Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 Jun;81(6):1725–1733. doi: 10.1172/JCI113512

Effects of decreasing the frequency of gonadotropin-releasing hormone stimulation on gonadotropin secretion in gonadotropin-releasing hormone-deficient men and perifused rat pituitary cells.

J S Finkelstein 1, T M Badger 1, L S O'Dea 1, D I Spratt 1, W F Crowley 1
PMCID: PMC442617  PMID: 3290251

Abstract

The effects of decreasing the frequency of pulsatile gonadotropin-releasing hormone (GnRH) stimulation on pituitary responsiveness were studied in (a) men with isolated GnRH deficiency who had achieved normal sex steroid levels during prior long-term pulsatile GnRH replacement and (b) perifused dispersed pituitary cells from male rats in the absence of sex steroids. In three groups of four GnRH-deficient men, the frequency of GnRH stimulation was decreased at weekly intervals from (a) every 2-3-4 h (group I), (b) every 2-8 h without testosterone replacement (group II), or (c) every 2-8 h with testosterone replacement (group III). In three groups of three columns of perifused dispersed pituitary cells, pulses of GnRH were administered every 2, 4, or 8 h. In groups I and II, mean area under the luteinizing hormone (LH) curve increased (P less than 0.025) and serum testosterone levels fell (P less than 0.035) as the frequency of GnRH stimulation was decreased. In group III, the area under the LH curve also increased (P less than 0.01) although serum testosterone levels were constant, thereby demonstrating that the increase in pituitary responsiveness to slow frequencies of GnRH stimulation occurs independently of changes in the sex steroid hormonal milieu. The area under the LH curve also increased in the perifused dispersed rat pituitary cells when the frequency of GnRH administration was decreased to every 8 h (P less than 0.05), thus demonstrating that the enhanced pituitary responsiveness to slow frequencies of GnRH stimulation is maintained even in the complete absence of gonadal steroids. Nadir LH levels fell in all three groups (P less than 0.01) as the frequency of GnRH stimulation was decreased. In contrast, mean peak LH levels, the rate of LH rise, and the rate of endogenous LH decay were constant as the frequency of GnRH stimulation was decreased. Finally, as the GnRH interpulse interval increased, mean LH levels fell, and mean follicle-stimulating hormone levels were stable or fell. These results indicate that (a) pituitary responsiveness to GnRH increases at slower frequencies of GnRH stimulation in models both in vivo and in vitro, (b) these changes in pituitary responsiveness occur independently of changes in gonadal steroid secretion, and (c) the increases in LH pulse amplitude and area under the curve at slow frequencies of GnRH stimulation are due to decreases in nadir, but not peak, LH levels. Slowing of the frequency of GnRH secretion may be an important independent variable in the control of pituitary gonadotropin secretion.

Full text

PDF
1725

Images in this article

1728Image
on p.1728
1728Image
on p.1728
1728Image
on p.1728
1728Image
on p.1728
1728Image
on p.1728
1728Image
on p.1728

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Badger T. M. Perifusion of anterior pituitary cells: release of gonadotropins and somatotropins. Methods Enzymol. 1986;124:79–90. doi: 10.1016/0076-6879(86)24010-0. [DOI] [PubMed] [Google Scholar]
  2. Belchetz P. E., Plant T. M., Nakai Y., Keogh E. J., Knobil E. Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Science. 1978 Nov 10;202(4368):631–633. doi: 10.1126/science.100883. [DOI] [PubMed] [Google Scholar]
  3. Clarke I. J., Cummins J. T., Findlay J. K., Burman K. J., Doughton B. W. Effects on plasma luteinizing hormone and follicle-stimulating hormone of varying the frequency and amplitude of gonadotropin-releasing hormone pulses in ovariectomized ewes with hypothalamo-pituitary disconnection. Neuroendocrinology. 1984 Sep;39(3):214–221. doi: 10.1159/000123982. [DOI] [PubMed] [Google Scholar]
  4. Clarke I. J., Cummins J. T. GnRH pulse frequency determines LH pulse amplitude by altering the amount of releasable LH in the pituitary glands of ewes. J Reprod Fertil. 1985 Mar;73(2):425–431. doi: 10.1530/jrf.0.0730425. [DOI] [PubMed] [Google Scholar]
  5. Crowley W. F., Jr, Comite F., Vale W., Rivier J., Loriaux D. L., Cutler G. B., Jr Therapeutic use of pituitary desensitization with a long-acting lhrh agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab. 1981 Feb;52(2):370–372. doi: 10.1210/jcem-52-2-370. [DOI] [PubMed] [Google Scholar]
  6. Crowley W. F., Jr, Filicori M., Spratt D. I., Santoro N. F. The physiology of gonadotropin-releasing hormone (GnRH) secretion in men and women. Recent Prog Horm Res. 1985;41:473–531. doi: 10.1016/b978-0-12-571141-8.50015-9. [DOI] [PubMed] [Google Scholar]
  7. Crowley W. F., Jr, McArthur J. W. Simulation of the normal menstrual cycle in Kallman's syndrome by pulsatile administration of luteinizing hormone-releasing hormone (LHRH). J Clin Endocrinol Metab. 1980 Jul;51(1):173–175. doi: 10.1210/jcem-51-1-173. [DOI] [PubMed] [Google Scholar]
  8. Filicori M., Butler J. P., Crowley W. F., Jr Neuroendocrine regulation of the corpus luteum in the human. Evidence for pulsatile progesterone secretion. J Clin Invest. 1984 Jun;73(6):1638–1647. doi: 10.1172/JCI111370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gross K. M., Matsumoto A. M., Bremner W. J. Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man. J Clin Endocrinol Metab. 1987 Apr;64(4):675–680. doi: 10.1210/jcem-64-4-675. [DOI] [PubMed] [Google Scholar]
  10. Hoffman A. R., Crowley W. F., Jr Induction of puberty in men by long-term pulsatile administration of low-dose gonadotropin-releasing hormone. N Engl J Med. 1982 Nov 11;307(20):1237–1241. doi: 10.1056/NEJM198211113072003. [DOI] [PubMed] [Google Scholar]
  11. Kamel F., Balz J. A., Kubajak C. L., Schneider V. A. Effects of luteinizing hormone (LH)-releasing hormone pulse amplitude and frequency on LH secretion by perifused rat anterior pituitary cells. Endocrinology. 1987 Apr;120(4):1644–1650. doi: 10.1210/endo-120-4-1644. [DOI] [PubMed] [Google Scholar]
  12. Katt J. A., Duncan J. A., Herbon L., Barkan A., Marshall J. C. The frequency of gonadotropin-releasing hormone stimulation determines the number of pituitary gonadotropin-releasing hormone receptors. Endocrinology. 1985 May;116(5):2113–2115. doi: 10.1210/endo-116-5-2113. [DOI] [PubMed] [Google Scholar]
  13. Lasley B. L., Wang C. F., Yen S. S. Assessments of the functional capacity of the gonadotrophs in men: effects of estrogen and clomiphene. J Clin Endocrinol Metab. 1976 Jul;43(1):182–189. doi: 10.1210/jcem-43-1-182. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Liu T. C., Jackson G. L. Long term superfusion of rat anterior pituitary cells: effects of repeated pulses of gonadotropin-releasing hormone at different doses, durations, and frequencies. Endocrinology. 1984 Aug;115(2):605–613. doi: 10.1210/endo-115-2-605. [DOI] [PubMed] [Google Scholar]
  16. McIntosh J. E., McIntosh R. P. Varying the patterns and concentrations of gonadotrophin-releasing hormone stimulation does not alter the ratio of LH and FSH released from perifused sheep pituitary cells. J Endocrinol. 1986 May;109(2):155–161. doi: 10.1677/joe.0.1090155. [DOI] [PubMed] [Google Scholar]
  17. McIntosh R. P., McIntosh J. E. Influence of the characteristics of pulses of gonadotrophin releasing hormone on the dynamics of luteinizing hormone release from perifused sheep pituitary cells. J Endocrinol. 1983 Sep;98(3):411–421. doi: 10.1677/joe.0.0980411. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Narasimha Rao P., Moore P. H., Jr Synthesis of new steroid haptens for radioimmunoassay. Part I. 15beta-Carboxyethylmercaptotestosterone-bovine serum albumin conjugate. Measurement of testosterone in male plasma without chromatography. Steroids. 1976 Jul;28(1):101–109. doi: 10.1016/0039-128x(76)90129-x. [DOI] [PubMed] [Google Scholar]
  20. Plant T. M., Dubey A. K. Evidence from the rhesus monkey (Macaca mulatta) for the view that negative feedback control of luteinizing hormone secretion by the testis is mediated by a deceleration of hypothalamic gonadotropin-releasing hormone pulse frequency. Endocrinology. 1984 Dec;115(6):2145–2153. doi: 10.1210/endo-115-6-2145. [DOI] [PubMed] [Google Scholar]
  21. Pohl C. R., Richardson D. W., Hutchison J. S., Germak J. A., Knobil E. Hypophysiotropic signal frequency and the functioning of the pituitary-ovarian system in the rhesus monkey. Endocrinology. 1983 Jun;112(6):2076–2080. doi: 10.1210/endo-112-6-2076. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Santen R. J. Is aromatization of testosterone to estradiol required for inhibition of luteinizing hormone secretion in men? J Clin Invest. 1975 Dec;56(6):1555–1563. doi: 10.1172/JCI108237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Soules M. R., Steiner R. A., Clifton D. K., Cohen N. L., Aksel S., Bremner W. J. Progesterone modulation of pulsatile luteinizing hormone secretion in normal women. J Clin Endocrinol Metab. 1984 Feb;58(2):378–383. doi: 10.1210/jcem-58-2-378. [DOI] [PubMed] [Google Scholar]
  25. Spratt D. I., Carr D. B., Merriam G. R., Scully R. E., Rao P. N., Crowley W. F., Jr The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations. J Clin Endocrinol Metab. 1987 Feb;64(2):283–291. doi: 10.1210/jcem-64-2-283. [DOI] [PubMed] [Google Scholar]
  26. Spratt D. I., Crowley W. F., Jr, Butler J. P., Hoffman A. R., Conn P. M., Badger T. M. Pituitary luteinizing hormone responses to intravenous and subcutaneous administration of gonadotropin-releasing hormone in men. J Clin Endocrinol Metab. 1985 Nov;61(5):890–895. doi: 10.1210/jcem-61-5-890. [DOI] [PubMed] [Google Scholar]
  27. Spratt D. I., Crowley W. F., Jr Pituitary and gonadal responsiveness is enhanced during GnRH-induced puberty. Am J Physiol. 1988 May;254(5 Pt 1):E652–E657. doi: 10.1152/ajpendo.1988.254.5.E652. [DOI] [PubMed] [Google Scholar]
  28. Spratt D. I., Finkelstein J. S., Badger T. M., Butler J. P., Crowley W. F., Jr Bio- and immunoactive luteinizing hormone responses to low doses of gonadotropin-releasing hormone (GnRH): dose-response curves in GnRH-deficient men. J Clin Endocrinol Metab. 1986 Jul;63(1):143–150. doi: 10.1210/jcem-63-1-143. [DOI] [PubMed] [Google Scholar]
  29. Spratt D. I., Finkelstein J. S., Butler J. P., Badger T. M., Crowley W. F., Jr Effects of increasing the frequency of low doses of gonadotropin-releasing hormone (GnRH) on gonadotropin secretion in GnRH-deficient men. J Clin Endocrinol Metab. 1987 Jun;64(6):1179–1186. doi: 10.1210/jcem-64-6-1179. [DOI] [PubMed] [Google Scholar]
  30. Spratt D. I., Finkelstein J. S., O'Dea L. S., Badger T. M., Rao P. N., Campbell J. D., Crowley W. F., Jr Long-term administration of gonadotropin-releasing hormone in men with idiopathic hypogonadotropic hypogonadism. A model for studies of the hormone's physiologic effects. Ann Intern Med. 1986 Dec;105(6):848–855. doi: 10.7326/0003-4819-105-6-848. [DOI] [PubMed] [Google Scholar]
  31. Spratt D. I., O'Dea L. S., Schoenfeld D., Butler J., Rao P. N., Crowley W. F., Jr Neuroendocrine-gonadal axis in men: frequent sampling of LH, FSH, and testosterone. Am J Physiol. 1988 May;254(5 Pt 1):E658–E666. doi: 10.1152/ajpendo.1988.254.5.E658. [DOI] [PubMed] [Google Scholar]
  32. Valk T. W., Corley K. P., Kelch R. P., Marshall J. C. Hypogonadotropic hypogonadism: hormonal responses to low dose pulsatile administration of gonadotropin-releasing hormone. J Clin Endocrinol Metab. 1980 Oct;51(4):730–738. doi: 10.1210/jcem-51-4-730. [DOI] [PubMed] [Google Scholar]
  33. Valk T. W., Corley K. P., Kelch R. P., Marshall J. C. Pulsatile gonadotropin-releasing hormone in gonadotropin deficient and normal men: suppression of follicle-stimulating hormone responses by testosterone. J Clin Endocrinol Metab. 1981 Jul;53(1):184–191. doi: 10.1210/jcem-53-1-184. [DOI] [PubMed] [Google Scholar]
  34. Veldhuis J. D., Rogol A. D., Samojlik E., Ertel N. H. Role of endogenous opiates in the expression of negative feedback actions of androgen and estrogen on pulsatile properties of luteinizing hormone secretion in man. J Clin Invest. 1984 Jul;74(1):47–55. doi: 10.1172/JCI111417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wehmann R. E., Blackman M. R., Harman S. M. Metabolic clearance rates of luteinizing hormone in women during different phases of the menstrual cycle and while taking an oral contraceptive. J Clin Endocrinol Metab. 1982 Oct;55(4):654–659. doi: 10.1210/jcem-55-4-654. [DOI] [PubMed] [Google Scholar]
  36. Wildt L., Häusler A., Marshall G., Hutchison J. S., Plant T. M., Belchetz P. E., Knobil E. Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Endocrinology. 1981 Aug;109(2):376–385. doi: 10.1210/endo-109-2-376. [DOI] [PubMed] [Google Scholar]
  37. Winters S. J., Janick J. J., Loriaux D. L., Sherins R. J. Studies on the role of sex steroids in the feedback control of gonadotropin concentrations in men. II. Use of the estrogen antagonist, clomiphene citrate. J Clin Endocrinol Metab. 1979 Feb;48(2):222–227. doi: 10.1210/jcem-48-2-222. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES