Journal Mobile Options
Table of Contents
Vol. 52, No. 2, 2006
Issue release date: February 2006
Gerontology 2006;52:76–84

Growth Hormone Responses to Low-Dose Physostigmine in Elderly vs. Young Women and Men

Rubin R.T. · Miller T.H. · Rhodes M.E. · Czambel R.K.
Department of Psychiatry and Mental Health, VA Greater Los Angeles Healthcare System, Los Angeles, Calif., and Center for Neurosciences Research, Drexel University College of Medicine, Allegheny General Hospital, Pittsburgh, Pa., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Background: Growth hormone (GH) secretion is a sensitive measure of CNS cholinergic neurotransmission, and GH decreases considerably with age. Cholinesterase inhibitors, which increase acetylcholine concentrations, have been used in elderly subjects to investigate the neuroendocrine effects of aging and Alzheimer’s disease. However, there have been only a few studies of a potential sex difference in GH responses to cholinesterase inhibitors in elderly subjects, with mixed results. Objective: We therefore administered low-dose physostigmine (PHYSO), a cholinesterase inhibitor, to normal, non-hormone-replaced, elderly women and men, to ascertain a potential sex difference in GH response. We hypothesized: (1) elderly women and men would have similar hormone responses, because of relatively low circulating estrogen in the women, and (2) the elderly women would have significantly lower baseline GH and GH responses to cholinergic challenge than the young women we studied previously. Methods: Normal elderly women and men ≧65 years of age meeting stringent inclusion and exclusion criteria were studied on three test days, 4–7 days apart, by serial blood sampling for several hours for baseline GH, followed by administration of low-dose PHYSO (first and third days) or saline (second day) at 18:00 h. Frequent blood sampling was continued for several hours. Plasma GH and hypothalamo-pituitary-adrenal cortical hormones were measured in each sample. Results: PHYSO administration produced no side effects in about half the elderly subjects and mild side effects in the other half, with no significant female-male differences and no significant relationship between the presence or absence of side effects and GH response. PHYSO significantly increased GH compared to saline, to a similar degree in the elderly women and men. The elderly women had a significantly greater GH response to PHYSO than did the young women, whereas GH responses were similar in the elderly and young men. Conclusions: These results indicate similar GH responses to low-dose PHYSO in elderly women compared to elderly men, and a significantly greater GH response in elderly women compared to young women. A likely mechanism is increased sensitivity of central cholinergic systems that inhibit somatostatin and/or enhance GHRH release from the hypothalamus.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Bertherat J, Bluet-Pajot MT, Epelbaum J: Neuroendocrine regulation of growth hormone. Eur J Endocrinol 1995;132:12–24.
  2. Casanueva FF, Villaneueva L, Cordido F, Diaz Y, Cabranes JA, Speigel R, Dieguez C: Differential effects of direct and indirectly acting cholinergic agonist on growth hormone release in man, and lack of effect on cortisol secretion. J Neuroendocrinol 1989;5:379–382.

    External Resources

  3. Giustina A, Veldhuis JD: Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 1998;19:717–797.
  4. Ho KY, Evans WS, Blizzard RM, Veldhuis JD, Merriam GR, Samojlik E, Furlanetto R, Rogol AD, Kaiser DL, Thorner MO: Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab 1987;64:51–58.
  5. Lang I, Schernthaner G, Pietschmann P, Kurz R, Stephenson JM, Templ H: Effects of sex and age on growth hormone response to growth hormone-releasing hormone in healthy individuals. J Clin Endocrinol Metab 1987;65:535–540.
  6. Giusti M, Marini G, Sessarego P, Peluffo F, Valenti S, Caratti C, Giordano G: Effect of cholinergic tone on growth hormone-releasing hormone-induced secretion of growth hormone in normal aging. Aging Clin Exp Res 1992;4:231–237.
  7. Vahl N, Jorgensen JO, Jurik AG, Christiansen JS: Abdominal adiposity and physical fitness are major determinants of the age associated decline in stimulated GH secretion in healthy adults. J Clin Endocrinol Metab 1996;81:2209–2215.
  8. Friend K, Iranmanesh A, Login IS, Veldhuis JD: Pyridostigmine treatment selectively amplifies the mass of GH secreted per burst without altering GH burst frequency, half-life, basal GH secretion or the orderliness of GH release. Eur J Endocrinol 1997;137:377–386.
  9. Müller EE, Rigamonti AE, Colonna VDG, Locatelli V, Berti F, Cella SG: GH-related and extra-endocrine actions of GH secretagogues in aging. Neurobiol Aging 2002;23:907–919.
  10. Smith RG, Betancourt L, Sun Y: Molecular endocrinology and physiology of the aging central nervous system. Endocr Rev 2005;26:203–250.
  11. Raskind MA, Wilkinson CW, Peskind ER: Aging and Alzheimer’s disease; in Pfaff D, Arnold AP, Etgen AM, Fahrbach SE, Moss RL, Rubin RT (eds): Hormones, Brain and Behavior. New York, Academic Press, 2001, vol 5, pp 637–664.
  12. Lucey JV, O’Keane V, O’Flynn K, Clare AW, Dinan TG: Gender and age differences in the growth hormone response to pyridostigmine. Int Clin Psychopharmacol 1991;6:105–109.
  13. Van Amelsvoort T, Murphy DG, Robertson D, Daly E, Whitehead M, Abel K: Effects of long-term estrogen replacement therapy on growth hormone response to pyridostigmine in healthy postmenopausal women. Psychoneuroendocrinology 2003;28:101–112.
  14. Raskind MA, Peskind ER, Veith RC, Wilkinson CW, Federighi D, Dorsa DM: Differential effects of aging on neuroendocrine responses to physostigmine in normal men. J Clin Endocrinol Metab 1990;70:1420–1425.
  15. Peskind ER, Raskind MA, Wingerson D, Pascualy M, Thal LJ, Dobie DJ, Veith RC, Dorsa DM, Murray S, Sikkema C, Galt SA, Wilkinson CW: Enhanced hypothalamic-pituitary-adrenocortical axis responses to physostigmine in normal aging. J Gerontol A Biol Sci Med Sci 1995;50:M114–M120.
  16. Peskind ER, Raskind MA, Wingerson D, Pascualy M, Thal LJ, Dobie DJ, Wilkinson CW: Hypothalamic-pituitary-adrenocortical axis responses to physostigmine: effects of Alzheimer’s disease and gender. Biol Psychiatry 1996;40:61–68.
  17. Lamperti E, Cocchi D, Parati EA, Caraceni T, Müller EE: Growth hormone responses to cholinergically active drugs in patients with dementia of the Alzheimer type. Alzheimer Dis Assoc Disord 1992;6:44–52.
  18. Ghigo E, Nicolosi M, Arvat E, Marcone A, Danelon F, Mucci M, Franceschi M, Smirne S, Camanni F: Growth hormone secretion in Alzheimer’s disease: studies with growth hormone-releasing hormone alone and combined with pyridostigmine or arginine. Dementia 1993;4:315–320.
  19. Corsello SM, Tofani A, Della Casa S, Rota CA, Sciuto R, Colasanti S, Barini A, Barbarino A: Effects of sex and age on pyridostigmine potentiation of growth hormone-releasing hormone-induced growth hormone release. Neuroendocrinology 1992;56:208–213.
  20. Obermayr RP, Mayerhofer L, Knechtelsdorfer M, Tragl KH, Geyer G: The reduced release of GH by GHRH in 8 subjects aged 65–69 years is augmented considerably by rivastigmine, a drug for Alzheimer’s disease. Gerontology 2003;49:191–195.
  21. Rubin RT, Sekula LK, O’Toole SM, Rhodes ME, Czambel RK: Pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration in normal women and men. Neuropsychopharmacology 1999;20:434–446.
  22. Rubin RT, O’Toole SM, Rhodes ME, Sekula LK, Czambel RK: Hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration: sex differences between major depressives and matched controls. Psychiatry Res 1999;89:1–20.
  23. Rubin RT, Rhodes ME, O’Toole S, Czambel RK: Sexual diergism of hypothalamo-pituitary-adrenal cortical responses to low-dose physostigmine in elderly vs. young women and men. Neuropsychopharmacology 2002;26:672–681.
  24. First MB, Spitzer RL, Gibbon M, Williams JBW: Structured Clinical Interview for DSM-IV Axis I Disorders – Non-Patient Edition. New York, Biometrics Research Department, NY State Psychiatric Institute, 1996.
  25. Hamilton M: Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol 1967;6:278–296.
  26. Rubin RT, Poland RE, Lesser IM, Winston RA, Blodgett ALN: Neuroendocrine aspects of primary endogenous depression I. Cortisol secretory dynamics in patients and matched control subjects. Arch Gen Psychiatry 1987;44:329–336.
  27. Rubin RT, Phillips JJ, Sadow TF, McCracken JT: Adrenal gland volume in major depression. Increase during the depressive episode and decrease with successful treatment. Arch Gen Psychiatry 1995;52:213–218.
  28. Odell WD, Rayford PL, Ross GT: Simplified, partially automated method for radioimmunoassay of human thyroid-stimulating, growth, luteinizing, and follicle stimulating hormones. J Lab Clin Med 1967;70:346–348.
  29. Rubin RT, Abbasi SA, Rhodes ME, Czambel RK: Growth hormone responses to low-dose physostigmine administration: functional sex differences (sexual diergism) between major depressives and matched controls. Psychol Med 2003;33:655–665.
  30. O’Keane V, Dinan TG: Sex steroid priming effects on growth hormone response to pyridostigmine throughout the menstrual cycle. J Clin Endocrinol Metab 1992;75:11–14.
  31. Fisher DA, Nelson JC: Endocrine testing; in DeGroot LJ, Jameson JL (eds): Endocrinology, ED 4. Philadelphia, Saunders, 2001, pp 2574–2600.
  32. Herrmann N, Lanctot KL, Eryavec G, Van Reekum R, Khan LR: Growth hormone response to clonidine predicts aggression in Alzheimer’s disease. Psychoneuroendocrinology 2004;29:1192–1197.
  33. Veldhuis JD, Iranmanesh A, Weltman A: Elements in the pathophysiology of diminished growth hormone secretion in aging humans. Endocrine 1997;7:41–48.
  34. Ross RJ, Tsagarakis S, Grossman A, Nhagafoong L, Touzel RJ, Rees LH, Besser GM: GH feedback occurs through modulation of hypothalamic somatostatin under cholinergic control: studies with pyridostigmine and GHRH. Clin Endocrinol 1987;27:727–733.
  35. Delitala G, Tomasi P, Virdis R: Neuroendocrine regulation of human growth hormone secretion. Diagnostic and clinical applications. J Endocrinol Invest 1988;11:441–462.
  36. Kelijman M, Frohman LA: The role of the cholinergic pathway in growth hormone feedback. J Clin Endocrinol Metab 1991;72:1081–1087.
  37. Magnan E, Cataldi M, Guillaume V, Mazzocchi L, Dutour A, Conte-Devolx B, Giraud P, Oliver C: Neostigmine stimulates growth hormone-releasing hormone release into hypophysial portal blood of conscious sheep. Endocrinology 1993;132:1247–1251.
  38. Jaffe CA, DeMott-Friberg R, Barkan AL: Endogenous growth hormone (GH)-releasing hormone is required for GH responses to pharmacological stimuli. J Clin Invest 1996;97:934–940.
  39. Gibson GE, Peterson C: Aging decreases oxidative metabolism and the release and synthesis of acetylcholine. J Neurochem 1981;37:978–984.
  40. Pepeu G, Marconcini Pepeu I: Dysfunction of the brain cholinergic system during aging and after lesions of the nucleus basalis of Meynert. J Neural Transm 1994;44(suppl):189–194.
  41. Strong R, Hicks P, Hsu L, Bartus RT, Enna SJ: Age-related alterations in the rodent brain cholinergic system and behavior. Neurobiol Aging 1980;1:59–63.
  42. Norman AB, Blaker SN, Thal L, Creese I: Effects of aging and cholinergic deafferentation on putative muscarinic cholinergic receptor subtypes in rat cerebral cortex. Neurosci Lett 1986;70:289–294.
  43. Decker MW: The effects of aging on hippocampal and cortical projections of the forebrain cholinergic system. Brain Res 1987;434:423–438.
  44. Rinne JO: Muscarinic and dopaminergic receptors in the human brain. Brain Res 1987;404:162–168.
  45. Coiro V, Volpi R, Bertoni P, Finzi G, Marcato A, Caiazza A, Colla R, Giacalone G, Rossi G, Chiodera P: Effect of potentiation of cholinergic tone by pyridostigmine on the GH response to GHRH in elderly men. Gerontology 1992;38:217–222.
  46. Rhodes ME, O’Toole SM, Wright SL, Czambel RK, Rubin RT: Sexual diergism in rat hypothalamic-pituitary-adrenal axis responses to cholinergic stimulation and antagonism. Brain Res Bull 2001;54:101–113.
  47. Rhodes ME, O’Toole SM, Czambel RK, Rubin RT: Male-female differences in rat hypothalamic-pituitary-adrenal axis responses to nicotine stimulation. Brain Res Bull 2001;54:681–688.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50