Neuroendocrine dysfunction in cluster headache
M Leone, G Patruno, A Vescovi, G Bussone
CEPHALALGIA Leone M, Patruno G, Vescovi A, Bussone G. Neuroendocrine dysfunction in cluster headache. Cephalalgia 1990;10:235-9. Oslo. ISSN 0333-1024 Current views on cluster headache pathogenesis indicate a primary central nervous system dysfunction, in particular a hypothalamic involvement. To confirm the hypothalamic involvement in cluster headache we evaluated the hypothalamic-pituitary axis responsiveness with the thyrotrophin releasing hormone (TRH) test. A dose of 200 µg of TRH was administered i.v. to nine healthy controls, 32 patients with cluster headache during cluster period and 16 in remission period. Delta maximum thyrotrophin (TSH) was significantly lower in patients with cluster headache during cluster period (p < 0.05 versus healthy controls and cluster headache patients in remission). No difference was observed between healthy controls and cluster headache patients in remission. A monoaminergic dysfunction at the hypothalamic level is hypothesized. • Cl uster period, hypothalamic-pituitary axis, monoaminergic dysfunction, reduced TSH response, TRH test M Leone, G Patruno, A Vescovi, G Bussone, Centro Cefalee, Istituto Neurologico "C. Besta", Via Celoria 11, 20133 Milano, Italy; Correspondence to G Bussone; Accepted 15 June 1990 The origin of cluster headache is unknown. A peripheral source of pain seems unlikely due to the poor effectiveness of surgical treatment and the difficulty in establishing a relationship between cluster attacks and vascular phenomena (1, 2). Current views on the pathogenesis of cluster headache indicate a primary central nervous system (CNS) dysfunction. The effectiveness of lithium therapy in cluster headache prophylaxis (3), a drug selectively stored in the hypothalamus (4), and its therapeutic effect in a central dysfunction such as manic-depressive disorders suggests a CNS site of action for lithium, again favouring central involvement in the pathogenesis of cluster headache. A hypothalamic involvement is also suggested by the typical temporal pattern of both cluster periods and attacks pointing to biorhythm generating centre dysfunction. The latter is supported by the deranged hormonal rhythms in patients with cluster headache (5-8). A central involvement is also suggested by evoked potentials (9), autonomic (10, 11) and pupillometric findings (12, 13) in patients with cluster headache. A cyclic impairment in brainstem nuclei has been hypothesized to explain cluster attacks (14). The cyclic occurrence of cluster headache seems not to be associated with obvious exogenous cyclic trigger factors, so it is necessary to hypothesize an endogenous cyclic dysfunction, probably in the rhythm generating centres at the hypothalamic level (5). The aim of this study was to verify the hypothalamic involvement in cluster headache by evaluating the hypothalamic-pituitary axis. The hypothalamus regulates anterior pituitary hormones by secretion of regulating hormones (releasing and inhibiting factors) into the hypophysealportal vessels. Pituitary dysfunction might derive from deranged hypothalamic control. In fact, in a preliminary study we showed a reduced thyrotrophin (TSH) response to the thyrotrophin releasing hormone (TRH) test in patients with cluster headache during cluster period, indicating a deranged hypothalamic-pituitary axis control in cluster headache (15). To confirm the reduced TSH response to TRH we administered the TRH test to a larger group of patients with cluster headache. Patients and methods
Fifty-seven subjects took part in the study:
Table 1. Clinical aspects of patients with cluster headache and healthy controls. Cluster headache Cluster headache in remission in cluster period Healthy subjects No. of subjects 16 32 9 Sex: Female 1 1 1 Male 15 31 8 Age (years) Mean ± SD 40.7 ± 11.2 39.4 ± 10.7 38.2 ± 14.6 Range 28-57 19-56 20 ± 59 Height (cm) 172 ± 10 171 ± 4 173 ± 8 Weight (kg) 77 ± 4 79 ± 7 74 ± l0 Onset (years) Mean ± SD 28 ± 11 29 ± 13 Range 18-53 19-56 Illness duration (years) Mean ± SD 17.0 ± 9.5 13.2 ± 8.7 Range 2-33 4-27 -
nine were healthy controls and 48 were episodic patients with cluster headache, diagnosed according to the International Headache Society (IHS) criteria (16). Sixteen of the 48 patients with cluster headache were in remission and the other 32 were in a cluster period. All patients gave written informed consent. Clinical data are shown in Table 1. Fifteen of the 32 patients studied with cluster headache during cluster period did not take any analgesics, nor was oxygen inhaled; the remaining 17 (53%) took indomethacin (50-100 mg/day) as necessary. A deranged hypothalamic-pituitary axis in certain psychiatric disorders, particularly in depression, is well established. In order to be included in this study, we assessed patients' personal history for psychiatric disorders by administering the Minnesota Multiphasic Personality Inventory (MMPI) and the Hamilton Rating Scale for Depression (HRSD). An assessment of familial psychiatric disorders was performed by interviewing the patients. Psychiatric interviews were conducted by two psychiatrists. We only accepted patients who had MMPI and HRSD scores within the normal range and had no family history of psychiatric disorders. None of the tests performed during the cluster period was conducted during an attaçk. In particular, the test was administered 10 h (mean time) after the end of an attack (range 90 min to 22 h) . The test was administered between 08:30 and 09:30 h after an overnight fast. A catheter was inserted into an antecubital vein and kept patent by a slow NaCl 0.9% infusion. Collection timings were: 0, 15, 30, 45, 60, 90 and 120 min. We excluded blood collection at -30 min because we did not observe any difference between basal TSH at -30 men and 0 min in our previous study (15). Blood samples were collected into EDTA (2 mg/ 5 ml) plastic tubes. Immediately after blood basal collection, 200 µg of TRH (Relefact, Hoechst) was administered over l min. Blood samples were rapidly centrifuged and plasma stored at -20°C until assayed. TSH was detected by IRMA (Spectria-Farmos Diagnostica, Turku, Finland) with a sensitivity of 0.01 mIU/1. The intra-assay coefficient of variation (CV%) was 4.7% and the inter-assay CV% was 7.9%. Cross-reactivity was: luteinizing hormone 0.1%; follicle stimulating hormone 0.2%; human chorionic gonadotrophin 0.001%. Triiodo-thyronine (T3) was detected by Mycro-particle Enzyme Immuno Assay (MEIA) (Abbott, Rome, Italy). Tetraiodothyronine (T4) was detected by fluorescence polarized immunoassay (FPIA) (Abbott, Rome, Italy).
Table 2. TSH response to TRH test, mean ± SD in each group. Healthy Cluster patients Time controls in remission (min) n=9 n = 16 x ± SD x ± SD 0 1.011 ± 0.22 1.24 ± 0.75 15 6.67 ± 4.22 9.51 ± 8.38 30 8.04 ± 3.2 10.9 ± 9.74 45 6.06 ± 2.49 9.47 ± 8.4 60 4.9 ± 2.19 7.89 ± 6.3 90 3.12 ± 1.7 5.64 ± 4.37 120 2.115 ± 1.23 4.0 ± 2.83
Cluster patients in cluster period n = 32 x ± SD 1.47 ± 0.14 6.91 ± 0.63 8.13 ± 0.81 7.23 ± 4.36 6.1 ± 3.72 4.26 ± 2.78 3.8 ± 2.23
Data analysis The maximum TSH response to TRH was evaluated as delta maximum TSH (= maximum response basal level/basal level) in each patient. Mean delta maximum TSH of each group as well as mean T3, T4 and basal TSH were compared by a two-tailed Student's t-test. The p values less than 0.05 were considered significant. Results
Nine subjects complained of side effects after TRH administration: two showed transient facial flushing and seven the desire to urinate. No one test was stopped. T3-T4 and basal TSH showed no difference among the groups. Mean TSH basal values and mean TSH responses to TRH in each group are shown in Table 2. Cluster period patients showed a reduced TSH response to TRH both versus healthy controls (p < 0.05; Table 3) and versus remission period patients (p < 0.05; Table 3). Discussion
A reduced TSH response to TRH during cluster period was observed in this study, confirming our previous finding (15), where prolactin response was normal in cluster male patients as also found by other workers (17). Prolonged TRH administration in man Table 3. Delta maximum TSH in three patients. Healthy Cluster patients Cluster patients controls in remission in cluster period n=9 n = 16 n = 32 6.19 4.73 6.96 3.92 10.12 9.42 0.56 3.05 10.04 14.22 13.65 4.68 9.2 8.54 1.53 6.0 6.15 11.21 5.3 5.35 16.5 17 4.88 5.73 2.48 8.91 7.74 3.46 11.3 5.0 9.04 6.5 5.5 9.2 5.38 6.4 15.32 7.18 8.01 8.57 8.78 13.65 2.93 4.89 6.35 3.24 10.68 2.11 6.52 5.1 5.51 3.39 7.7 4.92 7.6 0.63 4.74 x 8.61 8.49 5.95* SD 4.08 4.29 3.06 * p < 0.05 vs healthy controls and cluster headache in remission.
evokes a reduced TSH response to TRH while prolactin response remains normal (18). A reduced TSH response to TRH has also been observed in depression (19) and this strengthens the analogy between cluster headache and manic-depressive disorders, suggesting a central cause for cluster headache. Conversely, other authors have found no difference between the TSH response to TRH in male cluster patients and healthy controls, but a reduced TSH response in female cluster patients was observed during
cluster period (17). In the present study only two patients with cluster headache were female and their responses were no different from the group mean. How can we explain a reduced TSH response to TRH? The influence of drugs on TSH response to TRH in our patients during cluster period seems poor; in fact all patients were free of any prophylactic treatment at the test moment. Moreover, indomethacin, the only analgesic used by 53% of these subjects seems not to affect TSH response to TRH (20). Hypothalamic TRH over-secretion may induce down-regulation in the thyroid, with a secondary reduced sensitivity to TRH stimulus. This is consistent with the results seen in man after prolonged TRH administration (18). How can we explain a hypothalamic TRH oversecretion? TRH synthesis and release are controlled at the hypothalamic level by norepinephrinergic (21-23) and serotoninergic facilitatory pathways (24). The dopaminergic pathway seems to have an inhibitory role (25, 26). Norepinephrinergic hyperactivity at the hypothalamic level may cause TRH oversecretion with secondary down-regulation of the thyrotrophes. Pain related stress has been invoked as a possible cause of some hypothalamic-pituitary axis dysfunctions observed during cluster period (27). For example, during a cluster attack there is an increase in prolactin but no contemporary TSH variation (17). Notwithstanding the difference between the TSH and prolactin response to stress during cluster attacks, it is not possible to exclude that the reduced TSH response to TRH is also stress-related and not the consequence of a primary monoaminergic hypo-thalamic pathway dysfunction. In conclusion, we confirm the reduced TSH response to TRH in patients with cluster headache during cluster period. Further studies are necessary to clarify this finding so that it may be used as a state-marker of cluster headache. References
1.
Dahl A, Russell D. Transcranial doppler examination c f the middle cerebral arteries during cluster headache attacks. Cephalalgia 1987;7:343-4
2.
Gawel M, Krajewski A. Intracranial haemo-dynamics in cluster headache. Cephalalgia 1987;7: 345-6
3.
Bussone G, Leone M, Peccarisi C et al. Verapamil vs lithium in prophylactic treatment of chronic cluster headache: a double-blind cross-over study. In: Rose FC ed New advances in headache research. Proceedings of the 7th Migraine Trust International Symposium London September 1988. London: Smith-Gordon, Nishimura 1989:229-34
4.
Edelfors S, Gothgen I. Distribution of electrolytes within the brain in lithium treated rats. Acta Pharmacol Toxicol 1971;29(suppl 4):11 (abstr)
5.
Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G, Schott B. A chronobiological study of melatonin, cortisol, growth hormone and prolactin secretion in cluster headache. Cephalalgia 1984;4:213-20
6.
Waldenlind E, Gustafsson SA, Ekbom KA, Wetterberg L. Circadian secretion of cortisol and melatonin during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987;50:207-13
7.
Micieli G, Facchinetti F, Martignoni E, Manzoni GC, Cleva M, Nappi G. Disordered pulsatile LH release in cluster headache. Cephalalgia 1987;7:79-81
8.
Frediani F, Lamperti E, Leone M, Boiardi A, Grazzi L, Bussone G. Cluster headache patients' responses to dexamethasone suppression test. Headache 1988;28:130-2
9.
Boiardi A, Frediani F, Leone M, Munari L, Bussone G. Cluster headache: lack of central modulation? Funct Neurol 1988;3:79-87
10.
Saunte C. Autonomic disorders in cluster headache, with special reference to salivation, nasal secretion and tearing. Cephalalgia 1984;4:57-64
11.
Boiardi A, Munari L, Milanesi I, Paggetta C, Lamperti E, Bussone G. Impaired cardiovascular reflexes in cluster headache and migraine patients: evidence for an autonomic dysfunction. Headache 1988;28:417-22
12.
Fanciullacci M, Pietrini U, Gatto G, Boccuni M, Sicuteri F. Latent dysautonomic pupillary lateralization in cluster headache. A pupillometric study. Cephalalgia 1982;2:135-44
13.
Salvesen R, Bogucki A, Wysocka-Bakowska MM, Antonaci F, Fredriksen TA, Sjaastad O. Cluster headache pathogenesis: a pupillometric study. Cephalalgia 1987;4:273-84
14.
Nappi G, Savoldi F. Le cefalee. Sistema diagnostico e criteri di classificazione. Pavia, Edizioni Mediche Italiane 1984:89-102
15.
Bussone G, Frediani F, Leone M, Grazzi L, Lamperti E, Boiardi A. TRH test in cluster headache. Headache 1988;7:43-54
16.
Headache Classification Committee of the International Headache Society: Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain. Cephalalgia 1988;8:35-8
17.
Waldenlind E, Gustafsson SA. Prolactin in cluster headache: diurnal secretion, response to thyro-
tropin-releasing hormone and relation to sex steroids and gonadotropins. Cephalalgia 1987;7:43-54 18.
Lombardi G, Merola B, Tommaselli AP, Fariello C. Effects of TRH-T treatment on TSH, FT3, FT4 and PRL plasma levels. In: Agnoli A, Delwaide PJ, Prange A, Scapagnini V eds New prospects in neuropharmacology: 1. Protireline tartrate (TRH-T). London: John Libbey 1988:113-21
19.
Loosen PT, Prange AJ Jr. Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review. Am J Psychiatry 1982; 139:405-11
20.
Tal E, Mohari K, Koranyi L, Kovacs ZS, Endroczi E. The effect of indomethacin, ibuprofen and paracetamol on the TRH induced TSH secretion in the rat. Gen Pharmacol 1988;4:579-81
21.
Kotani M, Onaya T, Yamada T. Acute increase of thyroid hormone secretion in response to cold and its inhibition by drugs which act on autonomic or central nervous system. Endocrinology 1973;92: 288-94
22.
Krulich L, Giachetti A, Marchlewska-Koj A, Hefco E, Jameson HE. On the role of the central nor-adrenergic and dopaminergic systems in the regulation of TSH secretion in rat. Endocrinology 1977;100:496-505
23.
Scapagnini U, Annunziato L, Clementi Get al. Chronic depletion of brain cathecolamines and thyrotropine secretion in the rat. Endocrinology 1977 ;101: 1064-70
24.
Chen YF, Ramirez VD. Serotonin stimulates thyrotropin-releasing hormone release from superfused rats hypothalami. Endocrinology 1981 ;108:2359-66
25.
Mitsuma T, Hirooka Y, Wanibe S, Nihei M. The effect of L-DOPA administration on thyrotropin. (TSH) and thyrotropin releasing hormone (TRH) levels in serum in primary or pituitary hypo-thyroidism. Endocrinol Jpn 1978;25:499-501
26.
Jackson I. Thyrotropin releasing hormone. N Engl J Med 1982;306:145-55
27.
Murialdo G, Fanciullacci M, Nicoldi Met al. Cluster headache in the male: sex steroid pattern and gonadotropic response to luteinizing hormone releasing hormone. Cephalalgia 1989;9:91-8
M Leone, G Patruno, A Vescovi, G Bussone
CEPHALALGIA Leone M, Patruno G, Vescovi A, Bussone G. Neuroendocrine dysfunction in cluster headache. Cephalalgia 1990;10:235-9. Oslo. ISSN 0333-1024 Current views on cluster headache pathogenesis indicate a primary central nervous system dysfunction, in particular a hypothalamic involvement. To confirm the hypothalamic involvement in cluster headache we evaluated the hypothalamic-pituitary axis responsiveness with the thyrotrophin releasing hormone (TRH) test. A dose of 200 µg of TRH was administered i.v. to nine healthy controls, 32 patients with cluster headache during cluster period and 16 in remission period. Delta maximum thyrotrophin (TSH) was significantly lower in patients with cluster headache during cluster period (p < 0.05 versus healthy controls and cluster headache patients in remission). No difference was observed between healthy controls and cluster headache patients in remission. A monoaminergic dysfunction at the hypothalamic level is hypothesized. • Cl uster period, hypothalamic-pituitary axis, monoaminergic dysfunction, reduced TSH response, TRH test M Leone, G Patruno, A Vescovi, G Bussone, Centro Cefalee, Istituto Neurologico "C. Besta", Via Celoria 11, 20133 Milano, Italy; Correspondence to G Bussone; Accepted 15 June 1990 The origin of cluster headache is unknown. A peripheral source of pain seems unlikely due to the poor effectiveness of surgical treatment and the difficulty in establishing a relationship between cluster attacks and vascular phenomena (1, 2). Current views on the pathogenesis of cluster headache indicate a primary central nervous system (CNS) dysfunction. The effectiveness of lithium therapy in cluster headache prophylaxis (3), a drug selectively stored in the hypothalamus (4), and its therapeutic effect in a central dysfunction such as manic-depressive disorders suggests a CNS site of action for lithium, again favouring central involvement in the pathogenesis of cluster headache. A hypothalamic involvement is also suggested by the typical temporal pattern of both cluster periods and attacks pointing to biorhythm generating centre dysfunction. The latter is supported by the deranged hormonal rhythms in patients with cluster headache (5-8). A central involvement is also suggested by evoked potentials (9), autonomic (10, 11) and pupillometric findings (12, 13) in patients with cluster headache. A cyclic impairment in brainstem nuclei has been hypothesized to explain cluster attacks (14). The cyclic occurrence of cluster headache seems not to be associated with obvious exogenous cyclic trigger factors, so it is necessary to hypothesize an endogenous cyclic dysfunction, probably in the rhythm generating centres at the hypothalamic level (5). The aim of this study was to verify the hypothalamic involvement in cluster headache by evaluating the hypothalamic-pituitary axis. The hypothalamus regulates anterior pituitary hormones by secretion of regulating hormones (releasing and inhibiting factors) into the hypophysealportal vessels. Pituitary dysfunction might derive from deranged hypothalamic control. In fact, in a preliminary study we showed a reduced thyrotrophin (TSH) response to the thyrotrophin releasing hormone (TRH) test in patients with cluster headache during cluster period, indicating a deranged hypothalamic-pituitary axis control in cluster headache (15). To confirm the reduced TSH response to TRH we administered the TRH test to a larger group of patients with cluster headache. Patients and methods
Fifty-seven subjects took part in the study:
Table 1. Clinical aspects of patients with cluster headache and healthy controls. Cluster headache Cluster headache in remission in cluster period Healthy subjects No. of subjects 16 32 9 Sex: Female 1 1 1 Male 15 31 8 Age (years) Mean ± SD 40.7 ± 11.2 39.4 ± 10.7 38.2 ± 14.6 Range 28-57 19-56 20 ± 59 Height (cm) 172 ± 10 171 ± 4 173 ± 8 Weight (kg) 77 ± 4 79 ± 7 74 ± l0 Onset (years) Mean ± SD 28 ± 11 29 ± 13 Range 18-53 19-56 Illness duration (years) Mean ± SD 17.0 ± 9.5 13.2 ± 8.7 Range 2-33 4-27 -
nine were healthy controls and 48 were episodic patients with cluster headache, diagnosed according to the International Headache Society (IHS) criteria (16). Sixteen of the 48 patients with cluster headache were in remission and the other 32 were in a cluster period. All patients gave written informed consent. Clinical data are shown in Table 1. Fifteen of the 32 patients studied with cluster headache during cluster period did not take any analgesics, nor was oxygen inhaled; the remaining 17 (53%) took indomethacin (50-100 mg/day) as necessary. A deranged hypothalamic-pituitary axis in certain psychiatric disorders, particularly in depression, is well established. In order to be included in this study, we assessed patients' personal history for psychiatric disorders by administering the Minnesota Multiphasic Personality Inventory (MMPI) and the Hamilton Rating Scale for Depression (HRSD). An assessment of familial psychiatric disorders was performed by interviewing the patients. Psychiatric interviews were conducted by two psychiatrists. We only accepted patients who had MMPI and HRSD scores within the normal range and had no family history of psychiatric disorders. None of the tests performed during the cluster period was conducted during an attaçk. In particular, the test was administered 10 h (mean time) after the end of an attack (range 90 min to 22 h) . The test was administered between 08:30 and 09:30 h after an overnight fast. A catheter was inserted into an antecubital vein and kept patent by a slow NaCl 0.9% infusion. Collection timings were: 0, 15, 30, 45, 60, 90 and 120 min. We excluded blood collection at -30 min because we did not observe any difference between basal TSH at -30 men and 0 min in our previous study (15). Blood samples were collected into EDTA (2 mg/ 5 ml) plastic tubes. Immediately after blood basal collection, 200 µg of TRH (Relefact, Hoechst) was administered over l min. Blood samples were rapidly centrifuged and plasma stored at -20°C until assayed. TSH was detected by IRMA (Spectria-Farmos Diagnostica, Turku, Finland) with a sensitivity of 0.01 mIU/1. The intra-assay coefficient of variation (CV%) was 4.7% and the inter-assay CV% was 7.9%. Cross-reactivity was: luteinizing hormone 0.1%; follicle stimulating hormone 0.2%; human chorionic gonadotrophin 0.001%. Triiodo-thyronine (T3) was detected by Mycro-particle Enzyme Immuno Assay (MEIA) (Abbott, Rome, Italy). Tetraiodothyronine (T4) was detected by fluorescence polarized immunoassay (FPIA) (Abbott, Rome, Italy).
Table 2. TSH response to TRH test, mean ± SD in each group. Healthy Cluster patients Time controls in remission (min) n=9 n = 16 x ± SD x ± SD 0 1.011 ± 0.22 1.24 ± 0.75 15 6.67 ± 4.22 9.51 ± 8.38 30 8.04 ± 3.2 10.9 ± 9.74 45 6.06 ± 2.49 9.47 ± 8.4 60 4.9 ± 2.19 7.89 ± 6.3 90 3.12 ± 1.7 5.64 ± 4.37 120 2.115 ± 1.23 4.0 ± 2.83
Cluster patients in cluster period n = 32 x ± SD 1.47 ± 0.14 6.91 ± 0.63 8.13 ± 0.81 7.23 ± 4.36 6.1 ± 3.72 4.26 ± 2.78 3.8 ± 2.23
Data analysis The maximum TSH response to TRH was evaluated as delta maximum TSH (= maximum response basal level/basal level) in each patient. Mean delta maximum TSH of each group as well as mean T3, T4 and basal TSH were compared by a two-tailed Student's t-test. The p values less than 0.05 were considered significant. Results
Nine subjects complained of side effects after TRH administration: two showed transient facial flushing and seven the desire to urinate. No one test was stopped. T3-T4 and basal TSH showed no difference among the groups. Mean TSH basal values and mean TSH responses to TRH in each group are shown in Table 2. Cluster period patients showed a reduced TSH response to TRH both versus healthy controls (p < 0.05; Table 3) and versus remission period patients (p < 0.05; Table 3). Discussion
A reduced TSH response to TRH during cluster period was observed in this study, confirming our previous finding (15), where prolactin response was normal in cluster male patients as also found by other workers (17). Prolonged TRH administration in man Table 3. Delta maximum TSH in three patients. Healthy Cluster patients Cluster patients controls in remission in cluster period n=9 n = 16 n = 32 6.19 4.73 6.96 3.92 10.12 9.42 0.56 3.05 10.04 14.22 13.65 4.68 9.2 8.54 1.53 6.0 6.15 11.21 5.3 5.35 16.5 17 4.88 5.73 2.48 8.91 7.74 3.46 11.3 5.0 9.04 6.5 5.5 9.2 5.38 6.4 15.32 7.18 8.01 8.57 8.78 13.65 2.93 4.89 6.35 3.24 10.68 2.11 6.52 5.1 5.51 3.39 7.7 4.92 7.6 0.63 4.74 x 8.61 8.49 5.95* SD 4.08 4.29 3.06 * p < 0.05 vs healthy controls and cluster headache in remission.
evokes a reduced TSH response to TRH while prolactin response remains normal (18). A reduced TSH response to TRH has also been observed in depression (19) and this strengthens the analogy between cluster headache and manic-depressive disorders, suggesting a central cause for cluster headache. Conversely, other authors have found no difference between the TSH response to TRH in male cluster patients and healthy controls, but a reduced TSH response in female cluster patients was observed during
cluster period (17). In the present study only two patients with cluster headache were female and their responses were no different from the group mean. How can we explain a reduced TSH response to TRH? The influence of drugs on TSH response to TRH in our patients during cluster period seems poor; in fact all patients were free of any prophylactic treatment at the test moment. Moreover, indomethacin, the only analgesic used by 53% of these subjects seems not to affect TSH response to TRH (20). Hypothalamic TRH over-secretion may induce down-regulation in the thyroid, with a secondary reduced sensitivity to TRH stimulus. This is consistent with the results seen in man after prolonged TRH administration (18). How can we explain a hypothalamic TRH oversecretion? TRH synthesis and release are controlled at the hypothalamic level by norepinephrinergic (21-23) and serotoninergic facilitatory pathways (24). The dopaminergic pathway seems to have an inhibitory role (25, 26). Norepinephrinergic hyperactivity at the hypothalamic level may cause TRH oversecretion with secondary down-regulation of the thyrotrophes. Pain related stress has been invoked as a possible cause of some hypothalamic-pituitary axis dysfunctions observed during cluster period (27). For example, during a cluster attack there is an increase in prolactin but no contemporary TSH variation (17). Notwithstanding the difference between the TSH and prolactin response to stress during cluster attacks, it is not possible to exclude that the reduced TSH response to TRH is also stress-related and not the consequence of a primary monoaminergic hypo-thalamic pathway dysfunction. In conclusion, we confirm the reduced TSH response to TRH in patients with cluster headache during cluster period. Further studies are necessary to clarify this finding so that it may be used as a state-marker of cluster headache. References
1.
Dahl A, Russell D. Transcranial doppler examination c f the middle cerebral arteries during cluster headache attacks. Cephalalgia 1987;7:343-4
2.
Gawel M, Krajewski A. Intracranial haemo-dynamics in cluster headache. Cephalalgia 1987;7: 345-6
3.
Bussone G, Leone M, Peccarisi C et al. Verapamil vs lithium in prophylactic treatment of chronic cluster headache: a double-blind cross-over study. In: Rose FC ed New advances in headache research. Proceedings of the 7th Migraine Trust International Symposium London September 1988. London: Smith-Gordon, Nishimura 1989:229-34
4.
Edelfors S, Gothgen I. Distribution of electrolytes within the brain in lithium treated rats. Acta Pharmacol Toxicol 1971;29(suppl 4):11 (abstr)
5.
Chazot G, Claustrat B, Brun J, Jordan D, Sassolas G, Schott B. A chronobiological study of melatonin, cortisol, growth hormone and prolactin secretion in cluster headache. Cephalalgia 1984;4:213-20
6.
Waldenlind E, Gustafsson SA, Ekbom KA, Wetterberg L. Circadian secretion of cortisol and melatonin during active cluster periods and remission. J Neurol Neurosurg Psychiatry 1987;50:207-13
7.
Micieli G, Facchinetti F, Martignoni E, Manzoni GC, Cleva M, Nappi G. Disordered pulsatile LH release in cluster headache. Cephalalgia 1987;7:79-81
8.
Frediani F, Lamperti E, Leone M, Boiardi A, Grazzi L, Bussone G. Cluster headache patients' responses to dexamethasone suppression test. Headache 1988;28:130-2
9.
Boiardi A, Frediani F, Leone M, Munari L, Bussone G. Cluster headache: lack of central modulation? Funct Neurol 1988;3:79-87
10.
Saunte C. Autonomic disorders in cluster headache, with special reference to salivation, nasal secretion and tearing. Cephalalgia 1984;4:57-64
11.
Boiardi A, Munari L, Milanesi I, Paggetta C, Lamperti E, Bussone G. Impaired cardiovascular reflexes in cluster headache and migraine patients: evidence for an autonomic dysfunction. Headache 1988;28:417-22
12.
Fanciullacci M, Pietrini U, Gatto G, Boccuni M, Sicuteri F. Latent dysautonomic pupillary lateralization in cluster headache. A pupillometric study. Cephalalgia 1982;2:135-44
13.
Salvesen R, Bogucki A, Wysocka-Bakowska MM, Antonaci F, Fredriksen TA, Sjaastad O. Cluster headache pathogenesis: a pupillometric study. Cephalalgia 1987;4:273-84
14.
Nappi G, Savoldi F. Le cefalee. Sistema diagnostico e criteri di classificazione. Pavia, Edizioni Mediche Italiane 1984:89-102
15.
Bussone G, Frediani F, Leone M, Grazzi L, Lamperti E, Boiardi A. TRH test in cluster headache. Headache 1988;7:43-54
16.
Headache Classification Committee of the International Headache Society: Classification and Diagnostic Criteria for Headache Disorders, Cranial Neuralgias and Facial Pain. Cephalalgia 1988;8:35-8
17.
Waldenlind E, Gustafsson SA. Prolactin in cluster headache: diurnal secretion, response to thyro-
tropin-releasing hormone and relation to sex steroids and gonadotropins. Cephalalgia 1987;7:43-54 18.
Lombardi G, Merola B, Tommaselli AP, Fariello C. Effects of TRH-T treatment on TSH, FT3, FT4 and PRL plasma levels. In: Agnoli A, Delwaide PJ, Prange A, Scapagnini V eds New prospects in neuropharmacology: 1. Protireline tartrate (TRH-T). London: John Libbey 1988:113-21
19.
Loosen PT, Prange AJ Jr. Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review. Am J Psychiatry 1982; 139:405-11
20.
Tal E, Mohari K, Koranyi L, Kovacs ZS, Endroczi E. The effect of indomethacin, ibuprofen and paracetamol on the TRH induced TSH secretion in the rat. Gen Pharmacol 1988;4:579-81
21.
Kotani M, Onaya T, Yamada T. Acute increase of thyroid hormone secretion in response to cold and its inhibition by drugs which act on autonomic or central nervous system. Endocrinology 1973;92: 288-94
22.
Krulich L, Giachetti A, Marchlewska-Koj A, Hefco E, Jameson HE. On the role of the central nor-adrenergic and dopaminergic systems in the regulation of TSH secretion in rat. Endocrinology 1977;100:496-505
23.
Scapagnini U, Annunziato L, Clementi Get al. Chronic depletion of brain cathecolamines and thyrotropine secretion in the rat. Endocrinology 1977 ;101: 1064-70
24.
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