Postgrad Med J: first published as 10.1136/pgmj.57.667.310 on 1 May 1981. Downloaded from Postgraduate Medical Journal (May 1981) 57, 310-313 Pyrexia of unknown origin. Presenting sign of hypothalamic hypopituitarism R. MARILUS* A. BARKAN* M.D. M.D. S. LEIBAt R. ARIE* M.D. M.D. I. BLUM* M.D. *Department of Internal Medicine 'B' and tDepartment ofEndocrinology, Beilinson Medical Center, Petah Tiqva, The Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Israel Summary least 10 such admissions because offever of unknown A 62-year-old man was admitted to hospital 10 times origin had been recorded. During this period, he over 12 years because of pyrexia of unknown origin. was extensively investigated for possible infectious, Hypothalamic hypopituitarism was diagnosed by neoplastic, inflammatory and collagen diseases, but dynamic tests including clomiphene, LRH, TRH and the various tests failed to reveal the cause of theby copyright. chlorpromazine stimulation. Lack of ACTH was fever. demonstrated by long and short tetracosactrin tests. A detailed past history of the patient was non- The aetiology of the disorder was believed to be contributory. However, further questioning at a previous encephalitis. later period of his admission revealed interesting Following substitution therapy with adrenal and pertinent facts. Twelve years before the present gonadal steroids there were no further episodes of admission his body hair and sex activity had been fever. normal. At that time he had an acute febrile illness with severe headache which lasted for about one Introduction week. He was not admitted to hospital and did not http://pmj.bmj.com/ Pyrexia of unknown origin (PUO) may present receive any specific therapy. some of the most challenging problems that the Following this illness his hair started to fall and clinician is called upon to solve. Infectious, inflam- he noticed a decline in his sexual activity. In the matory, neoplastic and collagen diseases are the following years there were recurrent bouts of fever, most frequent final diagnoses in these cases (Jacoby sometimes accompanied by episodes of diarrhoea and Swartz, 1973). Fever may be the presenting and vomiting, with a picture of dehydration and symptom of several, less frequent entities which, if lowering of BP which were twice diagnosed as not specifically suspected, may be overlooked. septic and cardiogenic shock. During these episodes on September 30, 2021 by guest. Protected The authors present the case of a 62-year-old steroids were administered and the patient recovered. man, whose frequent bouts of fever were undiag- Concomitantly a psychiatric disorder developed with nosed for 12 years. The cause of his disease was auditory hallucinations and paranoidal thinking. finally proved to be hypothalamic hypopituitarism. On examination the patient appeared well nourished, his BP was 100/70 mmHg and his pulse Case report rate was regular at 80/min. There was no hair on his A 62-year-old man was admitted to the Depart- chest or axillae, his pubic hair had a feminine con- ment of Internal Medicine 'B' because of fever of up figuration, and his testes were hypotrophic (4ml to 38.5°C of one day's duration. There were no vol). No other abnormal physical findings were complaints concerning the urinary, respiratory or detected. gastrointestinal tracts. The body temperature re- A confrontation test revealed a bitemporal turned to normal one day after admission, without hemianopia. Routine laboratory tests which in- any specific therapy and remained so throughout his cluded total blood count, blood urea nitrogen, stay in hospital. creatinine and electrolytes were all in the normal In the 12 years before the present admission at range. 0032-5473/81/0500-0310 $02.00 © 1981 The Fellowship of Postgraduate Medicine Postgrad Med J: first published as 10.1136/pgmj.57.667.310 on 1 May 1981. Downloaded from Case reports 31i TABLE 1. Adrenal function. Plasma cortisol and urine 17-ketosteroid (17-KS), 17-hydroxycorticoid (17-OH), and 1 1-oxy-17-KS (11-OH) responses to tetracosactrin Base-line Short tetracosactrin test Long tetracosactrin test Plasma ACTH (pg/ml) 0 Cortisol (nmol/I) 27-6 41-4* Urine 17-KS mg/24/hr 0-6 3-0 0-4 17-OH mg/24/hr 1-3 3-5 18-5 11-OH [Lg/24/hr 9 130 *After 120 and 240 min or tetracosactrin infusion. Since the physical findings were suggestive of lack of prolactin-inhibiting factor (PIF) reaching adrenal and gonadal insufficiency, the functions of the pituitary gland, due to either a hypothalamic these glands were investigated basally and upon lesion or a hypophiseal stalk section (Thorner, 1977). stimulation. Administration of TRH is believed to stimulate Tertiary adrenal, gonodal and mild thyroid dys- directly the pituitary secretion of prolactin (Jacob function and hyperprolactinaemia were diagnosed et al., 1971). There was increased response to TRH (Tables 1, 2, 3). Basal 24-hr urinary steroid excretion, (Table 3), possibly as an expression of increased basal plasma cortisol and plasma ACTH levels were receptor sensitivity due to lack of PIF. Dopamine is all extremely low (Table 1), suggesting the presence believed to be a PIF (Shaar and Clemens, 1974; of adrenal insufficiency. A tetracosactrin (Synacthen) Enyalbert, Pria and Korden, 1977). Administration test (0-25 mg i.v. over 4 hr) revealed no increase in of chlorpromazine, known to be a hypothalamic plasma and urine steroid levels, suggesting either primary adrenal insufficiency or secondary adrenal TABLE 2. Hypothalamic-pituitary-gonadal axis function. atrophy resulting from long-standing absence of Follicle stimulating hormone (FSH) and luteinizing hormone by copyright. trophic action of endogenic ACTH. A long tetraco- (LH) responses to LH-releasing hormone (LHRH) and sactrin test (0-25 mg i.v. over 4 hr for 3 consecutive clomiphene days) revealed an appropriate rise of urine excretion LHRH test (100 jLg i.v.) of corticosteroids, suggesting the presence of Time Plasma FSH Plasma LH adrenal insufficiency of pituitary or hypothalamic (min) (mu./ml) (mu./ml) origin (Liddle, 1974). 0 2-3 2-2 Differentiation between these 2 possibilities is 15 4-1 4-4 generally accomplished by performing insulin 30 4-7 5.9 45 5-0 6-4 http://pmj.bmj.com/ tolerance (ITT) and vasopressin tests (Landon et al., 60 5-1 5-6 1966; Eddy, 1968), but these could not be performed 90 5.4 5-5 because of the presence of electrocardiographic abnormalities indicative of coronary insufficiency. Clomiphene test (200 mg/day for 6 days) Basal plasma levels of testosterone (62 ng/dl) and Time Plasma FSH Plasma LH gonadotrophins (FSH, LH) were low, suggesting the (mu./ml) (mu./ml) presence of gonadal insufficiency of pituitary or Base-line 2-3 2-2 2 4-0 0-4 hypothalamic origin (Table 2). Administration of day on September 30, 2021 by guest. Protected Iuteinizing hormone day 3 2-4 0-5 hormone-releasing (LHRH)(100 day 4 0-5 0-7 ,ig i.v.) gave an appropriate rise of plasma gonado- day 6 0-8 0-7 trophins, suggesting normal pituitary reserve (Morti- mer et al., 1973). Administration of clomiphene, which is believed to be a hypothalamic stimulator of dopaminergic receptor blocker (Streja, Corenblum LHRH secretion (Mortimer et al., 1973), failed to and Ezrim, 1978), failed to produce an adequate produce an adequate rise of gonadotrophin levels rise in plasma prolactin levels. The combination of (Table 2). The combination of a normal LHRH test an increased response of prolactin secretion to TRH and abnormal clomiphene test suggested a hypo- stimulation and a subnormal response to chlorpro- thalamic lesion as the cause of the hypogonadism in mazine suggested a hypothalamic lesion as the cause this patient (Mortimer, 1977). of the hyperprolactinaemia. Basal plasma levels of prolactin (10-23 ng/ml) Normal values of T3, T4, and TSH (6-8 ig/ml and were found to be above normal. 1-7 ,uu./ml) suggested a normal hypothalamic- Hyperprolactinaemia can be the result of one of pituitary thyroidal axis but cannot be taken as final 2 causes: a hypersecreting pituitary adenoma or a proof (Snyder et al., 1974). Administration of TRH, Postgrad Med J: first published as 10.1136/pgmj.57.667.310 on 1 May 1981. Downloaded from 312 Case reports which is believed to stimulate the pituitary to endocrinological deficits of hypothalamic origin, secrete TSH, showed a delayed peak (Table 3), thus hypersomnia and severe mental disturbances were all confirming impairment of TSH secretion of hypo- found in the patient. These findings may be attributed thalamic origin (Faglia et al., 1973). to what has been described in the literature as the diencephalic syndrome (Bower, 1954). Discussion Substitution therapy with 7-5 mg prednisone/day Endocrinological investigation pointed to a hypo- and injections of testosterone enanthate 250 mg/ thalamic lesion as being the cause of the abnormal month was started. During 16 months of follow-up function of the pituitary, concerning the secretion of there were no more episodes of fever, hypersomnia gonadotrophins, prolactin and TSH. Adrenal in- disappeared, and vigour and libido reappeared. sufficiency was proved but the patient's condition This amelioration on substitution therapy suggests made it technically impossible to determine whether that the adrenal and gonadal insufficiencies were the it was hypothalamic or pituitary in origin. cause of the above-mentioned symptoms, and that these were not due to a lesion of the hypothalamic centres of temperature and alertness, thus excluding TABLE 3. Plasma prolactin and TSH responses to TRH and the of The mental chlorpromazine (Baseline: 10-23 ng/ml; TSH=1-7 ,u./ml; diagnosis diencephalic syndrome. T4=6-8 ,ig/ml) disorder was probably the result of the severe cortex atrophy, a sequel of the encephalitis and/or of long- TRH test (200 ,ug i.v.) standing and irreversible adrenal Time Plasma prolactin Plasma TSH insufficiency (min) (Parker, Isaacs and McKerron, 1976).