QC
  1. Address correspondence to: Dr. Gordon H. Williams, Division of Endocrinology, Hypertension and Diabetes, Brigham and Women's Hospital, 221 Longwood Avenue, Boston, MA 02115; e-mail: gwilliams{at}
  2. The National Aeronautics and Space Administration (NASA) supported this work through NASA Cooperative Agreement NCC 9-58 with the National Space Biomedical Research Institute. The studies were conducted at the General Clinical Research Center of the Brigham and Women's Hospital, supported by a grant from the National Center for Research Resources (5M01RR02635). Dr. Grenon wishes to thank the Heart and Stroke Foundation of Canada for a Post-Doctoral Junior Fellowship Award.


Background Exposure to microgravity induces cardiovascular deconditioning, manifested by orthostatic intolerance (OI). We assessed the renal, cardioendocrine, and cardiovascular responses of women and men to simulated microgravity to examine the impact of gender on OI.

Methods Fifteen healthy female and 14 healthy male subjects were given a constant diet for 3 to 5 days, after which they underwent a tilt-stand test (pre-TST) and began 14 to 16 days of head-down tilt bed rest (HDTB), followed by a repeat tilt-stand test (post-TST). Female subjects began HDTB so that the post-TST was at the same time in their menstrual cycle as their pre-TST. Twenty-four-hour urine collections (daily), hormonal measurements, plethysmography, and cardiovascular system identification were performed.

Results The times to presyncope were significantly different for men and women before (p = .005) and after HDTB (p = .001), with all of the women but only 50% of the men experiencing presyncope during the pre-TST (p = .002) and all of the women but only 64% of the men experiencing presyncope during the post-TST. At baseline, the following differences between women and men were observed: women had higher serum aldosterone levels (p = .02), higher parasympathetic responsiveness (p = .01), lower sympathetic responsiveness (p = .05), and lower venous compliance (p = .05). Several parameters changed with HDTB in both men and women. In a double-blinded randomized trial, midodrine (5 mg orally) or placebo given to female subjects 1 hour before post-TST was ineffective in preventing OI.

Conclusion In conclusion, the frequency of OI is higher in women than in men and is not modified by midodrine at the dose used. This increased susceptibility is likely secondary to intrinsic basal differences in the activity of volume-mediated parasympathetic and adrenergic systems and in venous tone. Thus, approaches to reduce OI in women are likely to differ from those effective in men.

Key Words
  • gender
  • orthostatic intolerance
  • renin-angiotensin-aldosterone system
  • autonomic function
  • leg venous compliance
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