0013.7227/92/1313-1005$03.00/0 Endocrinology Copyright 0 1992 by The Endocrine
Vol. 131, No. 3 Printed
Society
Remembrance: The Discovery of the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator of its Physiological Significance Shortly after a specific RIA for monkey LH became available in the late 196Os, we began to investigate the dynamics of its secretion in a variety of physiological and experimental circumstances. One such early study was designed to determine whether a circadian rhythm in the plasma levels of the peptide could be detected. To this end, hourly blood samples were obtained for 24 h from chronically ovariectomized monkeys restrained in primate chairs. We were surprised to find frequent, apparently random, and often large LH peaks during this period that were unrelated to the time of day or to perturbations in the environment (1). Similarly unstable LH concentrations had been reported previously in gonadectomized rats (2) sampled at l-h intervals or longer. Having thoroughly reassured ourselves that the instability of our hormone measurements in the monkey were not attributable to assay error, a major concern at the time, we proceeded to take a much closer look at this apparent secretory discontinuity by sampling blood every 10, 20, or 30 min. These experiments were performed in ovariectomized monkeys chronically fitted with indwelling cardiac catheters and restrained in primate chairs. The results were literally breathtaking. We observed strikingly large, rhythmic oscillations in plasma LH concentrations with a period of approximately 1 h, leading us to coin the term “circhoral” (about 1 h) to describe this phenomenon (3). The peptide levels rose from nadir to maximum in a single sampling period (10 or 20 min) and then declined exponentially at a rate approximating that of exogenous rhesus monkey LH for the remainder of the hour. These observations suggested that the oscillatory pattern of LH seen in the peripheral circulation must be the consequence of brief intermittent releases of LH from the pituitary gland, and that the “major portion of the elevated mean LH levels in ovariectomized animals can be accounted for by these pulsatile discharges” (3). More importantly, we concluded that a. . . these discharges may be due to intermittent signals from the central nervous system . . . which, in turn, result in an increased production of LH-releasing factor . . .” (3). We recently discovered that a group of French investigators, also studying the diurnal variations of plasma gonadoReceived February 27, 1992. ‘Remembrance” articles discuss people and events as remembered the author. The opinion(s) expressed are solely those of the writer do not reflect the view of the Journal or The Endocrine Society.
by and
in U.S.A.
and
tropin levels in men and women reported, in 1970, (4) an unambiguous rhythmic pulsatile LH pattern with a period of 3-4 h in some of their subjects and were led to the conclusion that this rhythm was of physiological rather than experimental origin. Unfortunately, these workers did not, to my knowledge, pursue their observations and their paper, published contemporaneously with ours in the rhesus monkey, remained unknown to us until now. In any case, these rhythmic pulsatile patterns of LH secretion were described soon thereafter in a large number of vertebrate species, their origin in the rhythmic discharge of GnRH into the pituitary portal circulation was confirmed, and the putative neuronal construct responsible for this phenomenon was localized to the region of the arcuate nucleus in the mediobasal hypothalamus (see Ref. 5 for review). But the striking rhythmic patterns of pulsatile LH secretion remained in the realm of pure phenomenology for some 8 yr after their discovery. The physiological significance of intermittent LH secretion did not become evident until attempts were made to restore gonadotropin secretion in rhesus monkeys in whom endogenous GnRH secretion was abolished by lesions in the mediobasal hypothalamus. Continuous infusion of GnRH into such animals, while initially stimulating LH release for a day or so, failed to sustain LH secretion, the gonadotropin returning to undetectable levels despite continued administration of the decapeptide (5). Replacement with intermittent GnRH administration, however, at the frequency of one pulse per hour (the physiological frequency of LH pulses) did restore continued secretion of LH and FSH to prelesion levels (6). Furthermore, shifting from pulsatile to continuous administration of GnRH led to a decline in gonadotropin levels to zero, the consequence of a desensitization of the gonadotropes (7). These and related findings in the rhesus monkey led to the conclusion that the intermittency of the GnRH signal, within a relatively narrow window of frequencies, is an obligatory component of the neuroendocrine control system that governs normal gonadotropin secretion. These fundamental physiological observations in a nonhuman primate were transferred with remarkable rapidity to the clinical arena in the treatment of infertility attributable to hypothalamic dysfunction and in the suppression of inappropriate gonadotropin secretion (e.g. precocious puberty).
1005
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 June 2015. at 09:00 For personal use only. No other uses without permission. . All rights reserved.
Ernst Knobil H. Wayne Hightower Professor in the Medical Sciences The University of Texas Medical School at Houston
References 1.
Endo. 1992 Voll31 l No 3
REMEMBRANCE
1006
Atkinson LE, Bhattacharya AN, Monroe SE, Dierschke DJ, Knobil E 1970 Effects of gonahectomy on plasma LH concentra&ons in the rhesus
monkev.
87:847-849 of the adult rat to orchidectomy and ovariectomy as determined by LH radioimmunoassay. Endocrinology 84:1359-1364
2. Gay VL, Midgley
Endocrinolonv
AR 1969 Resi;bnse
3. Dierschke
DJ, Bhattacharya
AN, Atkinson
Circhoral oscillations of plasma LH levels rhesus monkey. Endocrinology 87~850-853
LE, Knobil
E 1970
in the ovariectomized
4. Dolais I, Valleron
A-L Graoin A-M, Rosselin G 1970 Etude de l’horm&e luteinisante%uma~e (HLH) au cows du nycthemere. C R Acad Sci [III1 270:3123-3126 5. Knobil E 1486 The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53-88 6. Nakai Y, Plant TM, Hess DL, Keogh EJ, Knobil E 1978 On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. Endocrinology 102:1008-1009 7. Belchetz P, Plant TM, Nakai Y, Keogh EJ, Knobil E 1978 Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science 202:631-633
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 June 2015. at 09:00 For personal use only. No other uses without permission. . All rights reserved.
Vol. 131, No. 3 Printed
Society
Remembrance: The Discovery of the Hypothalamic Gonadotropin-Releasing Hormone Pulse Generator of its Physiological Significance Shortly after a specific RIA for monkey LH became available in the late 196Os, we began to investigate the dynamics of its secretion in a variety of physiological and experimental circumstances. One such early study was designed to determine whether a circadian rhythm in the plasma levels of the peptide could be detected. To this end, hourly blood samples were obtained for 24 h from chronically ovariectomized monkeys restrained in primate chairs. We were surprised to find frequent, apparently random, and often large LH peaks during this period that were unrelated to the time of day or to perturbations in the environment (1). Similarly unstable LH concentrations had been reported previously in gonadectomized rats (2) sampled at l-h intervals or longer. Having thoroughly reassured ourselves that the instability of our hormone measurements in the monkey were not attributable to assay error, a major concern at the time, we proceeded to take a much closer look at this apparent secretory discontinuity by sampling blood every 10, 20, or 30 min. These experiments were performed in ovariectomized monkeys chronically fitted with indwelling cardiac catheters and restrained in primate chairs. The results were literally breathtaking. We observed strikingly large, rhythmic oscillations in plasma LH concentrations with a period of approximately 1 h, leading us to coin the term “circhoral” (about 1 h) to describe this phenomenon (3). The peptide levels rose from nadir to maximum in a single sampling period (10 or 20 min) and then declined exponentially at a rate approximating that of exogenous rhesus monkey LH for the remainder of the hour. These observations suggested that the oscillatory pattern of LH seen in the peripheral circulation must be the consequence of brief intermittent releases of LH from the pituitary gland, and that the “major portion of the elevated mean LH levels in ovariectomized animals can be accounted for by these pulsatile discharges” (3). More importantly, we concluded that a. . . these discharges may be due to intermittent signals from the central nervous system . . . which, in turn, result in an increased production of LH-releasing factor . . .” (3). We recently discovered that a group of French investigators, also studying the diurnal variations of plasma gonadoReceived February 27, 1992. ‘Remembrance” articles discuss people and events as remembered the author. The opinion(s) expressed are solely those of the writer do not reflect the view of the Journal or The Endocrine Society.
by and
in U.S.A.
and
tropin levels in men and women reported, in 1970, (4) an unambiguous rhythmic pulsatile LH pattern with a period of 3-4 h in some of their subjects and were led to the conclusion that this rhythm was of physiological rather than experimental origin. Unfortunately, these workers did not, to my knowledge, pursue their observations and their paper, published contemporaneously with ours in the rhesus monkey, remained unknown to us until now. In any case, these rhythmic pulsatile patterns of LH secretion were described soon thereafter in a large number of vertebrate species, their origin in the rhythmic discharge of GnRH into the pituitary portal circulation was confirmed, and the putative neuronal construct responsible for this phenomenon was localized to the region of the arcuate nucleus in the mediobasal hypothalamus (see Ref. 5 for review). But the striking rhythmic patterns of pulsatile LH secretion remained in the realm of pure phenomenology for some 8 yr after their discovery. The physiological significance of intermittent LH secretion did not become evident until attempts were made to restore gonadotropin secretion in rhesus monkeys in whom endogenous GnRH secretion was abolished by lesions in the mediobasal hypothalamus. Continuous infusion of GnRH into such animals, while initially stimulating LH release for a day or so, failed to sustain LH secretion, the gonadotropin returning to undetectable levels despite continued administration of the decapeptide (5). Replacement with intermittent GnRH administration, however, at the frequency of one pulse per hour (the physiological frequency of LH pulses) did restore continued secretion of LH and FSH to prelesion levels (6). Furthermore, shifting from pulsatile to continuous administration of GnRH led to a decline in gonadotropin levels to zero, the consequence of a desensitization of the gonadotropes (7). These and related findings in the rhesus monkey led to the conclusion that the intermittency of the GnRH signal, within a relatively narrow window of frequencies, is an obligatory component of the neuroendocrine control system that governs normal gonadotropin secretion. These fundamental physiological observations in a nonhuman primate were transferred with remarkable rapidity to the clinical arena in the treatment of infertility attributable to hypothalamic dysfunction and in the suppression of inappropriate gonadotropin secretion (e.g. precocious puberty).
1005
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 June 2015. at 09:00 For personal use only. No other uses without permission. . All rights reserved.
Ernst Knobil H. Wayne Hightower Professor in the Medical Sciences The University of Texas Medical School at Houston
References 1.
Endo. 1992 Voll31 l No 3
REMEMBRANCE
1006
Atkinson LE, Bhattacharya AN, Monroe SE, Dierschke DJ, Knobil E 1970 Effects of gonahectomy on plasma LH concentra&ons in the rhesus
monkev.
87:847-849 of the adult rat to orchidectomy and ovariectomy as determined by LH radioimmunoassay. Endocrinology 84:1359-1364
2. Gay VL, Midgley
Endocrinolonv
AR 1969 Resi;bnse
3. Dierschke
DJ, Bhattacharya
AN, Atkinson
Circhoral oscillations of plasma LH levels rhesus monkey. Endocrinology 87~850-853
LE, Knobil
E 1970
in the ovariectomized
4. Dolais I, Valleron
A-L Graoin A-M, Rosselin G 1970 Etude de l’horm&e luteinisante%uma~e (HLH) au cows du nycthemere. C R Acad Sci [III1 270:3123-3126 5. Knobil E 1486 The neuroendocrine control of the menstrual cycle. Recent Prog Horm Res 36:53-88 6. Nakai Y, Plant TM, Hess DL, Keogh EJ, Knobil E 1978 On the sites of the negative and positive feedback actions of estradiol in the control of gonadotropin secretion in the rhesus monkey. Endocrinology 102:1008-1009 7. Belchetz P, Plant TM, Nakai Y, Keogh EJ, Knobil E 1978 Hypophysial responses to continuous and intermittent delivery of hypothalamic gonadotropin releasing hormone. Science 202:631-633
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 June 2015. at 09:00 For personal use only. No other uses without permission. . All rights reserved.
