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. 1983 Dec;72(6):2031–2040. doi: 10.1172/JCI111168

Endogenous opiates modulate the pulsatile secretion of biologically active luteinizing hormone in man.

J D Veldhuis, A D Rogol, M L Johnson
PMCID: PMC437044  PMID: 6315775

Abstract

We studied the secretion of physiological pools of immunoreactive and biologically active luteinizing hormone in response to endogenous pulses of gonadotropin-releasing hormone (GNRH) in eugonadal men. Concentrations of immunoactive and bioactive luteinizing hormone (LH) were determined in blood drawn at 20-min intervals for 8 h in eight normal men under two conditions: (a) after placebo, in order to evaluate spontaneous LH pulsations in the basal state, and (b) after administration of the opiate-receptor antagonist, naltrexone, which is believed to amplify the pulsatile release of endogenous GNRH. Spontaneous and naltrexone-stimulated secretion of LH occurred in pulses of high biological activity, as measured in the RICT (rat interstitial cell testosterone bioassay), i.e., bioactive:immunoactive LH ratios within both spontaneous and naltrexone-stimulated LH pulses were higher than corresponding interpulse ratios (P less than 0.001). Quantitative characterization of the pulsatile release of bioactive LH revealed the following specific effects of opiate-receptor blockade: increased 8-h mean and integrated serum concentrations of bioactive LH (P less than 0.002), enhanced pulse frequency of bioactive LH release (P less than 0.001), and augmented peak amplitude of bio-LH pulses (P less than 0.01). Moreover, this increase in episodic secretion of bioactive LH was associated with increased 8-h mean and integrated serum testosterone concentrations in these men (P less than 0.05). We conclude the following: (a) LH is normally released in spontaneous pulses of high biological activity in men; (b) when the endogenous GNRH signal is amplified by opiate-receptor blockade, the pituitary gland releases more frequent bioactive LH pulses, which are of high amplitude and contain a high bioactive:immunoactive LH ratio. This increase in pulsatile release of bioactive LH quantitated in the RICT assay in vitro is reflected by acutely increased serum testosterone concentrations in vivo. We infer that modulation of the episodic GNRH signal by endogenous opiates provides another significant mechanism by which the hypothalamus can alter the biological activity of circulating gonadotropic hormone in man. Moreover, observed alterations in the pulsatile pattern of bioactive LH release were associated in turn with significant changes in testosterone concentrations. Thus, we hypothesize that alterations in the properties of the bioactive LH pulse signal can provide an important mechanism for regulating target-cell function within the gonad in states of health or disease.

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Selected References

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  1. Azizi F., Vagenakis A. G., Longcope C., Ingbar S. H., Braverman L. E. Decreased serum testosterone concentration in male heroin and methadone addicts. Steroids. 1973 Oct;22(4):467–472. doi: 10.1016/0039-128x(73)90002-0. [DOI] [PubMed] [Google Scholar]
  2. Bardin C. W., Ross G. T., Lipsett M. B. Site of action of clomiphene citrate in men: a study of the pituitary-Leydig cell axis. J Clin Endocrinol Metab. 1967 Nov;27(11):1558–1564. doi: 10.1210/jcem-27-11-1558. [DOI] [PubMed] [Google Scholar]
  3. Beitins I. Z., Dufau M. L., O'Loughlin K., Catt K. J., McArthur J. W. Analysis of biological and immunological activities in the two pools of LH released during constant infusion of luteinizing hormone-releasing hormone (LHRH) in men. J Clin Endocrinol Metab. 1977 Sep;45(3):605–608. doi: 10.1210/jcem-45-3-605. [DOI] [PubMed] [Google Scholar]
  4. Boyar R. M., Rosenfeld R. S., Kapen S., Finkelstein J. W., Roffwarg H. P., Weitzman E. D., Hellman L. Human puberty. Simultaneous augmented secretion of luteinizing hormone and testosterone during sleep. J Clin Invest. 1974 Sep;54(3):609–618. doi: 10.1172/JCI107798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bäckström C. T., McNeilly A. S., Leask R. M., Baird D. T. Pulsatile secretion of LH, FSH, prolactin, oestradiol and progesterone during the human menstrual cycle. Clin Endocrinol (Oxf) 1982 Jul 1;17(1):29–42. doi: 10.1111/j.1365-2265.1982.tb02631.x. [DOI] [PubMed] [Google Scholar]
  6. Cicero T. J., Meyer E. R., Bell R. D., Koch G. A. Effects of morphine and methadone on serum testosterone and luteinizing hormone levels and on the secondary sex organs of the male rat. Endocrinology. 1976 Feb;98(2):367–372. doi: 10.1210/endo-98-2-367. [DOI] [PubMed] [Google Scholar]
  7. Cicero T. J., Meyer E. R., Wiest W. G., Olney J. W., Bell R. D. Effects of chronic morphine administration on the reproductive system of the male rat. J Pharmacol Exp Ther. 1975 Mar;192(3):542–548. [PubMed] [Google Scholar]
  8. Cicero T. J., Wilcox C. E., Bell R. D., Meyer E. R. Naloxone-induced increases in serum luteinizing hormone in the male: mechanisms of action. J Pharmacol Exp Ther. 1980 Mar;212(3):573–578. [PubMed] [Google Scholar]
  9. Clarke I. J., Cummins J. T. The temporal relationship between gonadotropin releasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariectomized ewes. Endocrinology. 1982 Nov;111(5):1737–1739. doi: 10.1210/endo-111-5-1737. [DOI] [PubMed] [Google Scholar]
  10. Clifton D. K., Steiner R. A. Cycle detection: a technique for estimating the frequency and amplitude of episodic fluctuations in blood hormone and substrate concentrations. Endocrinology. 1983 Mar;112(3):1057–1064. doi: 10.1210/endo-112-3-1057. [DOI] [PubMed] [Google Scholar]
  11. Dierschke D. J., Bhattacharya A. N., Atkinson L. E., Knobil E. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology. 1970 Nov;87(5):850–853. doi: 10.1210/endo-87-5-850. [DOI] [PubMed] [Google Scholar]
  12. Dufau M. L., Beitins I. Z., McArthur J. W., Catt K. J. Effects of luteinizing hormone releasing hormone (LHRH) upon bioactive and immunoreactive serum LH levels in normal subjects. J Clin Endocrinol Metab. 1976 Sep;43(3):658–667. doi: 10.1210/jcem-43-3-658. [DOI] [PubMed] [Google Scholar]
  13. Dufau M. L., Catt K. J., Tsuruhara T. Retention of in vitro biological activities by desialylated human luteinizing hormone and chorionic gonadotropin. Biochem Biophys Res Commun. 1971 Sep;44(5):1022–1029. doi: 10.1016/s0006-291x(71)80188-2. [DOI] [PubMed] [Google Scholar]
  14. Dufau M. L., Hodgen G. D., Goodman A. L., Catt K. J. Bioassay of circulating luteinizing hormone in the rhesus monkey: comparison with radioimmunoassay during physiological changes. Endocrinology. 1977 Jun;100(6):1557–1565. doi: 10.1210/endo-100-6-1557. [DOI] [PubMed] [Google Scholar]
  15. Dufau M. L., Pock R., Neubauer A., Catt K. J. In vitro bioassay of LH in human serum: the rat interstitial cell testosterone (RICT) assay. J Clin Endocrinol Metab. 1976 May;42(5):958–969. doi: 10.1210/jcem-42-5-958. [DOI] [PubMed] [Google Scholar]
  16. Dufau M. L., Veldhuis J. D., Fraioli F., Johnson M. L., Beitins I. Z. Mode of secretion of bioactive luteinizing hormone in man. J Clin Endocrinol Metab. 1983 Nov;57(5):993–1000. doi: 10.1210/jcem-57-5-993. [DOI] [PubMed] [Google Scholar]
  17. Ellingboe J., Mendelson J. H., Kuehnle J. C. Effects of heroin and naltrexone on plasma prolactin levels in man. Pharmacol Biochem Behav. 1980 Jan;12(1):163–165. doi: 10.1016/0091-3057(80)90431-1. [DOI] [PubMed] [Google Scholar]
  18. Ellingboe J., Veldhuis J. D., Mendelson J. H., Kuehnle J. C., Mello N. K. Effect of endogenous opioid blockade on the amplitude and frequency of pulsatile luteinizing hormone secretion in normal men. J Clin Endocrinol Metab. 1982 Apr;54(4):854–857. doi: 10.1210/jcem-54-4-854. [DOI] [PubMed] [Google Scholar]
  19. Ellis G. B., Desjardins C. Male rats secrete luteinizing hormone and testosterone episodically. Endocrinology. 1982 May;110(5):1618–1627. doi: 10.1210/endo-110-5-1618. [DOI] [PubMed] [Google Scholar]
  20. Ellis G. B., Desjardins C. Male rats secrete luteinizing hormone and testosterone episodically. Endocrinology. 1982 May;110(5):1618–1627. doi: 10.1210/endo-110-5-1618. [DOI] [PubMed] [Google Scholar]
  21. Gay V. L., Sheth N. A. Evidence for a periodic release of LH in castrated male and female rats. Endocrinology. 1972 Jan;90(1):158–162. doi: 10.1210/endo-90-1-158. [DOI] [PubMed] [Google Scholar]
  22. Goodman R. L., Bittman E. L., Foster D. L., Karsch F. J. Alterations in the control of luteinizing hormone pulse frequency underlie the seasonal variation in estradiol negative feedback in the ewe. Biol Reprod. 1982 Oct;27(3):580–589. doi: 10.1095/biolreprod27.3.580. [DOI] [PubMed] [Google Scholar]
  23. Jakacki R. I., Kelch R. P., Sauder S. E., Lloyd J. S., Hopwood N. J., Marshall J. C. Pulsatile secretion of luteinizing hormone in children. J Clin Endocrinol Metab. 1982 Sep;55(3):453–458. doi: 10.1210/jcem-55-3-453. [DOI] [PubMed] [Google Scholar]
  24. Judd H. L., Parker D. C., Siler T. M., Yen S. S. The nocturnal rise of plasma testosterone in pubertal boys. J Clin Endocrinol Metab. 1974 Apr;38(4):710–713. doi: 10.1210/jcem-38-4-710. [DOI] [PubMed] [Google Scholar]
  25. Julius D. A. Research and development of naltrexone: a new narcotic antagonist. Am J Psychiatry. 1979 Jun;136(6):782–786. doi: 10.1176/ajp.136.6.782. [DOI] [PubMed] [Google Scholar]
  26. Katongole C. B., Naftolin F., Short R. V. Relationship between blood levels of luteinizing hormone and testosterone in bulls, and the effects of sexual stimulation. J Endocrinol. 1971 Jul;50(3):457–466. doi: 10.1677/joe.0.0500457. [DOI] [PubMed] [Google Scholar]
  27. Knobil E. The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res. 1980;36:53–88. doi: 10.1016/b978-0-12-571136-4.50008-5. [DOI] [PubMed] [Google Scholar]
  28. Levine J. E., Pau K. Y., Ramirez V. D., Jackson G. L. Simultaneous measurement of luteinizing hormone-releasing hormone and luteinizing hormone release in unanesthetized, ovariectomized sheep. Endocrinology. 1982 Nov;111(5):1449–1455. doi: 10.1210/endo-111-5-1449. [DOI] [PubMed] [Google Scholar]
  29. Levine J. E., Ramirez V. D. Luteinizing hormone-releasing hormone release during the rat estrous cycle and after ovariectomy, as estimated with push-pull cannulae. Endocrinology. 1982 Nov;111(5):1439–1448. doi: 10.1210/endo-111-5-1439. [DOI] [PubMed] [Google Scholar]
  30. Marut E. L., Williams R. F., Cowan B. D., Lynch A., Lerner S. P., Hodgen G. D. Pulsatile pituitary gonadotropin secretion during maturation of the dominant follicle in monkeys: estrogen positive feedback enhances the biological activity of LH. Endocrinology. 1981 Dec;109(6):2270–2272. doi: 10.1210/endo-109-6-2270. [DOI] [PubMed] [Google Scholar]
  31. McNeilly A. S., O'Connell M., Baird D. T. Induction of ovulation and normal luteal function by pulsed injections of luteinizing hormone in anestrous ewes. Endocrinology. 1982 Apr;110(4):1292–1299. doi: 10.1210/endo-110-4-1292. [DOI] [PubMed] [Google Scholar]
  32. Mendelson J. H., Ellingboe J., Kuehnle J. C., Mello N. K. Heroin and naltrexone effects on pituitary-gonadal hormones in man: interaction of steroid feedback effects, tolerance and supersensitivity. J Pharmacol Exp Ther. 1980 Sep;214(3):503–506. [PubMed] [Google Scholar]
  33. Midgley A. R., Jr, Jaffe R. B. Regulation of human gonadotropins. X. Episodic fluctuation of LH during the menstrual cycle. J Clin Endocrinol Metab. 1971 Dec;33(6):962–969. doi: 10.1210/jcem-33-6-962. [DOI] [PubMed] [Google Scholar]
  34. Naftolin F., Judd H. L., Yen S. S. Pulsatile patterns of gonadotropins and testosterone in man: the effects of clomiphene, with and without testosterone added. J Clin Endocrinol Metab. 1973 Feb;36(2):285–288. doi: 10.1210/jcem-36-2-285. [DOI] [PubMed] [Google Scholar]
  35. Naftolin F., Yen S. S., Perlman D., Tsai C. C., Parker D. C., Vargo T. Nocturnal patterns of serum gonadotropins during the menstrual cycle. J Clin Endocrinol Metab. 1973 Jul;37(1):6–10. doi: 10.1210/jcem-37-1-6. [DOI] [PubMed] [Google Scholar]
  36. Naftolin F., Yen S. S., Tsai C. C. Rapid cycling of plasma gonadotrophins in normal men as demonstrated by frequent sampling. Nat New Biol. 1972 Mar 22;236(64):92–93. doi: 10.1038/newbio236092a0. [DOI] [PubMed] [Google Scholar]
  37. Nankin H. R., Troen P. Repetitive luteinizing hormone elevations in serum of normal men. J Clin Endocrinol Metab. 1971 Sep;33(3):558–560. doi: 10.1210/jcem-33-3-558. [DOI] [PubMed] [Google Scholar]
  38. Naor Z., Katikineni M., Loumaye E., Vela A. G., Dufau M. L., Catt K. J. Compartmentalization of luteinizing hormone pools: dynamics of gonadotropin releasing hormone action in superfused pituitary cells. Mol Cell Endocrinol. 1982 Jul;27(2):213–220. doi: 10.1016/0303-7207(82)90110-1. [DOI] [PubMed] [Google Scholar]
  39. Odell W. D., Ross G. T., Rayford P. L. Radioimmunoassay for luteinizing hormone in human plasma or serum: physiological studies. J Clin Invest. 1967 Feb;46(2):248–255. doi: 10.1172/JCI105527. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Plant T. M. Time courses of concentrations of circulating gonadotropin, prolactin, testosterone, and cortisol in adult male rhesus monkeys (Macaca mulatta) throughout the 24 h light-dark cycle. Biol Reprod. 1981 Sep;25(2):244–252. doi: 10.1095/biolreprod25.2.244. [DOI] [PubMed] [Google Scholar]
  41. Reddy P. V., Menon K. M. Existence of multiple molecular forms of luteinizing hormone in rat: differences in immunological and biological activities between stored and circulating forms. Acta Endocrinol (Copenh) 1981 May;97(1):33–41. doi: 10.1530/acta.0.0970033. [DOI] [PubMed] [Google Scholar]
  42. Ropert J. F., Quigley M. E., Yen S. S. Endogenous opiates modulate pulsatile luteinizing hormone release in humans. J Clin Endocrinol Metab. 1981 Mar;52(3):583–585. doi: 10.1210/jcem-52-3-583. [DOI] [PubMed] [Google Scholar]
  43. Rowe P. H., Racey P. A., Lincoln G. A., Ellwood M., Lehane J., Shenton J. C. The temporal relationship between the secretion of luteinizing hormone and testosterone in man. J Endocrinol. 1975 Jan;64(1):17–26. [PubMed] [Google Scholar]
  44. Santen R. J., Bardin C. W. Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest. 1973 Oct;52(10):2617–2628. doi: 10.1172/JCI107454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Santen R. J., Bardin C. W. Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest. 1973 Oct;52(10):2617–2628. doi: 10.1172/JCI107454. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Solano A. R., Dufau M. L., Catt K. J. Bioassay and radioimmunoassay of serum luteinizing hormone in the male rat. Endocrinology. 1979 Aug;105(2):372–381. doi: 10.1210/endo-105-2-372. [DOI] [PubMed] [Google Scholar]
  47. Steiner R. A., Bremner W. J., Clifton D. K. Regulation of luteinizing hormone pulse frequency and amplitude by testosterone in the adult male rat. Endocrinology. 1982 Dec;111(6):2055–2061. doi: 10.1210/endo-111-6-2055. [DOI] [PubMed] [Google Scholar]
  48. Sylvester P. W., Van Vugt D. A., Aylsworth C. A., Hanson E. A., Meites J. Effects of morphine and naloxone on inhibition by ovarian hormones of pulsatile release of LH in ovariectomized rats. Neuroendocrinology. 1982 Apr;34(4):269–273. doi: 10.1159/000123311. [DOI] [PubMed] [Google Scholar]
  49. Tsuruhara T., Dufau M. L., Hickman J., Catt K. J. Biological properties of hCG after removal of terminal sialic acid and galactose residues. Endocrinology. 1972 Jul;91(1):296–301. doi: 10.1210/endo-91-1-296. [DOI] [PubMed] [Google Scholar]
  50. Verebey K., Volavka J., Mulé S. J., Resnick R. B. Naltrexone: disposition, metabolism, and effects after acute and chronic dosing. Clin Pharmacol Ther. 1976 Sep;20(3):315–328. doi: 10.1002/cpt1976203315. [DOI] [PubMed] [Google Scholar]
  51. Wilkes M. M., Yen S. S. Augmentation by naloxone of efflux of LRF from superfused medial basal hypothalamus. Life Sci. 1981 May 21;28(21):2355–2359. doi: 10.1016/0024-3205(81)90500-2. [DOI] [PubMed] [Google Scholar]
  52. Yen S. S., Tsai C. C., Naftolin F., Vandenberg G., Ajabor L. Pulsatile patterns of gonadotropin release in subjects with and without ovarian function. J Clin Endocrinol Metab. 1972 Apr;34(4):671–675. doi: 10.1210/jcem-34-4-671. [DOI] [PubMed] [Google Scholar]
  53. de la Torre B., Sjöberg B., Hedman M., Bártfai G., Diczfalusy E. A study of the short-time variation and interrelationship of plasma hormone levels reflecting pituitary, adrenocortical and testicular function in fertile men. Int J Androl. 1981 Oct;4(5):532–545. doi: 10.1111/j.1365-2605.1981.tb00736.x. [DOI] [PubMed] [Google Scholar]

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