![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Departments of Psychiatry, Pharmacology and Neuroscience and UPMC Center for Nutrition, University of Pittsburgh School of Medicine, Pittsburgh PA 15213
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONREFERENCES |
|---|
KEY WORDS: • glutamic acid • anterior pituitary • prolactin • plasma • humans
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
). A substantial
amount of GLU is ingested each day, principally as a component of
dietary protein; a small amount is also present in food as free
glutamate and monosodium glutamate (MSG, which occurs naturally in some
foods and is added to others as a flavor enhancer). Thirty years ago, a
link was forged between dietary MSG and brain function through the
report that the repeated injection of very large doses of the amino
acid into neonatal rodents could produce visible brain damage, notably
in the hypothalamus (Olney 1969
). This latter effect
reputedly follows from GLU penetration into the median eminence, a
hypothalamic area lacking a blood-brain barrier; from there, it
gains access to adjacent hypothalamic structures, notably the arcuate
nucleus (Hawkins et al. 1995
, Perez and Olney 1972
, Price et al. 1981
). Arcuate neurons
bearing GLU receptors thus become exposed to high local GLU
concentrations; as a result, they are subjected to excessive excitation
(because GLU is an excitatory neurotransmitter). Such excitation is
postulated to produce metabolic and functional exhaustion of the
affected neurons, and subsequently neuronal death (Olney 1994
). If the injection of very high doses of GLU (or MSG)
could result in its penetration into the arcuate hypothalamus, where it
could damage neurons, it was reasoned that perhaps lower,
non-neurotoxic doses could also penetrate sufficiently to
induce smaller, though physiologically undesirable effects without
damaging neurons (Olney et al. 1976
). In support of this
notion, Olney and colleagues injected 1000 mg/kg MSG into young adult
rats (defined as a subneurotoxic dose by the investigators, but
nonetheless an extremely high dose) and reported stimulation of
luteinizing hormone (LH) and testosterone secretion into blood
(Olney et al. 1976
). They argued that the release of LH
demonstrated that glutamate had indeed penetrated into neuroendocrine
portions of the hypothalamus and had stimulated neurons governing LH
secretion (via gonadotropin releasing hormone, GnRH, a hypothalamic
peptide that stimulates pituitary LH secretion). Some years later,
Terry et al. (1981)
observed in rats that the same MSG
dose caused the immediate release of prolactin, and inhibited growth
hormone (GH) secretion over a several hour period. These effects were
also attributed to the penetration of stimulatory amounts of GLU into
neuroendocrine areas of the hypothalamus (Terry et al. 1981
).
Rodent studies such as these have led to the notion that humans might
experience similar neuroendocrine sequelae when they ingest MSG in
foods. However, few data exist that examine this possibility, in human
or nonhuman primates. In nonhuman primates, for example,
Medhamurthy et al. (1990)
reported in castrated,
prepubertal male monkeys that the intravenous infusion of 150 mg/kg GLU
(but not 48 mg/kg) produced a robust burst of LH secretion. A later
study confirmed this finding and was associated with peak plasma GLU
concentrations ~50-fold above normal plasma concentrations (the
plasma GLU concentrations reported in this study were measured in our
laboratory) (Medhamurthy et al. 1992
). Further, repeated
GLU administration at 3-h intervals was associated with progressively
diminishing LH responses. This effect was not attributable
to a neurotoxic action of GLU, however, because the administration of a
potent GLU agonist, N-methyl-D-aspartate
(NMDA), after the last GLU infusion produced an immediate,
robust increase in plasma LH concentrations [this action of NMDA was
already known to occur in monkeys after a single injection (Gay and Plant 1987
, Wilson and Knobil 1982
)].
Additional support for the absence of an immediate neurotoxic action of
GLU was the finding that growth hormone (GH) secretion rose in these
animals after GLU infusion, but the effect did not
diminish with repeated GLU administration. These findings are
noteworthy, first, in that the release of LH and GH was observed only
at a dose of GLU that is extreme (150 mg/kg
intravenously, which produced a 50-fold rise in plasma GLU), and,
second, no functional toxicity was evident.
In humans, the only available study was that of Carlson et al. (1989)
, which examined the effects of a high oral dose of GLU
on the secretion of anterior pituitary hormones. These investigators
used an oral dose of glutamic acid (10 g, ~150 mg/kg), administered
in 0.7 L of saline. This dose of GLU, given as a single load, is
extremely large, approximating the amount of GLU a human would ingest
over an entire day as a component of 100 g of dietary protein. In
response to this treatment, plasma GLU rose 500 nmol/mL over baseline
values, a 5- to 10-fold increment over typical values. An increase of
this magnitude is extremely large. Notwithstanding, no changes were
observed in the plasma concentrations of LH, GH or
thyroid-stimulating hormone (TSH) over the succeeding 2.5-h period.
However, increments in plasma prolactin and cortisol [an index of
adrenocorticotropic hormone (ACTH) secretion] were noted. The increase
in prolactin secretion produced by GLU ingestion is compatible with
findings in male and nonlactating female rats administered a single,
high dose of MSG (Terry et al. 1981
) or of NMDA, a
direct acting GLU receptor agonist (Brann 1995
,
Pohl et al. 1989
), and in monkeys that received an
intravenous injection of NMDA (Arslan et al. 1991
,
Gay and Plant 1987
, Wilson and Knobil 1982
). The plasma cortisol finding is similarly compatible with
earlier findings after NMDA administration in both rats (Brann 1995
) and monkeys (Gay and Plant 1987
,
Reyes et al. 1990
). However, plasma prolactin and
cortisol concentrations might also have risen in response to stress
[plasma prolactin, like cortisol, rises in humans subjected to stress
(Herbert et al. 1986
)] because the rapid ingestion of a
large volume of a sour, salty solution (glutamic acid is sour in
solution) might be viewed as somewhat stressful. In addition, the study
offered no positive controls, pharmacologic or physiologic, against
which to measure the potency of the GLU effects on prolactin and
cortisol.
Because only a single human study existed, which reported
positive effects of GLU and offered no positive comparisons with which
to place a GLU effect in context, we undertook a further study in
humans to examine this phenomenon in greater detail (Fernstrom et al. 1996
). We chose prolactin as the primary outcome
measure, because both physiologic and pharmacologic positive control
treatments had been described previously for this hormone, and these
could serve as a basis for comparing any observed effects of MSG
treatment. The study involved eight men, who received oral MSG in the
morning after an overnight fast. They were fitted with an indwelling
venous line before treatment; samples were obtained at 20-min intervals
for 4 h. The overall design sought to minimize nonspecific stress.
Four treatments were studied, on separate days as follows (with at
least two nontreatment days intervening between each test day):
1) MSG, 12.7 g, dissolved in a noncaloric beverage
that tasted like a grapefruit-flavored sport drink;
2) vehicle, the same grapefruit-flavored beverage
containing 3 g sodium chloride (to approximate the saltiness of
the MSG beverage); 3) TRH (100 µg, intravenously); and
4) a palatable, high protein meal containing 643 kcal
(2691 kJ), 90 g protein, 18 g fat, and 25 g
carbohydrates [see Fernstrom et al. (1996)
]. MSG was
studied because it is consumed as the free amino acid in the diet and
does not have a sour taste. The MSG beverage was selected to mask the
savory MSG taste; subjects did not distinguish the MSG-containing
solution from the placebo solution (both had a salty taste, and were
administered on separate days), and did not find them unpleasant to
drink. The protein meal was administered as the
physiologic positive control for prolactin secretion,
i.e., its ingestion is reported to cause a small, but significant
increase in prolactin secretion in humans (Carlson et al. 1983
, Ishizuka et al. 1983
). A TRH challenge
test, which causes an immediate and substantial rise in plasma
prolactin concentrations (Rubin et al. 1989
), was
included as the pharmacologic stimulus of prolactin
secretion. If MSG ingestion produced an increase in plasma prolactin,
these two positive controls would allow us to scale the response
relative to known physiologic and pharmacologic stimuli. In addition to
measuring prolactin concentrations in plasma, we also measured the
concentrations of several other pituitary hormones (LH, FSH, GH, TSH),
cortisol and GLU.
Fasting plasma GLU concentrations were ~50 nmol/mL, and rose 11-fold
within 60 min of ingesting the MSG-containing solution (Fig. 1A
). On the placebo-treatment day, plasma GLU did not vary appreciably
from 50 nmol/mL. In addition, ingestion of the protein meal, which
contained 90 g protein (8–9 g glutamate), elicited no significant
rise in plasma GLU concentrations (Fig. 1B
). The
absolute increase in plasma GLU after MSG ingestion was comparable to
that observed in the study of Carlson et al. (1989)
. As
expected (Rubin et al. 1989
), TRH administration
produced an immediate and substantial rise in plasma prolactin
concentrations (Fig. 2
). The protein meal also produced a significant rise in plasma
prolactin, although the magnitude was much smaller, about twofold above
baseline (or placebo). This response to a protein meal is very similar
in magnitude to that reported previously by others (Carlson et al. 1983
, Ishizuka et al. 1983
). The MSG
solution produced a very small mean rise in plasma prolactin that
failed to reach significance (Fig. 2)
. In addition, at no time after
MSG ingestion did mean plasma prolactin concentrations rise above the
level associated with the ingestion of the protein meal. As was
observed in the Carlson study (Carlson et al. 1989
), the
plasma concentrations of LH and FSH were unaffected by MSG ingestion
(Fig. 3
). Plasma levels of GH, TSH and cortisol were also unchanged by this
treatment (Fernstrom et al. 1996
).
|
|
|
in some respects, in that they found no alterations in
the plasma concentrations of GH, TSH and LH. They differ in that we
also found no change in plasma prolactin or cortisol. Unlike the
Carlson study, we compared the MSG response in the same subjects to
that of treatments known to stimulate prolactin secretion, i.e., a
pharmacologic stimulus, TRH, which induced a very large rise in
prolactin, and a physiologic stimulus, a high protein meal, which
caused a relatively modest (but significant) prolactin increase. The
MSG response was below that of the protein meal and was not
significant. The power of our study was clearly adequate because it
revealed a significant response to protein, an effect that was of the
same magnitude as that reported previously by Carlson et al. (1989)
for GLU administration and for protein ingestion
(Carlson et al. 1983
). The only notable differences in
the study were the form in which GLU was administered and the subjects
employed. Carlson employed both men and women, whereas we examined male
subjects only. However, the sex difference probably does not explain
the difference in prolactin outcome, because they reported that men and
women responded alike to each treatment. The remaining possibility is
the difference in treatment. A solution of glutamic acid would have a
sour taste and, given the volume of 0.7 L that had to be ingested,
might constitute a significant stress to the subjects, thereby inducing
both prolactin (Cooke 1989
) and cortisol (Herbert et al. 1986
, Rose 1985
) secretion. The only
drawback to this possibility, however, is that in humans, stress also
induces GH secretion (Rose 1985
), an effect not observed
after GLU ingestion in the Carlson study. This difference thus remains
unexplained.
As noted above, the administration of excitatory amino acids (at
very high doses) or their more active analogs has been reported
previously in monkeys to stimulate the secretion of one or more
pituitary hormones [prolactin, GH, ACTH (cortisol), and LH and/or FSH:
(Arslan et al. 1991
, Gay and Plant 1987
,
Medhamurthy et al. 1990
and 1992
, Reyes et al. 1990
, Urbanski et al. 1997
, Wilson and Knobil 1982
)]. Typically, these effects are attributed to
actions of these agents within the brain (hypothalamus). If GLU must
cross the blood-brain barrier to exert such effects, the present
results in humans suggest that at the high dose tested (150 mg/kg), MSG
ingestion must not have elevated plasma GLU concentrations sufficiently
to promote GLU entry into brain in neurochemically meaningful amounts
(because no effects were observed). Alternatively, if circulating GLU
can gain access to hypothalamic regions outside the
blood-brain barrier (portions of the mediobasal hypothalamus and
the median eminence) to stimulate neuroendocrine function [a
possibility suggested by Olney (1994)
], the absence of
effects in this study indicates either that the relevant GLU receptors
in these exposed areas are not sensitive to the very high circulating
GLU concentrations produced by MSG ingestion (~0.55 mmol/L), or that
GLU reuptake mechanisms in the neurons and glial cells in these
hypothalamic areas are extremely efficient in keeping synaptic GLU
concentrations low in the face of a large influx of circulating GLU.
Regardless of the mechanism, the absence of pituitary effects indicates
that even extremely high circulating GLU concentrations are exerting no
appreciable effects within hypothalamus, at least in relation to the
neuroendocrine axis controlling anterior pituitary function. Further,
if GLU receptors exist on anterior pituitary cells, as some now suggest
from studies in nonprimates, and GLU receptor agonists can stimulate
the release of pituitary hormones by a direct action on these cells
(Barb et al. 1993
, Lindstrom and Ohlsson 1992
, Login 1990
, Niimi et al. 1994
; Zanisi et al. 1994
), our results indicate
that even at the very high circulating GLU concentrations produced by
MSG ingestion, no stimulation of pituitary hormone
secretion occurred. Hence, if such peripheral GLU receptors exist, they
appear to be relatively insensitive to circulating GLU concentrations.
[It should be borne in mind that not all investigators agree that GLU
agonists can stimulate pituitary hormone release via direct pituitary
sites, particularly in primates (Gay and Plant 1987
,
Tal et al. 1983
).]
In conclusion, a growing body of evidence indicates that neurons
utilizing excitatory amino acids as neurotransmitters participate in
hypothalamic function, particularly in the control of pituitary hormone
secretion (Brann 1995
, van den Pol et al. 1990
). In this context, data in animals indicate that
stimulating GLU receptors promotes the secretion of pituitary hormones,
an effect most commonly observed after the administration of potent GLU
receptor agonists, but also after the administration of GLU itself.
This latter finding has led to the suggestion that the GLU ingested in
the human diet (as MSG, but presumably also in other forms, such as
protein-bound GLU and free GLU) might also produce such effects,
possibly leading to neuroendocrine (i.e., hypothalamic-pituitary)
dysfunction in humans (Olney 1994
). Our recent findings
in humans, however, revealing that an extremely large dose of MSG does
not induce the secretion of pituitary hormones, suggest that this
concern is unwarranted.
|
FOOTNOTES |
|---|
2 Supported by grants from the National Institutes
of Health (HD24730) and the International Glutamate Technical
Committee.
3 Abbreviations used: ACTH, adrenocorticotropic
hormone; FSH, follicle-stimulating hormone; GH, growth hormone;
GLU, glutamic acid; GnRH, gonadotropin-releasing hormone; LH,
luteinizing hormone; MSG, monosodium glutamate; NMDA,
N-methyl-D-aspartate; TRH,
thyrotropin-releasing hormone; TSH, thyroid-stimulating
hormone.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONREFERENCES |
|---|
1. Arslan M., Rizvi S.S.R., Jahan S., Zaidi P., Shahab M. Possible modulation of N-methyl-D,L-aspartic acid induced prolactin release by testicular steroids in the adult male rhesus monkey. Life Sci 1991;49:1073-1077[Medline]
2. Barb C. R., Barrett J. B., Rampacek G. B., Kraeling R. R. N-Methyl-d,l-aspartate modulation of luteinizing hormone and growth hormone secretion from pig pituitary cells in culture. Life Sci 1993;53:1157-1164[Medline]
3. Brann D. W. Glutamate: a major excitatory transmitter in neuroendocrine regulation. Neuroendocrinology 1995;61:213-225[Medline]
4. Carlson H. E., Miglietta J. T., Roginsky M. S., Stegink L. D. Stimulation of pituitary hormone secretion by neurotransmitter amino acids in humans. Metabolism 1989;38:1179-1182[Medline]
5. Carlson H. E., Wasser H. L., Levin S. R., Wilkins J. N. Prolactin stimulation by meals is related to protein content. J. Clin. Endocrinol. Metab. 1983;57:334-338[Abstract]
6. Cooke N. E. Prolactin: normal synthesis, regulation, and actions. DeGroot L. J. eds. Endocrinology 1989:384-407 W. B. Saunders Philadelphia, PA.
7. Fernstrom J. D., Cameron J. L., Fernstrom M. H., McConaha C., Weltzin T. E., Kaye W. H. Short-term neuroendocrine effects of a large oral dose of monosodium glutamate in fasting male subjects. J. Clin. Endocrinol. Metab. 1996;81:184-191[Abstract]
8. Fonnum F. Glutamate: a neurotransmitter in mammalian brain. J. Neurochem. 1984;42:1-11[Medline]
9. Gay V. L., Plant T. M. N-Methyl-D,L-aspartate elicits hypothalamic gonadotropin-releasing hormone release in prepubertal male rhesus monkeys (Macaca mulatta). Endocrinology 1987;120:2289-2296[Abstract]
10. Hawkins R. A., DeJoseph M. R., Hawkins P. A. Regional brain glutamate transport in rats at normal and raised concentrations of circulating glutamate. Cell Tissue Res 1995;281:207-214[Medline]
11. Herbert J., Moore G. F., de la Riva C., Watts F. N. Endocrine responses and examination anxiety. Biol. Psychol. 1986;22:215-226[Medline]
12. Ishizuka B., Quigley M. E., Yen S. S. Pituitary hormone release in response to food ingestion: evidence for neuroendocrine signals from gut to brain. J. Clin. Endocrinol. Metab. 1983;57:1111-1116[Abstract]
13. Lindstrom P., Ohlsson L. Effect of N-methyl-d,l-aspartate on isolated rat somatotrophs. Endocrinology 1992;131:1903-1907[Abstract]
14. Login I. S. Direct stimulation of pituitary prolactin release by glutamate. Life Sci 1990;47:2269-2275[Medline]
15. Medhamurthy R., Dichek H. L., Plant T. M., Bernardini I., Cutler G. B. Stimulation of gonadotropin secretion in prepubertal monkeys after hypothalamic excitation with aspartate and glutamate. J. Clin. Endocrinol. Metab. 1990;71:1390-1392[Abstract]
16. Medhamurthy R., Gay V. L., Plant T. M. Repetitive injections of L-glutamic acid, in contrast to those of N-methyl-d,l-aspartic acid, fail to elicit sustained hypothalamic GnRH release in the prepubertal male rhesus monkey (Macaca mulatta). Neuroendocrinology 1992;55:660-666[Medline]
17. Niimi M., Sato M., Murao K., Takahara J., Kawanishi K. Effect of excitatory amino acid receptor agonists on secretion of growth hormone as assessed by the reverse hemolytic plaque assay. Neuroendocrinology 1994;60:173-178[Medline]
18.
Olney J. W. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science (Washington DC) 1969;164:719-721
19. Olney J. W. Excitotoxins in foods. Neurotoxicology 1994;15:535-544[Medline]
20. Olney J. W., Cicero T. J., Meyer E. R., de Gubareff T. Acute glutamate-induced elevations in serum testosterone and luteinizing hormone. Brain Res 1976;112:420-424[Medline]
21. Perez V. J., Olney J. W. Accumulation of glutamic acid in the arcuate nucleus of the hypothalamus of the infant mouse following subcutaneous administration of monosodium glutamate. J. Neurochem. 1972;19:1777-1782[Medline]
22. Pohl C. R., Lee L. R., Smith M. S. Qualitative changes in luteinizing hormone and prolactin responses to N-methyl-aspartic acid during lactation in the rat. Endocrinology 1989;124:1905-1911[Abstract]
23. Price M. T., Olney J. W., Lowry O. H., Buchsbaum S. Uptake of exogenous glutamate and aspartate by circumventricular organs but not other regions of brain. J. Neurochem. 1981;36:1774-1780[Medline]
24. Reyes A., Luckhaus J., Ferin M. Unexpected inhibitory action of N-methyl-D,L-aspartate or luteinizing hormone release in adult ovariectomized rhesus monkeys: a role of the hypothalamic-adrenal axis. Endocrinology 1990;127:724-729[Abstract]
25. Rose R. M. Psychoendocrinology. Wilson J. D. Foster D. W. eds. Williams Textbook of Endocrinology 1985:653-681 W. B. Saunders Philadelphia, PA.
26. Rubin R. T., Poland R. E., Lesser I. M., Martin D. J. Neuroendocrine aspects of primary endogenous depression. V. Serum prolactin measures in patients and matched control subjects/TITLE>. Biol. Psychiatry 1989;25:4-21[Medline]
27. Tal J., Price M. T., Olney J. W. Neuroactive amino acids influence gonadotrophin output by a suprapituitary mechanism in either rodents or primates. Brain Res 1983;273:179-182[Medline]
28. Terry L. C., Epelbaum J., Martin J. B. Monosodium glutamate: acute and chronic effects on rhythmic growth hormone and prolactin secretion, and somatostatin in the undisturbed male rat. Brain Res 1981;217:129-142[Medline]
29. Urbanski H. F., Garyfallou V. T., Kohama S. G., Hess D. L. Alpha-adrenergic receptor antagonism and N-methyl-D-aspartate (NMDA) induced luteinizing hormone release in female rhesus macaques. Brain Res 1997;744:96-104[Medline]
30.
van den Pol A. N., Wuarin J. P., Dudek F. E. Glutamate, the dominant excitatory transmitter in neuroendocrine regulation. Science (Washington DC) 1990;250:1276-1278
31. Wilson R. C., Knobil E. Acute effects of N-methyl-DL-aspartate on the release of pituitary gonadotropins and prolactin in the adult female rhesus monkey. Brain Res 1982;248:177-179[Medline]
32. Zanisi M., Galbiati M., Messi E., Martini L. The anterior pituitary gland as a possible site of action of kainic acid. Proc. Soc. Exp. Biol. Med. 1994;206:431-437[Abstract]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
