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The effect of lithium administration on LH response in healthy volunteers
Prop. Neuro-Psychopharmocol. & FJiol. Psychiat. 1966. Vol. 12, Printed in Great Britain. All rights reserved
Pp.263-267
Copyrir&t
0276-6646/66 $0.00 + SO @ 1966 Per9amon Press plc
THE EFFECT OF LITHIUM ADMINISTRATION ON LH RESPONSE IN HEALTHY VOLUNTEERS EVA GROF, GREGORY M. BROWN, PAUL GROF, BISHAN SAKENA Departments of Neurosciences and Psychiatry, McMaster University, Hamilton, Ontario, Canada
(Final form, September 1987)
Grof, Eva, Brown, Gregory, M., Grof, Paul, Saxena, Bishan: The Effects of Lithium Administration on LB Response in Healthy Volunteers. Ptog. Neuro-Psychopharmacol.& Biol. Psychiat. 1988, -12:263-267 Abstract 1. As part of a systematic investigation of the effects of lithium administration on neuroendocrine function we investigated the luteinizing hormone (LH) response to luteinizing hormone releasing hormone (LHRH) of healthy males. 2. In healthy volunteers after 3 weeks of therapeutic doses of lithium the LH response to LHRH was significantly increased in comparison with the responses prior to lithium administration. 3. An attempt is made to explain these findings by underlying neurotransmitter changes. Key Words: healthy volunteers, LH response, lithium.
Introduction Lithium is known to influence neuroendocrine function in man (Bunney 1979). Compared with
the systematic investigation of other neurohormones, such as thyroid stimulating
hormone (TSH), prolactin (PRL), cortisol and growth hormone (GH) there have been only a few studies carried out regarding lithium effects on luteinizing hormone (LB). Banerji et al. (1983) found significantly increased plasma levels of LH after 2 days of lithium treatment and significant reduction after 7 days in rats. The concentration of pituitary LH on the other hand remained unchanged both after 2 and 7 days of lithium treatment.
He found no change in plasma LH levels following 7 and 21 days of lithium
administration in mice (1982). Sanchez (1976) studied 10 patients treated with long-term lithium and described an increase of baseline LH in one out of 10 patients on lithium. A study on prisoners with aggressive behaviour showed an increase of basal LH after 8, 11 and 12 weeks of lithium treatment (Sheard 1977). to
Czernik and Kleesiak (1979) found no change in LH response
luteinizing hormone releasing hormone (LHRH) in symptom-free bipolar patients on
long-term lithium compared with healthy controls on no medication.
Joffe et al (1986)
studied 8 patients suffering from major depression and found no change in LH response to LHRH before and on lithium treatment.
Reduced circulating levels of LB in acutely
depressed patients have been found by Ettigi et al (1979).
263
No differences were found
264
E.Grofetal.
in the LH response to LHRH between patients with primary major depression and normal controls.
However a higher response to LHRH was
comparison with the primary ones.
found in secondary depression in
Moreover, evidence suggests that in man dopamine and
opiate systems may be involved in LH regulation (Quigley, 1984). We
(Brown et al. 1983) investigated LH response to LHRH in 3 healthy volunteers before
and on lithium and at that time an apparent difference did not reach statistical significance. We now have investigated the effects of lithium on the LH response to LHRH in additional healthy volunteers.
This study was part of a systematic investigation of
the effects of lithium administration on neuroendocrine function in man and in this project
decided to focus on the effect of lithium on LH which has not been
we
systematically explored before. In the larger study we employed a test battery including stimulation with insulin hypoglycemia, thyrotropin-releasinghormone (TRH) and LHRH and studied the responses of LH, GH, PRL, TSH and cortisol in subjects (healthy controls, symptom free bipolar patients and acutely depressed patients) prior to and during short and long-term lithium treatment. In this report only the LH findings in healthy controls are covered.
Methods Subjects.
9 healthy controls were tested before and after 3 weeks of lithium admin-
istration.
All subjects were male, with the mean age of 39 years, ranging from 28 to
60 years.
None of the subjects had any history of psychiatric illness or significant
family history of psychiatric disorder, none of them suffered any serious physical illness or were obese.
They received lithium carbonate (1050-1500 mg daily) for 3 weeks with
the lithium plasma levels ranging from 0.60 to 0.90 mqE/l, but no other medication. Experimental Procedure.
On the testing day a 118 angiocatheter was inserted into
an anticubital vein before 8:00 a.m. and kept open with heparin solution. Blood samples for determination of resting levels of hormones were taken every 20 minutes. a.m.,
At 9:00
insulin was
given intravenously and samples for hormonal assays were taken at
regular intervals.
Prior to the testing the subjects had to refrain from alcohol for
a minimum of
3 days and from physical exercise for one day.
instructed to get a good night's sleep prior to testing. resting in bed and awake.
Furthermore they were
During the testing they were
Except for avoiding alcohol and drugs there was no attempt
made to control their diet, however, before testing the subjects fasted overnight. The findings of the effects of lithium on neuroendocrine responses to insulin stimulation have been reported previously (E. Grof et al. 1982, 1983, 1984, 1985). LHRH micrograms was
administered through the angiocatheter.
At 11:OO a.m.
Afterwards samples for
hormonal assays were taken at 11:15, 11:30, 11:45, 12:00, 12:30 and 13:00 hours. Plasma LH was assayed by
double antibody immunoassay using materials supplied by
National Pituitary Agency (reference preparation - LER-907; antiserum anti HLH Batch 82) and labelled hormone (NEX 106) from NEN DuPont.
Interassay CV was 8.8% and intraassay
CV 6.5% to a sample of 72.2 ngfml. Limit of sensitivity was 9.6 ngfml.
Effect of lithium on LH response inhealthy volunteers
265
Analysis of variance for repeated measures was used for statistical analysis of the data. Results In a group of healthy controls the LH response to LRRH after 3 weeks of therapeutic doses of lithium was significantly increased in comparison with the responses prior to lithium administration (Fig. 1).
Fig 1. LH response to LHRH in 9 healthy volunteers. Prior to lithium administration: interrupted line. Three weeks on lithium: solid line. Analysis of variance.
Discussion Lithium has been used successfully in the stabilization of bipolar illness and yet, the mechanisms of its action remain unclear. Neuroendocrine strategies represent approaches which promise to offer important
E.C&ofetal.
266
insights into the lithium action. In
this
study we
have
found
that
lithium administration in healthy controls
signfieantly increases the LH response to LRRH.
Of the 9 subjects, a dramatic increase
after lithium administration was observable in 3, a clear increase in 5 and a slight decrease was present in 1 subject.
Initially in our pilot study on healthy volunteers
(Brown et al 1983), the LW responses were not significantly altered by lithium treatment. It appears this was due to the small number of subjects. In our protocol, insulin was given 2 hours prior to LHRR so that hormonal responses to hypoglycemia could be assessed.
These have been reported elsewhere (E. Grof et al.
1982, 1983, 1984, 1985). No effect of hypoglycemia or LH was expected and none was found. However, it remains possible that the prior treatment influenced the subsequent response toLRRR. It is very interesting that in healthy volunteers an increase in LH response to LRRH is induced by
lithium administration.
The only other response Increase in healthy
volunteers on lithium is an elevation of TSH response to TRR (Czernik, Kleesiek 1979, Grof, E. et al. 1984).
Other neuroendocrine responses, in particular growth hormone and
prolactfn responses to hypoglycemia have remained unaffected by lithium administration in subjects without a history of affective illness (E. Grof et al. 1983, 1984, 1985). It
would
appear
that
in
healthy volunteers the neuroendocrine effect of lithium
administration is limited to the NPG (hypothalamic-pituitary-gonadal) and thyroid axes while
the HPA
significantly
(hypothalamic-pituitary-adrenal)axis and other neurohormones are not influenced.
The
significance of
these
findings with
respect
to
neurotransmitters remains to be established. As with other hormonal systems, brain catecholamines have a major role in regulating LH secretion (Ramires et al. 1984). Multiple eatecholamine systems have been shown to influence the IiPGaxis in lower animals but which major transmitters are involved in the human system is not fully resolved. Extrapolating from animal pharmacology, norepinephrine appears to be the major stimulant and dopamine the major inhibitor.
In man there is evidence for an inhibitory role of
both dopamine and endogenous opoid peptides, which is best studied in women (Quigley 1984).
Effects of lithium may be to augment opiate or dopamine activity which in turn
alters the endogenous output of LHRH.
Further studies would be necessary to determine
whether either of these interpretationsis correct.
Acknowledgements This research project was supported by grants from ONHF and Psychiatric Research Foundation Hamilton. We appreciate the technical assistance of Mrs. Reeta Varma.
References T.A., COLLINS, T.J. (1982): Lithium: Short-term and chronic BANi%JI, T.K., PINING, effects on plasma testosterone and luteinizing hormone concentrations in mice. Life Sciences 30, 1045-1050. BANERJI, T.K., PARKENING, T.A., COLLINS, T.J., RASSOLI, A. (1983): Lithium induced changes
Effect of lithium on LH response inhealthy volunteers
267
in the plasma and pituitary levels of luteinizing hormone, follicle stimulating hormone and prolactin in rats. Life Sciences 33, 1621-1627. BROWN, G.M., GROF, E., GROF, P. (1981): Neuroendocrinologyof depression: a discussion. Psychopharmacol.Bull. 17: 10-12. BUNNEY, W.E., PERT, A., ROSENBLATT, J., PERT, C., GALLOPER, D. (1979): Mode of Action, Some Biological Considerations. Arch. Gen. Psych. 36, 898-901. CZERNIK, A., KLEESIEK, K. (1979): NeuroendokrinologischeVernaderungen unter Langzeitbehandlung mit Lithiumsalzen. Pharmakopsychiat. 12: 305-312. ETTIGI, P.G., BROWN, G.M., SEGGIE, J.A. (1979): TSB and LB responses in subtypes of depression. Psychosomatic Med. 41, 203-208. GROF, E., BROWN, G.M., GROF, P. (1982): Prolactin Response to Hypoglycemia in Acute Depression. Prog. Neuro-Psychopharmacol.and Biol. Psychiat. Vol. 6, pp. 487-490. GROF, E., BROWN, G.M., GROF, P. (1983): Neuroendocrine strategies in affective disorders. Prog. Neuro-Psychopharmacol.6 Biol. Psychiat. 7, 557-562. GROF, E., GROF, P., BROWN, G.M. (1984): Lithium Effects on Neuroendocrine Function. Prog. Neuro-Psychopharmacol.h Biol. Psychiat. 8, 541-546. GROF, E., GROF, P., BROWN, G.M. (1985): Effects of Long-Term Lithium Treatment on Prolactin Regulation. In: Chronic Treatments in Neuropsychiatry,D. Kemali and G. Racagni (Eds.) Raven Press, New York, 81-87. JOFFE, R.T., POST, R.M., BALLENGER, J.C., REBAR, R., GOLD, P.W. (1986). The effects of lithium on neuroendocrine function in affectively ill patients. Acta psychiatr. stand. 73: 524-528. QUIGLEY, M.E. (1984): Influences on gonadotropin secretion in normal cycling and hypogonadotropic emenorrheic women. In: G.M. Brown, S.H. Koslow, S. Reichlin (Eds.) Neuroendocrinology and Psychiatrid Disorder, Reven Press, 357-371. RAMIREZ V.D., FEDER, H.B., SAWYER, C.H. (1984): The role of brain cateholamines in the regulation of LH secretion: a critical inquiry. In: Martini I., Ganong W.F. (Eds.). Frontiers in neuroendocrinology,New York: Raven Press, Vol 8, pp 27-84. SANCHEZ, R.S., MURTHY. G.G., MEHTA, J., SHREEVE, W.W., SINGH, F.R. (1976): PituitaryTesticular axis in patients on lithium therapy. Fertility and Sterility 27: 667-669. SHEARD. M.H., MARINI, J.L., GIDDINGS, M.S. (1977). The effect of lithium on luteinizing hormone and testosterone in man. Diseases of the Nervous System 38: 765-769.
Inquiries and reprint requests should be addressed to: Dr. Eva Grof Departments of Neurosciences and Psychiatry McMaster University Hamilton, Ontario, Canada L8N 325
Pp.263-267
Copyrir&t
0276-6646/66 $0.00 + SO @ 1966 Per9amon Press plc
THE EFFECT OF LITHIUM ADMINISTRATION ON LH RESPONSE IN HEALTHY VOLUNTEERS EVA GROF, GREGORY M. BROWN, PAUL GROF, BISHAN SAKENA Departments of Neurosciences and Psychiatry, McMaster University, Hamilton, Ontario, Canada
(Final form, September 1987)
Grof, Eva, Brown, Gregory, M., Grof, Paul, Saxena, Bishan: The Effects of Lithium Administration on LB Response in Healthy Volunteers. Ptog. Neuro-Psychopharmacol.& Biol. Psychiat. 1988, -12:263-267 Abstract 1. As part of a systematic investigation of the effects of lithium administration on neuroendocrine function we investigated the luteinizing hormone (LH) response to luteinizing hormone releasing hormone (LHRH) of healthy males. 2. In healthy volunteers after 3 weeks of therapeutic doses of lithium the LH response to LHRH was significantly increased in comparison with the responses prior to lithium administration. 3. An attempt is made to explain these findings by underlying neurotransmitter changes. Key Words: healthy volunteers, LH response, lithium.
Introduction Lithium is known to influence neuroendocrine function in man (Bunney 1979). Compared with
the systematic investigation of other neurohormones, such as thyroid stimulating
hormone (TSH), prolactin (PRL), cortisol and growth hormone (GH) there have been only a few studies carried out regarding lithium effects on luteinizing hormone (LB). Banerji et al. (1983) found significantly increased plasma levels of LH after 2 days of lithium treatment and significant reduction after 7 days in rats. The concentration of pituitary LH on the other hand remained unchanged both after 2 and 7 days of lithium treatment.
He found no change in plasma LH levels following 7 and 21 days of lithium
administration in mice (1982). Sanchez (1976) studied 10 patients treated with long-term lithium and described an increase of baseline LH in one out of 10 patients on lithium. A study on prisoners with aggressive behaviour showed an increase of basal LH after 8, 11 and 12 weeks of lithium treatment (Sheard 1977). to
Czernik and Kleesiak (1979) found no change in LH response
luteinizing hormone releasing hormone (LHRH) in symptom-free bipolar patients on
long-term lithium compared with healthy controls on no medication.
Joffe et al (1986)
studied 8 patients suffering from major depression and found no change in LH response to LHRH before and on lithium treatment.
Reduced circulating levels of LB in acutely
depressed patients have been found by Ettigi et al (1979).
263
No differences were found
264
E.Grofetal.
in the LH response to LHRH between patients with primary major depression and normal controls.
However a higher response to LHRH was
comparison with the primary ones.
found in secondary depression in
Moreover, evidence suggests that in man dopamine and
opiate systems may be involved in LH regulation (Quigley, 1984). We
(Brown et al. 1983) investigated LH response to LHRH in 3 healthy volunteers before
and on lithium and at that time an apparent difference did not reach statistical significance. We now have investigated the effects of lithium on the LH response to LHRH in additional healthy volunteers.
This study was part of a systematic investigation of
the effects of lithium administration on neuroendocrine function in man and in this project
decided to focus on the effect of lithium on LH which has not been
we
systematically explored before. In the larger study we employed a test battery including stimulation with insulin hypoglycemia, thyrotropin-releasinghormone (TRH) and LHRH and studied the responses of LH, GH, PRL, TSH and cortisol in subjects (healthy controls, symptom free bipolar patients and acutely depressed patients) prior to and during short and long-term lithium treatment. In this report only the LH findings in healthy controls are covered.
Methods Subjects.
9 healthy controls were tested before and after 3 weeks of lithium admin-
istration.
All subjects were male, with the mean age of 39 years, ranging from 28 to
60 years.
None of the subjects had any history of psychiatric illness or significant
family history of psychiatric disorder, none of them suffered any serious physical illness or were obese.
They received lithium carbonate (1050-1500 mg daily) for 3 weeks with
the lithium plasma levels ranging from 0.60 to 0.90 mqE/l, but no other medication. Experimental Procedure.
On the testing day a 118 angiocatheter was inserted into
an anticubital vein before 8:00 a.m. and kept open with heparin solution. Blood samples for determination of resting levels of hormones were taken every 20 minutes. a.m.,
At 9:00
insulin was
given intravenously and samples for hormonal assays were taken at
regular intervals.
Prior to the testing the subjects had to refrain from alcohol for
a minimum of
3 days and from physical exercise for one day.
instructed to get a good night's sleep prior to testing. resting in bed and awake.
Furthermore they were
During the testing they were
Except for avoiding alcohol and drugs there was no attempt
made to control their diet, however, before testing the subjects fasted overnight. The findings of the effects of lithium on neuroendocrine responses to insulin stimulation have been reported previously (E. Grof et al. 1982, 1983, 1984, 1985). LHRH micrograms was
administered through the angiocatheter.
At 11:OO a.m.
Afterwards samples for
hormonal assays were taken at 11:15, 11:30, 11:45, 12:00, 12:30 and 13:00 hours. Plasma LH was assayed by
double antibody immunoassay using materials supplied by
National Pituitary Agency (reference preparation - LER-907; antiserum anti HLH Batch 82) and labelled hormone (NEX 106) from NEN DuPont.
Interassay CV was 8.8% and intraassay
CV 6.5% to a sample of 72.2 ngfml. Limit of sensitivity was 9.6 ngfml.
Effect of lithium on LH response inhealthy volunteers
265
Analysis of variance for repeated measures was used for statistical analysis of the data. Results In a group of healthy controls the LH response to LRRH after 3 weeks of therapeutic doses of lithium was significantly increased in comparison with the responses prior to lithium administration (Fig. 1).
Fig 1. LH response to LHRH in 9 healthy volunteers. Prior to lithium administration: interrupted line. Three weeks on lithium: solid line. Analysis of variance.
Discussion Lithium has been used successfully in the stabilization of bipolar illness and yet, the mechanisms of its action remain unclear. Neuroendocrine strategies represent approaches which promise to offer important
E.C&ofetal.
266
insights into the lithium action. In
this
study we
have
found
that
lithium administration in healthy controls
signfieantly increases the LH response to LRRH.
Of the 9 subjects, a dramatic increase
after lithium administration was observable in 3, a clear increase in 5 and a slight decrease was present in 1 subject.
Initially in our pilot study on healthy volunteers
(Brown et al 1983), the LW responses were not significantly altered by lithium treatment. It appears this was due to the small number of subjects. In our protocol, insulin was given 2 hours prior to LHRR so that hormonal responses to hypoglycemia could be assessed.
These have been reported elsewhere (E. Grof et al.
1982, 1983, 1984, 1985). No effect of hypoglycemia or LH was expected and none was found. However, it remains possible that the prior treatment influenced the subsequent response toLRRR. It is very interesting that in healthy volunteers an increase in LH response to LRRH is induced by
lithium administration.
The only other response Increase in healthy
volunteers on lithium is an elevation of TSH response to TRR (Czernik, Kleesiek 1979, Grof, E. et al. 1984).
Other neuroendocrine responses, in particular growth hormone and
prolactfn responses to hypoglycemia have remained unaffected by lithium administration in subjects without a history of affective illness (E. Grof et al. 1983, 1984, 1985). It
would
appear
that
in
healthy volunteers the neuroendocrine effect of lithium
administration is limited to the NPG (hypothalamic-pituitary-gonadal) and thyroid axes while
the HPA
significantly
(hypothalamic-pituitary-adrenal)axis and other neurohormones are not influenced.
The
significance of
these
findings with
respect
to
neurotransmitters remains to be established. As with other hormonal systems, brain catecholamines have a major role in regulating LH secretion (Ramires et al. 1984). Multiple eatecholamine systems have been shown to influence the IiPGaxis in lower animals but which major transmitters are involved in the human system is not fully resolved. Extrapolating from animal pharmacology, norepinephrine appears to be the major stimulant and dopamine the major inhibitor.
In man there is evidence for an inhibitory role of
both dopamine and endogenous opoid peptides, which is best studied in women (Quigley 1984).
Effects of lithium may be to augment opiate or dopamine activity which in turn
alters the endogenous output of LHRH.
Further studies would be necessary to determine
whether either of these interpretationsis correct.
Acknowledgements This research project was supported by grants from ONHF and Psychiatric Research Foundation Hamilton. We appreciate the technical assistance of Mrs. Reeta Varma.
References T.A., COLLINS, T.J. (1982): Lithium: Short-term and chronic BANi%JI, T.K., PINING, effects on plasma testosterone and luteinizing hormone concentrations in mice. Life Sciences 30, 1045-1050. BANERJI, T.K., PARKENING, T.A., COLLINS, T.J., RASSOLI, A. (1983): Lithium induced changes
Effect of lithium on LH response inhealthy volunteers
267
in the plasma and pituitary levels of luteinizing hormone, follicle stimulating hormone and prolactin in rats. Life Sciences 33, 1621-1627. BROWN, G.M., GROF, E., GROF, P. (1981): Neuroendocrinologyof depression: a discussion. Psychopharmacol.Bull. 17: 10-12. BUNNEY, W.E., PERT, A., ROSENBLATT, J., PERT, C., GALLOPER, D. (1979): Mode of Action, Some Biological Considerations. Arch. Gen. Psych. 36, 898-901. CZERNIK, A., KLEESIEK, K. (1979): NeuroendokrinologischeVernaderungen unter Langzeitbehandlung mit Lithiumsalzen. Pharmakopsychiat. 12: 305-312. ETTIGI, P.G., BROWN, G.M., SEGGIE, J.A. (1979): TSB and LB responses in subtypes of depression. Psychosomatic Med. 41, 203-208. GROF, E., BROWN, G.M., GROF, P. (1982): Prolactin Response to Hypoglycemia in Acute Depression. Prog. Neuro-Psychopharmacol.and Biol. Psychiat. Vol. 6, pp. 487-490. GROF, E., BROWN, G.M., GROF, P. (1983): Neuroendocrine strategies in affective disorders. Prog. Neuro-Psychopharmacol.6 Biol. Psychiat. 7, 557-562. GROF, E., GROF, P., BROWN, G.M. (1984): Lithium Effects on Neuroendocrine Function. Prog. Neuro-Psychopharmacol.h Biol. Psychiat. 8, 541-546. GROF, E., GROF, P., BROWN, G.M. (1985): Effects of Long-Term Lithium Treatment on Prolactin Regulation. In: Chronic Treatments in Neuropsychiatry,D. Kemali and G. Racagni (Eds.) Raven Press, New York, 81-87. JOFFE, R.T., POST, R.M., BALLENGER, J.C., REBAR, R., GOLD, P.W. (1986). The effects of lithium on neuroendocrine function in affectively ill patients. Acta psychiatr. stand. 73: 524-528. QUIGLEY, M.E. (1984): Influences on gonadotropin secretion in normal cycling and hypogonadotropic emenorrheic women. In: G.M. Brown, S.H. Koslow, S. Reichlin (Eds.) Neuroendocrinology and Psychiatrid Disorder, Reven Press, 357-371. RAMIREZ V.D., FEDER, H.B., SAWYER, C.H. (1984): The role of brain cateholamines in the regulation of LH secretion: a critical inquiry. In: Martini I., Ganong W.F. (Eds.). Frontiers in neuroendocrinology,New York: Raven Press, Vol 8, pp 27-84. SANCHEZ, R.S., MURTHY. G.G., MEHTA, J., SHREEVE, W.W., SINGH, F.R. (1976): PituitaryTesticular axis in patients on lithium therapy. Fertility and Sterility 27: 667-669. SHEARD. M.H., MARINI, J.L., GIDDINGS, M.S. (1977). The effect of lithium on luteinizing hormone and testosterone in man. Diseases of the Nervous System 38: 765-769.
Inquiries and reprint requests should be addressed to: Dr. Eva Grof Departments of Neurosciences and Psychiatry McMaster University Hamilton, Ontario, Canada L8N 325