Pulsatile Hormone Secretion: Mechanisms, Significance and Evaluation

  • J. D. Veldhuis


Secretion of anterior and posterior pituitary hormones, adrenal glucocorticoids, mineralocorticoids and catecholamines, gonadal sex steroids, parathormone, insulin and glucagon is pulsatile (burst-like or episodic). Neuronal inputs, cellular excitability and feedback with time delays constitute proximate mechanisms driving recurrent pulses. Both the amplitude and frequency of gonadotropin, thyrotropin, prolactin and sex-steroid pulses determine their mean concentrations. In contradistinction, primarily the amplitude of growth hormone, adrenocorticotropin, cortisol, parathormone and insulin pulses controls their average values. Gonadotropin-releasing hormone and growth-hormone pulses convey unique signaling information to target tissues. Evaluation of the mechanisms that govern pulsatile hormone secretion requires simultaneous quantification of the number, size and shape of secretory bursts, underlying nonpulsatile (basal) secretion and associated elimination kinetics. The necessary methodology is termed deconvolution analysis. More complex ensemble models are used to interlink neurohormone signals by estimating endogenous dose-response curves noninvasively. The approximate entropy statistic is a specific and sensitive measure of feedback fidelity within an ensemble system, Implications of neurohormone pulsatility include regulation of somatic growth, reproduction, muscle and bone mass, visceral fat burden, glucose metabolism, parturition, and sodium and water balance.


Pulsatile hormone analysis secretion model deconvolution signal endocrine 


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  1. Biermasz NR, Pereira AM, Frolich M, Romijn JA, Veldhuis JD, Roelfsema F 2004. Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly. Am J Physiol Endocrinol Metab 286:E25–E30.PubMedCrossRefGoogle Scholar
  2. Bowers CY, Granda R, Mohan S, Kuipers J, Baylink D, Veldhuis JD 2004. Sustained elevation of pulsatile growth hormone (GH) secretion and insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), and IGFBP-5 concentrations during 30-day continuous subcutaneous infusion of GH-releasing peptide-2 in older men and women. J Clin Endocrinol Metab 89:2290–2300.PubMedCrossRefGoogle Scholar
  3. Chase DJ, Schanbacher B, Lunstra DD 1988. Effects of pulsatile and continuous luteinizing hormone (LH) infusions on testosterone responses to LH in rams actively immunized against gonadotropin-releasing hormone. Endocrinology 123:816–826.PubMedCrossRefGoogle Scholar
  4. Clarke IJ, Cummins JT 1982. The temporal relationship between gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinol 111:1737–1739.CrossRefGoogle Scholar
  5. Conn PM, Crowley Jr. WF 1991. Gonadotropin-releasing hormone and its analogs. New Engl J Med 324:93–103.PubMedCrossRefGoogle Scholar
  6. Engler D, Pham T, Fullerton MJ, Ooi G, Funder JW, Clarke IJ 1989. Studies of the secretion of corticotropin-releasing factor and arginine vasopressin into the hypophysial-portal circulation of the conscious sheep. I. Effect of an audiovisual stimulus and insulin-induced hypoglycemia. Neuroendocrinol 49:367–381.CrossRefGoogle Scholar
  7. Evans WS, Sollenberger MJ, Booth Jr. RA, Rogol AD, Urban RJ, Carlsen EC, Johnson ML, Veldhuis JD 1992. Contemporary aspects of discrete peak detection algorithms. II. The paradigm of the luteinizing hormone pulse signal in women. Endocr Rev 13:81–104.PubMedGoogle Scholar
  8. Farhy LS, Veldhuis JD 2004. Putative GH pulse renewal: periventricular somatostatinergic control of an arcuate-nuclear somatostatin and GH-releasing hormone oscillator. Am J Physiol 286:R1030–R1042.Google Scholar
  9. Farhy LS, Bowers CY, Veldhuis JD 2007. Model-projected mechanistic bases for sex differences in growth-hormone regulation in humans. Am J Physiol Regul Integr Comp Physiol 292:R1577–R1593.PubMedGoogle Scholar
  10. Foresta C, Bordon P, Rossato M, Mioni R, Veldhuis JD 1997. Specific linkages among luteinizing hormone, follicle stimulating hormone, and testosterone release in the peripheral blood and human spermatic vein: evidence for both positive (feed-forward) and negative (feedback) within-axis regulation. J Clin Endocrinol Metab 82:3040–3046.PubMedCrossRefGoogle Scholar
  11. Gibson-Berry KL, Chase DJ 1990. Continuous and pulsatile infusions of luteinizing hormone have identical effects on steroidogenic capacity and sensitivity of Leydig cell in rats passively immunized against gonadotropin-releasing hormone. Endocrinol 126:3107–3115.CrossRefGoogle Scholar
  12. Giustina A, Veldhuis JD 1998. Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717–797.PubMedCrossRefGoogle Scholar
  13. Goodman WG, Veldhuis JD, Belin TR, Van Herle A, Juppner H, Salusky IB 1998. Calcium-sensing by parathyroid glands in secondary hyperparathyroidism. J Clin Endocrinol Metab 83:2765–2772.PubMedCrossRefGoogle Scholar
  14. Hartman ML, Pincus SM, Johnson ML, Matthews DH, Faunt LM, Vance ML, Thorner MO, Veldhuis JD 1994. Enhanced basal and disorderly growth hormone secretion distinguish acromegalic from normal pulsatile growth hormone release. J Clin Invest 94:1277–1288.PubMedCrossRefGoogle Scholar
  15. Hwa V, Little B, Adiyaman P, Kofoed EM, Pratt KL, Ocal G, Berberoglu M, Rosenfeld RG 2005. Severe growth hormone insensitivity resulting from total absence of signal transducer and activator of transcription 5b. J Clin Endocrinol Metab 90:4260–4266.PubMedCrossRefGoogle Scholar
  16. Jaffe CA, Turgeon DK, Lown K, DeMott-Friberg R, Watkins PB 2002. Growth hormone secretion pattern is an independent regulator of growth hormone actions in humans. Am J Physiol Endocrinol Metab 283:E1008–E1015.PubMedGoogle Scholar
  17. Keenan DM, Veldhuis JD 2003a. Cortisol feedback state governs adrenocorticotropin secretory-burst shape, frequency and mass in a dual-waveform construct: time-of-day dependent regulation. Am J Physiol 285:R950–R961.Google Scholar
  18. Keenan DM, Veldhuis JD 2003b. Mathematical modeling of receptor-mediated interlinked systems. Encyclopedia of Hormones. Academic, San Diego, CA, pp. 286–294.Google Scholar
  19. Keenan DM, Veldhuis JD, Yang R 1998. Joint recovery of pulsatile and basal hormone secretion by stochastic nonlinear random-effects analysis. Am J Physiol 275:R1939–R1949.PubMedGoogle Scholar
  20. Keenan DM, Licinio J, Veldhuis JD 2001. A feedback-controlled ensemble model of the stress-responsive hypothalamo-pituitary-adrenal axis. Proc Natl Acad Sci USA 98:4028–4033.PubMedCrossRefGoogle Scholar
  21. Keenan DM, Alexander SL, Irvine CHG, Clarke IJ, Canny BJ, Scott CJ, Tilbrook AJ, Turner AI, Veldhuis JD 2004. Reconstruction of in vivo time-evolving neuroendocrine dose-response properties unveils admixed deterministic and stochastic elements in interglandular signaling. Proc Natl Acad Sci USA 101:6740–6745.PubMedCrossRefGoogle Scholar
  22. Keenan DM, Chattopadhyay S, Veldhuis JD 2005. Composite model of time-varying appearance and disappearance of neurohormone pulse signals in blood. J Theor Biol 236:242–255.PubMedCrossRefGoogle Scholar
  23. Keenan DM, Takahashi PY, Liu PY, Roebuck PD, Nehra AX, Iranmanesh A, Veldhuis JD 2006. An ensemble model of the male gonadal axis: illustrative application in aging men. Endocrinol 147:2817–2828.CrossRefGoogle Scholar
  24. Knobil E 1990. The neuroendocrine control of the menstrual cycle. Rec Prog Horm Res 36:53–88.Google Scholar
  25. Leung KC, Doyle N, Ballesteros M, Sjogren K, Watts CK, Low TH, Leong GM, Ross RJ, Ho KK 2003. Estrogen inhibits GH signaling by suppressing GH-induced JAK2 phosphorylation, an effect mediated by SOCS-2. Proc Natl Acad Sci USA 100:1016–1021.PubMedCrossRefGoogle Scholar
  26. Meier JJ, Veldhuis JD, Butler PC 2005. Pulsatile insulin secretion dictates systemic insulin delivery by regulating hepatic insulin extraction in humans. Diabetes 54:1649–1656.PubMedCrossRefGoogle Scholar
  27. Moos F, Fontanaud P, Mekaouche M, Brown D 2004. Oxytocin neurones are recruited into co-ordinated fluctuations of firing before bursting in the rat. Neuroscience 125:391–410.PubMedCrossRefGoogle Scholar
  28. Morley P 2005. Delivery of parathyroid hormone for the treatment of osteoporosis. Expert Opin Drug Deliv 2:993–1002.PubMedCrossRefGoogle Scholar
  29. Pincus SM 2000. Irregularity and asynchrony in biologic network signals. Methods Enzymol 321:149–182.PubMedCrossRefGoogle Scholar
  30. Pincus SM, Mulligan T, Iranmanesh A, Gheorghiu S, Godschalk M, Veldhuis JD 1996. Older males secrete luteinizing hormone and testosterone more irregularly, and jointly more asynchronously, than younger males. Proc Natl Acad Sci USA 93:14100–14105.PubMedCrossRefGoogle Scholar
  31. Pincus SM, Hartman ML, Roelfsema F, Thorner MO, Veldhuis JD 1999. Hormone pulsatility discrimination via coarse and short time sampling. Am J Physiol 277:E948–E957.PubMedGoogle Scholar
  32. Pincus SM, Veldhuis JD, Rogol AD 2000. Longitudinal changes in growth hormone secretory process irregularity assessed transpubertally in healthy boys. Am J Physiol Endocrinol Metab 279:E417–E424.PubMedGoogle Scholar
  33. Porksen N, Munn S, Steers J, Veldhuis JD, Butler P 1996. Effects of somatostatin on pulsatile insulin secretion; selective inhibition of insulin burst mass. Am J Physiol 270:E1043–E1049.PubMedGoogle Scholar
  34. Porksen N, Nyholm B, Veldhuis JD, Butler PC, Schmitz O 1997. In humans at least seventy-five percent of overall insulin secretion arises from punctuated high-frequency insulin secretory bursts. Am J Physiol 273:E908–E914.PubMedGoogle Scholar
  35. Porksen N, Hollingdal M, Juhl CB, Butler P, Veldhuis JD, Schmitz O 2002. Pulsatile insulin secretion: detection, regulation and role in diabetes. Diabetes 51:S245–S254.PubMedCrossRefGoogle Scholar
  36. Redekopp C, Irvine CH, Donald RA, Livesey JH, Sadler W, Nicholls MG, Alexander SL, Evans MJ 1986. Spontaneous and stimulated adrenocorticotropin and vasopressin pulsatile secretion in the pituitary venous effluent of the horse. Endocrinol 118:1410–1416.CrossRefGoogle Scholar
  37. Ritzel RA, Veldhuis JD, Butler PC 2003. Glucose stimulates pulsatile insulin secretion from human pancreatic islets by increasing secretory burst mass: dose-response relationships. J Clin Endocrinol Metab 88:742–747.PubMedCrossRefGoogle Scholar
  38. Roelfsema F, Pincus SM, Veldhuis JD 1998. Patients with Cushing’s disease secrete adrenocorticotropin and cortisol jointly more asynchronously than healthy subjects. J Clin Endocrinol Metab 83:688–692.PubMedCrossRefGoogle Scholar
  39. Roelfsema F, Biermasz NR, Veldman RG, Veldhuis JD, Frolich M, Stokvis-Brantsma WH, Wit J-M 2000. Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role for non-GHRH inputs into the generation of GH pulses. J Clin Endocrinol Metab 86:2459–2464.CrossRefGoogle Scholar
  40. Salamalekis E, Vitoratos N, Kassanos D, Loghis C, Panayotopoulos N, Sykiotis C 2000. A randomized trial of pulsatile vs continuous oxytocin infusion for labor induction. Clin Exp Obstet Gynecol 27:21–23.PubMedGoogle Scholar
  41. Schaefer F, Daschner M, Veldhuis JD, Oh J, Qadri F, Scharer K 1994. In vivo alterations in the gonadotropin releasing hormone (GnRH) pulse generator and the secretion and clearance of luteinizing hormone in the uremic castrate rat. Neuroendocrinol 59:285–296.CrossRefGoogle Scholar
  42. Schmitz O, Porksen N, Nyholm B, Skjaerback C, Butler PC, Veldhuis JD, Pincus SM 1997. Disorderly and nonstationary insulin secretion in relatives of patients with NIDDM. Am J Physiol 35:E218–E226.Google Scholar
  43. Shapiro BH, MacLeod JN, Pampori NA, Morrissey JJ, Lapenson DP, Waxman DJ 1989. Signaling elements in the ultradian rhythm of circulating growth hormone regulating expression of sex-dependent forms of hepatic cytochrome P450. Endocrinol 125:2935–2944.CrossRefGoogle Scholar
  44. Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura H, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I 2002. Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 109:1429–1436.PubMedGoogle Scholar
  45. Siragy HM, Vieweg WVR, Pincus SM, Veldhuis JD 1995. Increased disorderliness and amplified basal and pulsatile aldosterone secretion in patients with primary aldosteronism. J Clin Endocrinol Metab 80:28–33.PubMedCrossRefGoogle Scholar
  46. Urban RJ, Evans WS, Rogol AD, Kaiser DL, Johnson ML, Veldhuis JD 1988. Contemporary aspects of discrete peak detection algorithms. I. The paradigm of the luteinizing hormone pulse signal in men. Endocr Rev 9:3–37.PubMedCrossRefGoogle Scholar
  47. Vance ML, Kaiser DL, Evans WS, Furlanetto R, Vale WW, Rivier J, Thorner MO 1985. Pulsatile growth hormone secretion in normal man during a continuous 24-hour infusion of human growth hormone releasing factor (1–40). J Clin Invest 75:1584–1590.PubMedCrossRefGoogle Scholar
  48. Vance ML, Kaiser DL, Martha Jr. PM, Furlanetto R, Rivier J, Vale WW, Thorner MO 1989. Lack of in vivo somatotroph densensitization or depletion after 14 days of continuous growth hormone (GH)-releasing hormone administration in normal men and a GH-deficient boy. J Clin Endocrinol Metab 68:22–28.PubMedCrossRefGoogle Scholar
  49. Veldhuis JD, Iranmanesh A, Lizarralde G, Johnson ML 1989a. Amplitude modulation of a burst-like mode of cortisol secretion subserves the circadian glucocorticoid rhythm in man. Am J Physiol 257:E6–E14.PubMedGoogle Scholar
  50. Veldhuis JD, O’Dea LS, Johnson ML 1989b. The nature of the gonadotropin-releasing hormone stimulus-luteinizing hormone secretory response of human gonadotrophs in vivo. J Clin Endocrinol Metab 68:661–670.PubMedCrossRefGoogle Scholar
  51. Veldhuis JD, Iranmanesh A, Johnson ML, Lizarralde G 1990. Twenty-four hour rhythms in plasma concentrations of adenohypophyseal hormones are generated by distinct amplitude and/or frequency modulation of underlying pituitary secretory bursts. J Clin Endocrinol Metab 71:1616–1623.PubMedCrossRefGoogle Scholar
  52. Veldhuis JD, Iranmanesh A, Godschalk M, Mulligan T 2000. Older men manifest multifold synchrony disruption of reproductive neurohormone outflow. J Clin Endocrinol Metab 85:1477–1486.PubMedCrossRefGoogle Scholar
  53. Veldhuis JD, Pincus SM, Mitamura R, Yano K, Suzuki N, Ito Y, Makita Y, Okuno A 2001a. Developmentally delimited emergence of more orderly luteinizing hormone and testosterone secretion in late prepuberty in boys. J Clin Endocrinol Metab 86:80–89.PubMedCrossRefGoogle Scholar
  54. Veldhuis JD, Anderson SM, Shah N, Bray M, Vick T, Gentili A, Mulligan T, Johnson ML, Weltman A, Evans WS, Iranmanesh A 2001b. Neurophysiological regulation and target-tissue impact of the pulsatile mode of growth hormone secretion in the human. Growth Horm IGF Res 11:S25–S37.PubMedCrossRefGoogle Scholar
  55. Veldhuis JD, Straume M, Iranmanesh A, Mulligan T, Jaffe CA, Barkan A, Johnson ML, Pincus SM 2001c. Secretory process regularity monitors neuroendocrine feedback and feedforward signaling strength in humans. Am J Physiol 280:R721–R729.Google Scholar
  56. Veldhuis JD, Evans WS, Bowers CY 2002. Impact of estradiol supplementation on dual peptidyl drive of growth-hormone secretion in postmenopausal women. J Clin Endocrinol Metab 87:859–866.PubMedCrossRefGoogle Scholar
  57. Veldhuis JD, Iranmanesh A, Keenan DM 2004. An ensemble perspective of aging-related hypoandrogenemia in men. In: Winters SJ (ed.), Male Hypogonadism: Basic, Clinical, and Theoretical Principles. Humana, Totowa, NJ, pp. 261–284.Google Scholar
  58. Veldhuis JD, Roemmich JN, Richmond EJ, Bowers CY 2006. Somatotropic and gonadotropic axes linkages in infancy, childhood, and the puberty-adult transition. Endocr Rev 27:101–140.PubMedCrossRefGoogle Scholar

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© Springer Science + Business Media B.V 2008

Authors and Affiliations

  • J. D. Veldhuis
    • 1
  1. 1.Endocrine Research Unit, Mayo Medical and Graduate SchoolCenter for Translational Science Mayo ClinicRochesterUSA

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