David S. Goldstein, MD, PhD, Clinical Neurocardiology Section, NINDS:

Dysautonomias Differentially Affecting Women

Dysautonomias are conditions where altered function of one or more components of the autonomic nervous system adversely affects health.¹ Dysautonomias can manifest as occasional episodes, such as fainting, in otherwise healthy people; chronic, persistent multi-system disorders, such as postural tachycardia syndrome; or progressive degenerative diseases, such as Parkinson disease.² Some entail observable macroscopic or microscopic abnormalities or quantifiable chemical or physiological changes, while others remain mysterious and controversial because of a lack of consistent objective findings. Some are rare and some common, but all involve more than one body function, and all negatively impact a person’s sense of well-being.

Some dysautonomias are much more prevalent in women than in men.³ Despite the frequency, debility, and societal burden associated with these conditions, they have received relatively little research attention. Dysautonomias are often frustrating for patients, clinicians, and researchers, because of the complexity of the disorders, their multi-disciplinary nature, and insufficient understanding of the underlying etiologic and pathogenetic mechanisms.⁴ Many dysautonomia patients are labeled incorrectly as having a purely psychiatric problem.

Research of the Clinical Neurocardiology Section has for several years included studies of chronic orthostatic intolerance syndromes. Two of the most common of these syndromes are postural tachycardia syndrome (POTS) and neurocardiogenic syncope (NCS).⁵ Both forms of chronic orthostatic intolerance are remarkably more prevalent in women than in men.⁶ Indeed, about 90% of patients with either condition are women. The reasons for these extraordinary gender differences remain mysterious. POTS and NCS entail complex mind-body components and multiple non-specific systemic complaints without objective external changes, such as chronic fatigue, exercise intolerance, heat intolerance, headache, chest pain with normal coronary arteries, and musculoskeletal pain.

Among our findings we have noted neurocirculatory abnormalities in patients with chronic orthostatic intolerance even when the patients are studied while they are resting supine.^{7, 8} POTS seems to entail increased sympathetic nervous outflow to the heart and also increased activity of the adrenomedullary hormonal system, two major components of the autonomic nervous system. Our impression is that most patients with chronic orthostatic intolerance do not have a primary abnormality of the autonomic nervous system but instead suffer from adverse effects of compensatory responses to decreased venous return to the heart. We hypothesize that endocrine, vascular, autonomic, and anthropometric differences in combination explain why chronic orthostatic intolerance is much more common in women than in men. We also predict that understanding the pathogenetic mechanisms of chronic orthostatic intolerance in individual patients will lead to rational, effective treatment and prevention measures.

Under Clinical Protocol 03-N-0314 we are examining whether POTS entails inefficient means to retain salt and water, by measuring blood volume, cardiac stroke volume, leg volume, and indices of neuroendocrine systems determining sodium and water balances. Since a one-year Fellowship is too short for development and implementation of a clinical project de novo, the Fellow would help carry out this important protocol, which is already active. The Fellow would learn both theoretical bases for and gain practical, hands-on experience with a large variety of assessment tools for evaluation of patients with dysautonomias, including clinical, physiologic, pharmacologic, neurochemical, neuroimaging, and genetic approaches. The Fellow would have specific responsibility for evaluating and testing referred patients with chronic orthostatic intolerance associated with POTS or NCS, with a goal of identifying processes distinguishing women with POTS from women with NCS, men with POTS, and healthy volunteers of either gender.

REFERENCES
      1. Goldstein DS, Smith LJ. The NDRF Handbook for Patients with Dysautonomias. Armonk, NY: Futura; 2002.
      2. Goldstein D, Eisenhofer G, Robertson D, et al. Dysautonomias: Clinical disorders of the autonomic nervous system. Ann Intern Med 2002;137:753-763.
      3. Robertson D. The epidemic of orthostatic tachycardia and orthostatic intolerance. Am J Med Sci 1999;317:75-77.
      4. Dietz NM, Joyner MJ, Shepherd JT. Vasovagal syncope and skeletal muscle vasodilatation: the continuing conundrum. Pacing Clin Electrophysiol 1997;20:775-780.
      5. Abboud FM. Neurocardiogenic syncope. N Engl J Med 1993;328:1117-1120.
      6. Ali YS, Daamen N, Jacob G, et al. Orthostatic intolerance: a disorder of young women. Obstet Gynecol Surv 2000;55:251-259.
      7. Goldstein DS, Eldadah B, Holmes C, et al. Neurocirculatory abnormalities in chronic orthostatic intolerance. Circulation 2005;111:839-845.
      8. Goldstein DS, Holmes C, Frank SM, et al. Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes. Circulation 2002;106:2358-2365.