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Neuroendocrine mechanisms mediating awakening of the human gonadotropic axis in puberty

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  • 21 Citations


The hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator presides over the pulsatile and feedback-regulated activities of the pituitary-gonadal axis. Awakening of synchronous activity of the GnRH neuronal ensemble in the earliest stages of puberty heralds the onset of full activation of the reproductive axis in girls and boys. Progression from prepuberty to adulthood in boys is directed by marked (30-fold) amplitude enhancement of pulsatile luteinizing hormone (LH) secretion, as assessed by an ultrasensitive immunofluorometric assay and deconvolution analysis. There is a much less apparent rise in LH secretory burst frequency (approximately 1.3-fold increase). Consequently, human puberty is an amplitudedriven neuroendocrine maturational process. However, less is known about pulsatile follicle-stimulating hormone (FSH) release in puberty. Multiple pathophysiologies that result in hypogonadotropic hypogonadism can converge on a final common mechanism of attenuated hypothalamic GnRH pulse generator output and hence reduced LH (and FSH) secretion. Disturbances may take the form of reduced GnRH pulse frequency and/or attenuated GnRH secretory burst mass. When the pathophysiology of hypogonadism originates exclusively in a failed GnRH pulse generator, then either treatment of the primary disease process where possible (e.g., by refeeding in starvation, improved metabolic control in diabetes mellitus, dopamine agonist treatment in hyperprolactinemia, etc.) and/or treatment with pulsatile GnRH (e.g., in Kallmann's syndrome, isolated hypothalamic lesions, etc.) can provide relevant therapeutic options in children and adults.

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  1. 1.

    Juul A, Bang P, Hertel NT, Main K, Dalgaard P, Jorgensen K, Muller J, Hall K, Skakkebaek NE (1994) Serum insulin-like growth factor-I in 1030 healthy children, adolescents, and adults: relation to age, sex, stage of puberty, testicular size, and body mass index. J Clin Endocrinol Metab 78: 744–752

  2. 2.

    Tanner JM, Whitehouse RH, Hughes PCR, Carter BS (1976) Relative importance of growth hormone and sex steroids for the growth at puberty of trunk length, limb length, and muscle width in growth hormone-deficient children. J Pediatr 89: 1000–1008

  3. 3.

    Wennink JM, Delemarre-van de Waal HA, Schoemaker R, Blaauw G, Braken-van den C, Schoemaker J (1990) Growth hormone secretion patterns in relation to LH and testosterone secretion throughout normal male puberty. Acta Endocrinol (Copenh) 123: 263–270

  4. 4.

    Wennink JM, Delemarre-van de Waal HA, Schoemaker R, Blaauw G, Brakern C van den, Schoemaker J (1991) Growth hormone secretion patterns in relation to LH and estradiol secretion throughout normal female puberty. Acta Endocrinol (Copenh) 124: 129–135

  5. 5.

    Tanner JM, Davies PW (1985) Clinical longitudinal standards for height and weight velocity for Northern American children. J Pediatr 107: 317–329

  6. 6.

    Tanner JM, Whitehouse RH, Takaishi M (1966) Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children 1965. Arch Dis Child 41: 613–635

  7. 7.

    Martha PM Jr, Goorman KM, Blizzard RM, Rogol AD, Veldhuis JD (1992) Endogenous growth hormone secretion and clearance rates in normal boys as determined by deconvolution analysis: relationship to age, pubertal status and body mass. J Clin Endocrinol Metab 74: 336–344

  8. 8.

    Martha PM, Rogol AD, Veldhuis JD, Kerrigan JR, Goodman DW, Blizzard RM (1989) Alterations in the pulsatile properties of circulating growth hormone concentrations during puberty in boys. J Clin Endocrinol Metab 69: 563–570

  9. 9.

    Veldhuis JD (1991) The hypothalamic pituitary-testicular axis. In: Yen SSC, Jaffe RB (eds) Reproductive endocrinology, 3rd edn. Saunders, Philadelphia, pp 409–459

  10. 10.

    Parker DC, Judd HL, Rossmann LG, Yen SSC (1975) Pubertal sleep-wake patterns of episodic LH, FSH and testosterone release in twin boys. J Clin Endocrinol Metab 40: 1099–1109

  11. 11.

    Lee PA, Plotnick LP, Steel PE, Thompson RG, Blizzard RM (1976) Integrated concentrations of luteinizing hormone in puberty. J Clin Endocrinol Metab 43: 168–172

  12. 12.

    Marshall WA, Tanner JM (1970) Variation in the pattern of pubertal changes in boys. Arch Dis Child 45: 13–23

  13. 13.

    Boyar M, Finkelstein J, Kapen S, Roffwarg H, Weitzman E, Hellman L (1973) Simultaneous episodic secretion of luteinizing hormone and testosterone during sleep in puberty. J Clin Invest 52: 11–12

  14. 14.

    Blizzard RM, Thompson RG, Baghdassarian A (1974) The interrelationship of steroids, growth hormone and other hormones in pubertal growth. In: Grumbach MN, Graye JD, Mayer FE (eds) The control of the onset of puberty. Wiley, New York, pp 342–359

  15. 15.

    Wierman ME, Beardsworth DE, Crawford JD, Crigler JF, Mansfield MJ, Bode HH, Boepple PA, Kushner DC, Crowley WF (1986) Adrenarche and skeletal maturation during luteinizing hormone-releasing hormone analogue suppression of gonadarche. J Clin Invest 77: 121–126

  16. 16.

    Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD (1993) Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab 76: 1505–1510

  17. 17.

    Waldhauser F, Weißenbacher G, Frisch H, Pollack A (1981) Pulsatile secretion of gonadotropins in early infancy. Eur J Pediatr 137: 71–76

  18. 18.

    Zegher F de, Devlieger H, Veldhuis JD (1992) Pulsatile and sexually dimorphic secretion of luteinizing hormone in the human infant on the day of birth. Pediatr Res 32: 605–607

  19. 19.

    Lucky AW, Rich BH, Rosenfield RL, Fang VS, Roche-Bender N (1980) Bioactive LH: a test to discriminate precocious puberty from premature thelarche and adrenarche. J Pediatr 97: 214–216

  20. 20.

    Dunkel L, Alfthan H, Stenman UH, Tapanainen P, Perheentupa J (1990) Pulsatile secretion of LH and FSH in prepubertal and early pubertal boys revealed by ultrasensitive time-resolved immunofluorometric assay. Pediatr Res 27: 215–219

  21. 21.

    Apter D, Cacciatore B, Alfthan H, Stenman U-H (1989) Serum luteinizing hormone concentrations increase 100-fold in females from 7 years of age to adulthood, as measured by time-resolved immunofluorometric assay. J Clin Endocrinol Metab 68: 53–57

  22. 22.

    Goji K, Tanikaze S (1992) Comparison between spontaneous gonadotropin concentration profiles and gonadotropin response to low-dose gonadotropin-releasing hormone in prepubertal and early pubertal boys and patients with hypogonadotropic hypogonadism: assessment by using ultrasensitive, time-resolved immunofluorometric assay. Pediatr Res 31: 535–539

  23. 23.

    Haavisto A-M, Dunkel L, Pettersson K, Huhtaniemi I (1990) LH measurements by in vitro bioassay and a highly sensitive immunofluorometric assay improve the distinction between boys with constitutional delay of puberty and hypogonadotropic hypogonadism. Pediatr Res 27: 211–214

  24. 24.

    Wu FCW, Butler GE, Kelnar CJH, Stirling HF, Huhtaniemi I (1991) Patterns of pulsatile luteinizing hormone and folliclestimulating hormone secretion in prepubertal (midchildhood) boys and girls and patients with idiopathic hypogonadotropic hypogonadism (Kallmann's syndrome): a study using an ultrasensitive time-resolved immunofluorometric assay. J Clin Endocrinol Metab 72: 1229–1237

  25. 25.

    Reiter EO, Biggs DE, Veldhuis JD, Beitins IZ (1987) Pulsatile release of bioactive LH in prepubertal girls: discordance with immunoreactive LH pulses. Pediatr Res 21: 409–413

  26. 26.

    Reiter EO, Dufau ML, Root AW (1978) Bioactive and immunoreactive serum LH in normal prepubertal and pubertal boys. Pediatr Res 12: 330–336

  27. 27.

    Rich BH, Rosenfield RL, Moll GW Jr, Lucky AW, Roche-Bender N, Fang V (1982) Bioactive luteinizing hormone pituitary reserves during normal and abnormal male puberty. J Clin Endocrinol Metab 55: 140–146

  28. 28.

    Lucky AW, Rich BH, Rosenfield RL, Fang VS, Roche-Bender N (1980) LH bioactivity increases more than immunoreactivity during puberty. J Pediatr 97: 205–213

  29. 29.

    Hassing JM, Padmanabhan V, Kelch RP, Brown MB, Olton PR, Sonstein JS, Foster CM, Beitins IZ (1990) Differential regulation of serum immunoreactive luteinizing hormone and bioactive follicle-stimulating hormone by testosterone in early pubertal boys. J Clin Endocrinol Metab 70: 1082–1089

  30. 30.

    Marshall JC, Kelch RP (1979) Low dose pulsatile gonadotropinreleasing hormone in anorexia nervosa: a model for human pubertal development. J Clin Endocrinol Metab 49: 712–718

  31. 31.

    Gordon D, Gray CE, Beastall GH, Thomson JA (1989) The effects of pulsatile GnRH infusion upon the diurnal variations in serum LH and testosterone in prepubertal and pubertal boys. Acta Endocrinol (Copenh) 121: 241–245

  32. 32.

    Wagner TOF, Brabant G, Warsch F, Hesch RD, Uhler M von zur (1985) Pulsatile gonadotropin-releasing hormone treatment in idiopathic delayed puberty. J Clin Endocrinol Metab 43: 447–452

  33. 33.

    Bourguignon JP, Franchimont P (1984) Puberty-related increase in episodic LHRH release from rat hypothalamus in vitro. Endocrinology 114: 1941–1943

  34. 34.

    Wildt L, Marshall G, Knobil E (1980) Experimental induction of puberty in the infantile female rhesus monkey. Science 47: 465–468

  35. 35.

    Hoffman AR, Crowley WF Jr (1982) Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med 307: 1237–1242

  36. 36.

    Watanabe G, Terasawa E (1989) In vivo release of luteinizing hormone releasing hormone increases with puberty in the female Rhesus monkey. Endocrinology 125: 92–99

  37. 37.

    Crowley WF, Filicori M, Spratt DI, Santoro NF (1985) The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res 41: 473–531

  38. 38.

    Bremner WJ, Matsumoto AM, Paulsen CA (1984) Gonadotropin control of spermatogenesis in man: studies of gonadotropin administration in spontaneous and experimentally induced hypogonadotropic states. Ann N Y Acad Sci 438: 465–470

  39. 39.

    Veldhuis JD, Kulin HE, Warner BA, Santner SJ (1982) Responsiveness of gonadotropin secretion to infusion of an opiate-receptor antagonist in hypogonadotropic individuals. J Clin Endocrinol Metab 55: 649–653

  40. 40.

    Mauras N, Veldhuis JD, Rogol AD (1986) Role of endogenous opiates in pubertal maturation: opposing actions of naltrexone in prepubertal and late pubertal boys. J Clin Endocrinol Metab 62: 1256–1263

  41. 41.

    Kulin HE, Demers LM, Rogol AD, Veldhuis JD (1987) The effect of long-term opiate agonist administration to peripubertal boys. J Androl 8: 374–377

  42. 42.

    Minami S, Frautschy SA, Plotsky PM, Sutton SW, Sarkar K (1990) Facilitatory role of neuropeptide Y on the onset of puberty: effect of immunoneutralization of neuropeptide Y on the release of luteinizing hormone and luteinizing-hormone-releasing hormone. Neuroendocrinology 42: 112–115

  43. 43.

    Gay VL, Plant TM (1988) Sustained intermittent release of gonadotropin-releasing hormone in the prepubertal male rhesus monkeys induced byN-methyl-DL-aspartic acid. Neuroendocrinology 48: 147–152

  44. 44.

    Plant TM, Gay VL, Marshall GR, Arslan M (1989) Puberty in monkeys is triggered by chemical stimulation of the hypothalamus. Proc Natl Acad Sci USA 86: 2506–2510

  45. 45.

    Silverman AJ, Krey LC, Zimmerman EA (1979) A comparative study of the luteinizing hormone releasing hormone (LHRH) neuronal networks in mammals. Biol Reprod 20:98–106

  46. 46.

    Schwanzel-Fukuda M, Pfaff DW (1989) Origin of luteinizing hormone-releasing hormone neurons. Nature 338:161–164

  47. 47.

    Wray S, Nieburgs A, Elkabes S (1989) Spatiotemporal cell expression of luteinzing hormone-releasing hormone in the prenatal mouse: evidence for an embryonic origin in the olfactory placode. Dev Brain Res 46:309–315

  48. 48.

    Mortimer CH (1977) Gonadotropin-releasing hormone. In: Martini L, Besser GM (eds) Clinical neuroendocrinology. Academic Press, New York, pp 213–236

  49. 49.

    Conn PM, Crowley WF (1991) Gonadotropin-releasing hormone and its analogs. N Engl J Med 324:93–103

  50. 50.

    Veldhuis JD (1990) The hypothalamic pulse generator: the reproductive core. In: Adashi EY (eds) Clinical obstetrics and gynecology: reproductive endocrinology update, 33rd edn. J.B. Lippincott, Hagerstown, M.D., pp 538–550

  51. 51.

    Schwanzel-Fukuda M, Bick D, Pfaff DW (1989) Luteinizing hormone-releasing hormone (LHRH) cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. Mol Brain Res 6:311–326

  52. 52.

    Reame NE, Sauder SE, Case GD, Kelch RP, Marshall JC (1985) Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J Clin Endocrinol Metab 61:851–856

  53. 53.

    Moult PJA, Rees LH, Besser GM (1982) Pulsatile gonadotrophin secretion in hyperprolactinaemic amenorrhea and the response to bromocriptine therapy. Clin Endocrinol (Oxf) 16:153–160

  54. 54.

    Knobil E (1980) The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53–88

  55. 55.

    Marshall JC, Kelch RP (1986) Gonadotropin-releasing hormone: role of pulsatile secretion in the regulation of reproduction. N Engl J Med 315:1459–1467

  56. 56.

    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

  57. 57.

    Evans WS, Christiansen E, Urban RJ, Rogol AD, 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

  58. 58.

    Veldhuis JD (1995) Pulsatile hormone release as a window into the brain's control of the anterior pituitary gland in health and disease: implications and consequences of pulsatile luteinizing hormone secretion. In: Loriaux L (ed) The endocrinologist. Williams and Wilkins, Baltimore, pp 454–469

  59. 59.

    Veldhuis JD, Moorman J, Johnson ML (1994) Deconvolution analysis of neuroendocrine data: waveform-specific and wave-form-independent methods and applications. Methods Neurosci 20:279–325

  60. 60.

    Reyes-Fuentes A, Veldhuis JD (1993) Neuroendocrine physiology of the normal male gonadal axis. In: Veldhuis JD (eds) Endocrinology and metabolism clinics of North America. Saunders, Philadelphia, pp 93–124

  61. 61.

    Neill JD, Patton JM, Dailey RA, Tsou RC, Tindall GT (1977) Luteinizing hormone releasing hormone (LHRH) in pituitary stalk blood of rhesus monkeys: relationship to level of LH release. Endocrinology 101:430–434

  62. 62.

    Levine JE, Pau K-YF, Ramirez VD, Jackson GL (1982) Simultaneous measurement of luteinizing hormone-releasing and luteinizing hormone release in unanesthetized, ovariectomized sheep. Endocrinology 111:1449–1455

  63. 63.

    Dluzen DE, Ramirez VD (1987) In vivo activity of the LHRH pulse generator as determined with push-pull perfusion of the anterior pituitary gland of unrestrained intact and castrate male rats. Neuroendocrinology 45:328–332

  64. 64.

    Urbanski HF, Pickle RL, Ramirez VD (1988) Simultaneous measurement of gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone in the orchidectomized rat. Endocrinology 123:413–419

  65. 65.

    Alexander SL, Irvine CHG (1987) Secretion rates and short-term patterns of gonadotropin-releasing hormone, FSH and LH throughout the preovulatory period in the mare. J Endocrinol 114: 351–362

  66. 66.

    Carmel PW, Araki S, Ferin M (1976) Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin releasing hormone (GnRH). Endocrinology 99: 243–248

  67. 67.

    Clarke IJ, Cummins JT (1982) The temporal relationship between gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology 111: 1737–1739

  68. 68.

    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. Neuroendocrinology 50:285–296

  69. 69.

    Knobil E (1989) The electrophysiology of the GnRH pulse generator in the rhesus monkey. J Steroid Biochem 33:669–671

  70. 70.

    Santen RJ, Bardin CW (1973) Episodic luteinizing hormone secretion in man: pulse analysis, clinical interpretation, and pathological mechanisms. J Clin Invest 52:2617–2628

  71. 71.

    Veldhuis JD, Fraoili F, Rogol AD, Dufau ML (1986) Metabolic clearance of biologically active luteinizing hormone in man. J Clin Invest 77:1122–1128

  72. 72.

    Veldhuis JD, Johnson ML, Dufau ML (1989) Physiological attributes of endogenous bioactive luteinizing hormone secretory bursts in man: assessment by deconvolution analysis and in vitro bioassay of LH. Am J Physiol 256:E199-E207

  73. 73.

    Urban RJ, Padmanablan V, Beitins I, Veldhuis JD (1991) Metabolic clearance of human follicle-stimulating hormone assessed by radioimmunoassay, immunoradiometric assay, and in vitro Sertoli cell bioassay. J Clin Endocrinol Metab 73:818–823

  74. 74.

    Urban RJ, Johnson ML, Veldhuis JD (1989) In vivo biological validation and biophysical modeling of the sensitivity and positive accuracy of endocrine peak detection. I. The LH pulse signal. Endocrinology 124:2541–2547

  75. 75.

    Urban RJ, Johnson ML, Veldhuis JD (1991) In vivo biological validation and biophysical modeling of the sensitivity and positive accuracy of endocrine peak detection. II. The FSH pulse signal. Endocrinology 128:2008–2014

  76. 76.

    Veldhuis JD, Carlson ML, Johnson ML (1987) The pituitary gland secretes in bursts: appraising the nature of glandular secretory impulses by simultaneous multiple-parameter deconvolution of plasma hormone concentrations. Proc Natl Acad Sci USA 84: 7686–7690

  77. 77.

    Veldhuis JD, Johnson ML (1992) Deconvolution analysis of hormone data. Methods Enzymol 210:539–575

  78. 78.

    Veldhuis JD, Evans WS, Butler JP, Johnson ML (1992) Computer algorithms for deconvolution-based assessment of in vivo neuroendocrine secretory events. Methods Neurosci 10:241–277

  79. 79.

    Johnson ML, Veldhuis JD (1995) Evolution of deconvolution analysis as a hormone pulse detection method. Methods Neurosci 28:1–24

  80. 80.

    Veldhuis JD, Johnson ML (1995) Specific methodological approaches to selected contemporary issues in deconvolution analysis of pulsatile neuroendocrine data. Method Neurosci 28: 25–92

  81. 81.

    Sollenberger ML, Carlson EC, Johnson ML, Veldhuis JD, Evans WS (1990) Specific physiological regulation of LH secretory events throughout the human menstrual cycle: new insights into the pulsatile mode of gonadotropin release. J Neuroendocrinol 2: 845–852

  82. 82.

    Veldhuis JD, Iranmanesh A, Evans WS, Lizarralde G, Thorner MO, Vance ML (1993) Amplitude suppression of the pulsatile mode of immunoradiometric LH release in fasting-induced hypoandrogenemia in normal men. J Clin Endocrinol Metab 76: 587–593

  83. 83.

    Veldhuis JD, O'Dea L St L, Johnson ML (1989) The nature of the gonadotropin-releasing hormone stimulus-luteinizing hormone secretory response of human gonadotrophs in vivo. J Clin Endocrinol Metab 68:661–670

  84. 84.

    Veldhuis JD, Urban RJ, Lizarralde G, Johnson ML, Iranmanesh A (1992) Attenuation of luteinizing hormone secretory burst amplitude is a proximate basis for the hypoandrogenism of healthy aging in men. J Clin Endocrinol Metab 75:707–713

  85. 85.

    Sollenberger MJ, Carlsen ES, Booth RA Jr, Johnson ML, Veldhuis JD, Evans WS (1990) Nature of gonadotropin-releasing hormone self-priming of LH secretion during, the normal menstrual cycle. Am J Obstet Gynecol 163:1529–1534

  86. 86.

    Urban RJ, Dahl KD, Padmanabhan V, Beitins IZ, Veldhuis JD (1991) Specific regulatory actions of dihydrotestosterone and estradiol on the dynamics of FSH secretion and clearance in man. J Androl 12:27–35

  87. 87.

    Veldhuis JD, Urban RJ, Dufau ML (1992) Evidence that androgen negative-feedback regulates hypothalamic GnRH impulse strength and the burst-like secretion of biologically active luteinizing hormone in men. J Clin Endocrinol Metab 74:1227–1235

  88. 88.

    Urban RJ, Dahl KD, Lippert MC, Veldhuis JD (1992) Endogenous androgen and estrogen modulate immunoradiometric and bioactive FSH secretion and clearance in young and elderly men. J Androl 13:579–586

  89. 89.

    Quyyumi SA, Pinkerton JV, Evans WS, Veldhuis JD (1993) Estradiol amplifies the amount of luteinizing hormone secreted in response to increasing doses of gonadotropin-releasing hormone (GnRH) by specifically augmenting the duration of evoked LH secretory events and hence their mass. J Clin Endocrinol Metab 76:594–600

  90. 90.

    Veldhuis JD, Urban RJ, Dufau ML (1994) Differential responses of biologically active LH secretion in older versus young men to interruption of androgen negative feedback. J Clin Endocrinol Metab 79:1763–1770

  91. 91.

    Kerrigan JR, Veldhuis JD, Rogol AD (1994) Androgen-receptor blockade enhances pulsatile luteinizing hormone production in late pubertal males: evidence for a hypothalamic site of physiological androgen feedback action. Pediatr Res 35:102–106

  92. 92.

    Mulligan T, Delemarre-van de Waal HA, Johnson ML, Veldhuis JD (1994) Validation of deconvolution analysis of LH secretion and half-life. Am J Physiol 267:R202-R211

  93. 93.

    Partsch C-J, Abrahams S, Herholz N, Peter M, Veldhuis JD, Sippell WG (1994) Variability of pulsatile LH secretion in young male volunteers. Eur J Endocrinol 131:263–272

  94. 94.

    Wu FCW, Butler GE, Kelnar CJH, Huhtaniemi I, Veldhuis JD (1995) Patterns of pulsatile luteinizing hormone secretion from childhood to adulthood in the human male: a study using deconvolution analysis and an ultrasensitive immunofluorometric assay. J Clin Endocrinol Metab (in press)

  95. 95.

    Veldhuis JD, Rogol AD, Johnson ML, Dufau ML (1983) Endogenous opiates modulate the pulsatile secretion of biologically active luteinizing hormone in man. J Clin Invest 72:2031–2040

  96. 96.

    Veldhuis JD, Rogol AD, Samojlik E, Ertel N (1984) Role of endogenous opiates in the expression of negative feedback actions of estrogen and androgen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest 74:47–55

  97. 97.

    Evans WS, Weltman JY, Johnson ML, Weltman A, Veldhuis JD, Rogol AD (1992) Effects of opioid receptor blackade on luteinizing hormone (LH) pulses and interpulse LH concentrations in normal women during the early phase of the menstrual cycle. J Endocrinol Invest 15:525–531

  98. 98.

    Veldhuis JD, Johnson ML, Gallo RV (1993) Reanalysis of the rat proestrous LH surge by deconvolution analysis. Am J Physiol 265:R240-R248

  99. 99.

    Veldhuis JD, Evans WS, Rogol AD, Kolp L, Thorner MO, Stumpf P (1986) The pituitary self-priming actions of gonadotropin-releasing hormone: kinetics of estradiol's potentiating effects on GnRH-facilitated LH and FSH release in healthy post-menopausal women. J Clin Invest 77:1849–1856

  100. 100.

    Urban RJ, Veldhuis JD, Dufau ML (1991) Estrogen regulates the gonadotropin-releasing-hormone stimulated secretion of biologically active luteinizing hormone in man. J Clin Endocrinol Metab 72:660–668

  101. 101.

    Mauras N, Rogol AD, Veldhuis JD (1991) Estrogenic modulation of the GnRH-stimulated secretory activity of the human prepubertal female gonadotrope and lactotrope. J Clin Endocrinol Metab 73:1202–1209

  102. 102.

    Veldhuis JD, Dufau ML (1987) Estradiol modulates the pulsatile secretion of biologically active luteinizing hormone in man. J Clin Invest 80:631–638

  103. 103.

    Goodman RL, Knobil E (1981) The sites of action of ovarian steroids in the regulation of LH secretion. Neuroendocrinology 32:57–63

  104. 104.

    Clarke IJ, Thomas SB, Yao B, Cummins JI (1987) GnRH secretion throughout the ovine estrous cycle. Neuroendocrinology 46:82

  105. 105.

    Santen RJ, Leonard JM, Sherins RJ, Gandy HM, Paulsen CA (1971) Short-and long-term effects of clomiphene citrate on the pituitary-testicular axis. J Clin Endocrinol Metab 33:970

  106. 106.

    Winters SJ, Troen P (1985) Evidence for a role of endogenous estrogen in the hypothalamic control of gonadotropin secretion in men. J Clin Endocrinol Metab 61:842–845

  107. 107.

    Chongthammakun S, Terasawa E (1993) Negative feedback effects of estrogen on luteinizing hormone-releasing hormone release occur in pubertal, but not prepubertal, ovariectomized female Rhesus monkeys. Endocrinology 132:735–743

  108. 108.

    Kesner JS, Yamamoto H, Pardo RR, Knobil E (1987) Unexpected response of the hypothalamic GnRH pulse generator to physiological estradiol inputs in the absence of the ovary. Proc Natl Acad Sci USA 84:8745–8749

  109. 109.

    Veldhuis JD, Evans WS, Rogol AD, Thorner MO, Stumpf P (1987) Actions of estradiol on discrete attributes of the luteinizing hormone pulse signal in man: studies in postmenopausal women treated with pure estradiol. J Clin Invest. 79:769–776

  110. 110.

    Veldhuis JD, Rogol AD, Perez-Palacios G, Stumpf P, Kitchin JD, Dufau ML (1985) Endogenous opiates participate in the regulation of pulsatile LH release in an unopposed estrogen milieu: studies in estrogen-replaced, gonadectomized, patients with testicular feminization. J Clin Endocrinol Metab 61:790–793

  111. 111.

    Santen RJ (1975) Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in man. J Clin Invest 56:1555–1563

  112. 112.

    Shecker CB, Matsumoto AM, Bremner WJ (1989) Testosterone administration inhibits gonadotropin secretion by an effect directly on the human pituitary. J Clin Endocrinol Metab 68: 397–403

  113. 113.

    Finkelstein JS, Whitcomb R, O'Dea LStL, Longcope C, Schoenfield DA, Crowley WF (1991) Sex steroid control of gonadotropin secretion in the human male. I. Effects of testosterone administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 73:609–620

  114. 114.

    Finkelstein JS, O'Dea LStL, Whitcomb RW, Crowley WF Jr (1991) Sex steroid control of gonadotropin secretion in the human male. II. Effects of estradiol administration in normal and gonadotropin-releasing hormone-deficient men. J Clin Endocrinol Metab 73:621–628

  115. 115.

    Pincus SM (1991) Approximate entropy as a measure of system complexity (statistic/stochastic processes/chaos/dimension). Proc Natl Acad Sci USA 88:2297–2301

  116. 116.

    Pincus SM, Huang WM (1992) Approximate entropy: statistical properties and applications. Commun Statist Theory Methods 21: 3061–3077

  117. 117.

    Pincus SM, Keefe DL (1992) Quantification of hormone pulsatility via an approximate entropy algorithm. Am J Physiol 262: E741-E754

  118. 118.

    Pincus SM, Gevers E, Robinson ICA, Roelfsema F, Hartman ML, Veldhuis JD (1996) Females secrete growth hormone with more process irregularity than males in both human and rat. Am J Physiol 270:E107–115

  119. 119.

    Hartman ML, Pincus SM, Johnson ML, Matthews DH, Faunt LM, Vance ML, Thorner MO, Veldhuis JD (1994) Enhanced basal and disorderly growth hormone (GH) secretion distinguish acromegalic from normal pulsatile GH release. J Clin Invest 94: 1277–1288

  120. 120.

    Siragy HM, Vieweg WVR, Pincus S, Veldhuis JD (1995) Increased disorderliness and amplified basal and pulsatile aldosterone secretion in patients with primary aldosteronism. J Clin Endocrinol Metab 80:28–33

  121. 121.

    South SA, Asplin CM, Carlsen EC, Booth RA Jr, Johnson ML, Veldhuis MD, Evans WS (1993) Alterations in luteinizing hormone secretory activity in women with insulin-dependent diabetes mellitus and secondary amenorrhea. J Clin Endocrinol Metab 76:1048–1053

  122. 122.

    Lim VS, Henriquez C, Sievertsen G, Frohman LA (1980) Ovarian function in chronic renal failure: evidence suggesting hypothalamic anovulation. Ann Intern Med 93:21–270

  123. 123.

    Veldhuis JD, Wilkowski MJ, Urban RJ, Lizarralde G, Iranmanesh A, Bolton WK (1993) Evidence for attenuation of hypothalamic GnRH impulse strength with preservation of gonadotropin-releasing hormone (GnRH) pulse frequency in men with chronic renal failure. J Clin Endocrinol Metab 76:648–654

  124. 124.

    Schaefer F, Kaick B van Veldhuis JD, Stein G, Scharer K, Robertson WR, Ritz E (1994) Changes in the kinetics and biopotency of luteinizing hormone in hemodialyzed men during treatment with recombinant human erythropoietin. J Am Soc Nephrol 5:1208–1215

  125. 125.

    Veldhuis JD, Evans WS, Demers LM, Thorner MO, Wakat D, Rogol AD (1985) Altered neuroendocrine regulation of gonadotropin secretion in women distance runners. J Clin Endocrinol Metab 61:557–563

  126. 126.

    Leyendecker G, Wildt L, Hansmann M (1980) Pregnancies following chronic intermittent (pulsatile) administration of GnRH by means of a portable pump (“Zyklomat”) — a new approach to the treatment of infertility in hypothalamic amenorrhea. J Clin Endocrinol Metab 51:1214

  127. 127.

    Nillius SJ, Fries H, Wide L (1975) Successful induction of follicular maturation and ovulation by prolonged treatment with LH-releasing hormone in women with anorexia nervosa. Am J Obstet Gynecol 122:921–928

  128. 128.

    Bergendahl M, Perheentupa A, Huhtaniemi I (1991) Starvation-induced suppression of pituitary-testicular function in rats is reversed by pulsatile GnRH substitution. Biol Reprod 44:413–419

  129. 129.

    Bronson FH (1986) Food-restricted, prepubertal, female rats: rapid recovery of luteinizing hormone pulsing with excess food, and full recovery of pubertal development with gonadotropin-releasing hormone. Endocrinology 118:2483–2487

  130. 130.

    Schreihofer DA, Amico JA, Cameron JL (1993) Reversal of fasting-induced suppression of luteinizing hormone (LH) secretion in male rhesus monkeys by intragastric nutrient infusion: evidence for rapid stimulation of LH by nutritional signals. Endocrinology 132:1890–1897

  131. 131.

    Bergendahl M, Veldhuis JD (1995) Altered pulsatile gonadotropin signaling in nutritional deficiency in the male. Trends Endocrinol Metab 6:145–159

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Veldhuis, J.D. Neuroendocrine mechanisms mediating awakening of the human gonadotropic axis in puberty. Pediatr Nephrol 10, 304–317 (1996).

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Key words

  • Puberty
  • Gonadotropin
  • Pituitary
  • Reproduction
  • Growth