Endocrine function in multiple sclerosis Klapps P, Seyfert S, Fischer T, Scherbaum WA. Endocrine function in multiple sclerosis. Acta Neurol Scand 1992: 85: 353-357.

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In 31 patients with multiple sclerosis (MS) the endocrine functions of the hypothalamus, the pituitary and several peripheral endocrine glands were assessed with a combined pituitary test; 3/31 patients had an endocrine disease: one primary hypothyroidism, one primary amenorrhea and one primary male hypogonadism. We found no patient with endocrine disease of the hypothalamus, the pituitary or the adrenals. However, the poststimulatory secretion of cortisol, growth hormone or thyroid-stimulating hormone was impaired in 7/31 patients, suggesting a possible preclinical endocrine insufficiency in these patients.

When clinical improvement of multiple sclerosis (MS) with ACTH therapy became apparent (1,2), the question arose, whether this indicated a defect of the adrenal and/or pituitary. Measurements of cortisol and corticosteroid metabolites in urine and later in plasma showed conflicting results with normal values in some reports, yet elevated basal or depressed stimulatory values in others (3-13). The abnormal values were hypothetically related to MSinduced stress, to MS lesions in the hypothalamus, to an insufficiency of the pituitary, or to an adrenal disturbance associated with MS. Other anterior pituitary hormones also showed unexplained abnormal values in some MS patients (12, 14-16). Manifest endocrine diseases of these organs were not identfied. In fact, there are only singular reports on the coincidence of MS and such diseases (17-21). Because of the unresolved abnormal endocrine findings, we evaluated MS patients with a combined pituitary test, by which the interactions between hypothalamus, pituitary and several endocrine endorgans including the adrenals can be determined. Patients and methods

Of 101 consecutively admitted patients with clinically definite or probable MS (65 f, 36 m) 3 1 patients (16 f, 15 m) participated after thorough information and written consent. 46 patients were excluded because of medical or ethical reasons, 24 patients refused. The 3 1 patients were 20-58 years old (median 42 yrs), the disease duration was 1-21 years (median 7 yrs), the total disability score (22) was 0-2 in 18 patients, 3-5 in 7 patients, and 6-7 in 6 patients. The MS course was relapsing-remitting in 16 patients, relapsing-remitting/progressivein 10 and pri-

P. Klapps’, S.Seyfert’, T. Fischer’, W. A. Scherbaum’



Neurology Clinic, Steglitz Clinic, Free University of Berlin, Medical Clinic, University of Ulm, Germany

Key words: multiple sclerosis; endocrine function; gonadal failure

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Sepp Seyfert, Neurologische Klinik, Klinikum Steglitz, Klingsorstr., D 1000 Berlin 45, Germany Accepted for publication October 30, 199 1

marily progressive in 5. 2/31 patients took a partly test-interfering medication: 1 pt sulpirid, 1 pt Lthyroxin. Insulin-induced hypoglycemia was used to activate hypothalamic hormones which in turn release ACTH, growth hormone (GH) and prolactin. Protirelin and gonadorelin were simultaneously applied to release prolactin, thyroid-stimulating hormone (TSH), luteotropic hormone (LH) and fokcle stimulating hormone (FSH). Before and after stimulation cortisol, GH, TSH, prolactin, LH and FSH weremeasured (23,24). Insulin Actrapid H M (Novo. Mainz) 0.1 IE/kg bodyweight, Thyroliberin TRH (Merck, Darmstadt) 0.2 mg and LH-RH Relefact (Hoechst, Frankfurt/M.) 0.1 mg were given as intravenous bolus, after an overnight fast. Blood samples were taken at 0, 15, 30, 45, 60 and 90 min. The patients were monitored for blood glucose and clinically for signs of hypoglycemia and stress. The hormones were measured with RIA-Kits (for cortisol, prolactin, LH and FSH from Serono, for TSH from Becton & Dickinson and for Cis H G H from Sorin Biomedica). The results were compared with normal values from DeGroot et al. (1979), Labhart et al. (1978) and the laboratories of the Endocrinological and the Nuclear Medicine Departments of the Klinikum Steglitz. The sera were also tested with standard methods for circulating autoantibodies to adreno-cortical cells, thyroid cells, thyroglobulin, thyrotropin receptor, and anterior pituitary (25,26). Results

Cortisol (Fig. 1). Basal levels were normal or near normal in 29/31 patients (135-756 nmol/l). 2 pa-

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Fig. 6 Fig. 1-6: Basal and poststimulatory values of cortisol, GH, TSH, prolactin, LH and FSH after insulin-induced hypoglycemia, and i.v. protirelin and gonadorelin in 31 MS patients, Normal ranges shaded, reverse shading for postmenstrual normal ranges. 0 males and females; 0fo1licula.r or 0 luteal phase of menstrual cycle; * postmenstrual; 0 males

tients had increased levels; in a follow-up dexamethasone suppression test their basal cortisol was again elevated, but cortisol suppression was normal. 26/3 1 patients reached an adequate insulin-induced

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hypoglycemia of 2.2 mmol/l or less; 20 of these 26 patients had a normal stimulatory cortisol increase of 146 nmol/l or more, in 2/26 it was subnormal, and in 4/26 patients cortisol only decreased. They were

Endocrine function & MS not retested. None of the 6 patients had signs of an adrenal insufficiency; the basal cortisol of all was at or slightly above the upper normal range and 5 of the 6 patients were tense during the test, compared to only 4 of 20 patients with a normal cortisol rise (p 5 pg/l. 3 of these 25 patients showed no increase; they were not retested. TSH (Fig. 3). All 3 1 patients had normal basal TSH values (0.5-7.0 mUj1) and normal thyroid hormone levels. The TSH rise after TRH was normal or near normal in 20/30 patients, and insufficient in 10 (< 2.5 mU/l). 9 of the latter 10 patients had another TRH test, the TSH rise being insufficient in only 2 now. One patient took L-thyroxin because of hypothyroidism.

Prolactin (Fig. 4). 21/30 patients showed normal basal prolactin values. 3/30 patients with high values were in the luteal phase where such values may be physiologic; repeat fasting prolactin was done in 2 and was normal. Patient 31 had taken sulpirid. The prolactin rise after TRH and hypoglycemia was normal in 25/30 patients; of 5 patients with low values, 4 were in the luteal phase and one was male; low values may be physiologic here.

LH and FSH (Fig. 5 , 6). Basal and stirnulatory values of LH and of FSH of all 16 female patients were normal or near normal according to the menstrual situation. One 57 years old patient had a primary amenorrhea with a normal female phenotype and a normal chromosomal analysis (Prof. Dr. K. Sperling, Inst. f. Humangenetik, F U Berlin). Serum auroantibodies against steroid-hormone producing cells were not found. The MS had become manifest at 35 years. The cause of the amenorrhea remained undear. The LH and FSH values were also normal in 14 I5 male patients. One 44 years old patient had rncreased basal and poststimulatory FSH values. He had fathered two children and had a normal male phenotype. Serum testosterone and sex-hormone binding globulin were normal. Serum autoantibodies against steroid-hormone producing cells were not found. The MS had become manifest 6 years ago and had caused only minor disturbances without

disfunction of the lumbosacral cord. There had been no immunosuppressive therapy. The cause of the primary hypogonadism remained unresolved. Discussion

We did not find an endocrine disease of the hypothalamus, the pituitary and the adrenals among the 3 1 tested MS patients. 8 patients had elevated basal and/or depressed post-stimulatory cortisol or GH values without other signs of an endocrine disorder. One of the patients had both a deficient poststimulatory rise of cortisol and GH, another one had a deficient poststimulatory rise of cortisol and TSH; the other hormonal functions in these patients were normal. Stress-induced prestimulation (23,24) is a likely explanation for the elevated basal values, since the patients had normal suppression tests or a normal basal level on follow-up, and most of them were tense during the test. Prestimulation may also, at least partly, explain the deficient poststimulatory rise of cortisol or GH, since the patients were tense during the test and some had basal levels at or slightly above the upper normal range. It cannot be excluded, however, that these values indicate otherwise latent disturbances of the hypothalamus-pituitary (-adrenal) axis of an, as yet, unclear meaning. The rate of such disturbances in our MS group (4/26 patients with only decreasing poststimulatory cortisol values, and 3/25 patients with no poststimulatory G H rise) would be far above expectation, since they do not occur in healthy subjects under appropriate conditions (23, 24, 27, 28). The number of patients in our group with stress during the test appears high; patients with a chronic disease like MS possibly are prone to a stress reaction, especially if a new test is applied that may evoke expectations. Our results indicate, that the hypothalamus-pituitary axis and its interaction with the adrenals is normal in most MS patients (9); a biochemically manifest insufficiency cannot be excluded in some patients, however. One female patient had a primary hypothyroidism of autoimmune origin. The coincidence with MS may be accidental, or may reflect a common immune defect (17, 26, 29). Two patients had an insufficient TSH rise after protirelin on two occasions, thyroid hormone levels being normal. Such a finding has been reported in MS and other CNS diseases, the cause has remained unclear (16, 23, 24). 2/31 patients had a gonadal disorder, one patient had a primary amenorrhea, the other was a male with a primary hypogonadism. No obvious underlying diseases could be identified. This is a surprising coincidence. We would like to add, that in the original sample of 101 MS patients, from which the present series was drawn, we had found a further patient with primary amenorrhea among the 65 fe-

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Klapps et al. males. She had a normal female phenotype, streak ovaries and a male chromosomal set: 46, XY (Prof. Dr. K. Sperling, Inst. f. Humangenetik, FU Berlin). The only known related prevalence figure is that of female gonadal dysgenesis, which is the most frequent cause of primary amenorrhea; it was reported in 1/2700 phenotypically female newborns (30), which is significantly lower than the rate of 2 patients with primary amenorrhea in our original MS sample of 65 females (binomial test, comparing the 99% confidence limits of the respective rates). Gonadal functions have been addressed only sporadically in MS, although sexual disturbances are a major problem (31-33). Poser et al. (14) reported an irregular menstrual cycle in 50/352 female MS patients; in our sample of 65 female MS patients, 10 described menstrual irregularities. Both rates correspond to that in the population (34). Poser et al. (14) and Hyyppa et al. (15) found plasma LH, FSH, estradiol and progesteron normal or only slightly elevated in small \IS series. Vas (31) reported increased urinary gonadotropins in 5 30 MS patients and speculated on a ncurogenic cause; t h s may be relevant, since gonadal dishnction has been described in patients with posttraumatic paraplegia (35). In view of the conflicting results, a further search for the incidence of gonadal disorders in MS is desirable. 5j3 1 patients had circulating autoantibodies against epitopes of endocrine organs: all had normal hormone values (except the patient with primary hypothyroidism). The significance of these antibodies is unclear; they may be a concomitant feature of the presumably autoimmune disease MS (26). c

Acknowledgements We would like to thank Prof. Dr. H.-J. Quabbe, Department of Internal Medicine, Section of Endocrinology, Klinikum Steglitz, F U Berlin, for detailed advice throughout the study and Prof. Dr. H. Meinhold, Department of Nuclear Medicine, Klinikum Steglitz, FU Berlin for methodological help.

References I . JONSSONB, REIS G VON,SAHLGREN E. Experience of ACTH and cortisone treatment in some organic neurological cases. Acta Psychiat Neurol Scand (suppl) 1951: 74: 60-65. 2. FOGT. ACTH in therapy of multiple sclerosis. Nord Med 1951: 46: 1742-1748. 3. GARCIA-REYES JA, JENKINSD, FORSHAM PH, THORN GW. Adrenocortical function in multiple sclerosis. Arch Neurol Psychiat 1952: 68: 776-782. 4. BIRKMAYER W, ISELSTOGER H, SEEMANN D. Hormonstatus und Verlaufsform der multiplen Sklerose. Klin Med 1955: 10: 550-554. 5. WENDERM, GUTOWSKI J. Zur Frage der Funktion der Nebennierenrinde bei der multiplen Sklerose. Wien Klin Wschr 1959: 71: 648-650. 6. TEASDALE GM, SMITHPA, WILKINSON R, LATNERAL, MILLERH. Endocrine activity in multiple sclerosis. Lancet 1: 1967: 64-68.

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7. RINNE UK. Corticotrophin secretion capacity in multiple sclerosis. Europ Neurol 1968: 1: 221-233. 8. CAZZULLO CL, PIOTTILE, MONTANINI R, MONTALBETTI N, BONINIPA, MARFORIO S. Pituitary adrenocortical function in multiple sclerosis. Life Sci 1968: 7: 137-144. 9. MILLACP, COOKDB, CHASEK. Endocrine function in multiple sclerosis. J Neurol Neurosurg Psychiat 1969: 32: 4 14-4 18. 10. ALEXANDER L, CASSLJ, ZUNIGAJA. ACTH-induced adrenocortical response patterns in multiple sclerosis and their relation to the clinical effectiveness of ACTH therapy. Confm Neurol 1971: 33: 1-24. 11. KETELAER CJ. DELMOTTE P. Results of adrenal and pituitary stimulation tests in patients with multiple sclerosis. Acta Neurol Scand 1972: 48: 467-478. F, CAZZULLO CL, SMERALDI E, ZIBETTIA. 12. BRAMBILLA Endocrine function in multiple sclerosis: possible correlation with immunitary phenomena. Acta Neurol (Napoli) 1974: 29: 6 18-625. 13. MAIDAE, SUMMER K. Serum cortisol levels of multiple sclerosis patients during ACTH treatment. J Neurol 1979: 220: 143-148. K, KONIGA, POSERW, EVERS 14. POSERS, KREIKENBAUM P, WIKSTROM J. Endokrinologische Befunde bei Patientinnen mit multipler Sklerose. Geburtsh u Frauenheilk 1981: 41: 353-358. 15. HYYPPAMT, FALCKSC. L-Tryptophan and neuroendocrine regulation in neurologic patients: Gonadotrophin secretion, sexual motivation and responsiveness during LTryptophan treatment in patients with multiple sclerosis (MS). Psychoneuroendocrinol 1977: 2: 359-363. 16. KIESSLING WR, PFLUGHAUPT KW, HAUBITZ I, MERTENS HG. Thyroid function in multiple sclerosis. Acta Neurol Scand 1980: 62: 255-258. 17. BAKERHWG, BALLAJI, BURGERHG, EBELINGP, MACKAYIR. Multiple sclerosis and autoimmune disease. Aust N Z J Med 1972: 3: 256-260. 18. IRVINEWJ. Adrenalitis, hypoparathyroidism, and associated diseases. In: Immunological Diseases. SAMTER M. (ed.). Little, Brown and Company (1978). 19. VANDER SANDEJJ, VAN SETERSAP. The adrenal gland: its relationship to neurology. In: Handbook of Clinical Neurology, Vol. 39. VINKENPJ, BRUYNGW, KLAWANS HL. (eds.). North Holland Pub1 Comp, 1980, Amsterdam. 20. NAGASHIMA T, YAMADAK, UONO M, NAGASHIMA K. Multiple sclerosis co-existent with myxedema. J Neurol Sci 1984: 66: 217-221. 21. APPLED, KREINESK, BIEHLJP. The syndrome of inappropriate antidiuretic hormone secretion in multiple sclerosis. Arch Intern Med 1978: 138: 1713-1714. 22. KURTZKE JF. Further notes on disability evaluation in multiple sclerosis, with scale modifications. Neurol 1965: 15: 654-66 1. 23. LABHART A (ed): Klinik der inneren Sekretion. Springer, Berlin 1978. 24. DEGROOTLJ (ed): Endocrinology. Grune & Stratton, New York (1979). 25. SCHERBAUM WA, SCHRELL U, GLUCKM, FAHLBUSCH R. PFEIFFEREF. Autoantibodies to pituitary corticotrophproducing cells: possible markers for unfavourable outcome after pituitary microsurgery for Cushing’s disease. Lancet 1987: 1: 1394-1398. 26. SEYFERTS, KLAPPSP, MEISELC, FISCHER T, JUNGHAS U. Multiple sclerosis and other immunologic diseases. Acta Neurol Scand 1990: 81: 37-42. 27. HARTZBAND PI, VANHERLE AJ, SORGERL, COPED. Assessment of hypothalamic-pituitary-adrenal axis dysfunction. J Endocrinol Invest 1988: 11: 769-776. 28. LANDGRAF-LEURS MM, BRUGELMANN T, KAMMERERS.

Endocrine function & MS LORENZR, LANDCRAF R. Counterregulators hormone release after human and porcine insulin in healthy subjects and patients with pituitary disorders. Klin Wochenschr 1984: 62: 659-668. 29. DEKEYSER J. Autoimmunity in multiple sclerosis. Neurology 1988: 38: 371-374. 30. Ross GT. Diagnosis and treatment of primary amenorrhea, secondary amenorrhea, and dysfunctional uterine bleeding. In: Endocrinology, Vol. 3. DEGROOTLJ. (ed). Grune & Stratton, New York (1979). 3 1. VASCJ. Sexual impotence and some autonomic disturbances in men with multiple sclerosis. Acta Neurol Scand 1969: 45: 166- 182.

32. LILIUSHG, VALTONEN J, WIKSTROM J. Sexual problems in patients suffering from multiple sclerosis. J C h o n Dis 1976: 29: 643-647. 33. MINDERHOUD JM, LEEMHUIS JG, KREMER J, LABANE, SMITSPML. Sexual disturbances arising from multiple sclerosis. Acta Neurol Scand 1984: 70: 299-306. 34. DORINGGK. Zahlen zur Physiologie des Zyklus. Fortschr Med 1966: 84: 694-696. 35. STEINBERGER E. Disorders of testicular function (male hypogonadism). In: Endocrinology, Vol. 3. DEGROOT LJ. (ed). Grune & Stratton, New York (1979).

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Endocrine function in multiple sclerosis.

In 31 patients with multiple sclerosis (MS) the endocrine functions of the hypothalamus, the pituitary and several peripheral endocrine glands were as...
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