changes in extracellular sodium or potassium concentration or in extracellular fluid volume could not account for these effects (1, 2).

Transcription

1 Journal of Clinical Investigation Vol. 46, No. 3, 1967 Studies on Auditory Thresholds in Noral Man and in Patients with Adrenal Cortical Insufficiency: The Role of Adrenal Cortical Steroids * ROBERT I. HENKIN,t ROBERT E. MCGLONE, ROBERT DALY, AND FREDERIC C. BARTTER (Fro the Clinical Endocrinology Branch, National Heart Institute, and the National Institute of Dental Research, Bethesda, Md.; and Gallaudet College, Washington, D. C.) Suary. Auditory thresholds for sinusoidal tones were deterined in eight patients with adrenal cortical insufficiency (four with Addison's disease and four with panhypopituitaris) and copared to those in noral volunteers. In adrenal cortical insufficiency (ACI) the auditory detection sensitivity is significantly ore acute than that of noral subjects over ost of the frequency range, but especially in the region of greatest hearing sensitivity of noral subjects, 1, to 2, cycles per second (cps). Treatent of the patients with deoxycorticosterone acetate decreased seru potassiu concentration and produced gains in body weight but did not alter auditory detection thresholds. Treatent with prednisolone or with aintenance doses of carbohydrateactive steroids returned the auditory detection threshold to noral in every patient tested. The echanis by which carbohydrate-active steroids affect the sensitivity of the nervous syste to sound is not known. However, since the senses of taste, sell, and hearing are all affected in siilar fashion by their reoval and replaceent, there appears to be a generalized increase in sensitivity to all sensory stiuli in patients with ACI not receiving steroids. These horones ay play a significant role in aintaining the level of responsiveness of the sensory syste to incoing stiuli. Introduction It has been shown previously that patients with untreated adrenal cortical insufficiency exhibit arkedly increased detection sensitivity for all four odalities of taste and for the sells of various vapors (1, 2). Treatent of the patients with ACI with deoxycorticosterqne acetate (DOCA) for 2 to 9 days produced no alteration in taste or sell thresholds, but treatent with carbohydrate-active steroids for 18 to 36 hours returned taste and sell thresholds to noral (1, 2). These studies indicated further that * Subitted for publication May 26, 1966; accepted Noveber 28, t Address requests for reprints to Dr. Robert I. Henkin, Clinical Endocrinology Branch, National Heart Institute, Bethesda, Md changes in extracellular sodiu or potassiu concentration or in extracellular fluid volue could not account for these effects (1, 2). The present study was designed to evaluate the detection thresholds of patients with ACI with respect to another sensory odality, audition, and to explore the effects of treatent with adrenal cortical horones and adrenocorticotropin on auditory thresholds. Methods The subjects of this study were 15 noral volunteers aged 18 to 26 (ean age, 21.6) ; 1 noral volunteers aged 39 to 61 (ean age, 47.1) ; 4 patients with anterior pituitary insufficiency aged 14 to 57; and 4 patients with adrenal cortical insufficiency aged 19 to 52. All patients with adrenal cortical insufficiency had clinical features of this disease, urinary 17-hydroxycorticosteroids that were

2 43 8 TRShOILD 32 L 1 F i ' FREQUENCY HENKIN, McGLONE, DALY, AND BARTTER El3~~ K oral Mearn +SEM FIG. 1. COMPARISON OF DETECTION THRESHOLDS FOR SINUSOIDAL TONES IN 15 f v NORMAL VOLUNTEERS, MEAN AGE 21.6, WITH THOSE OBTAINED IN 4 PATIENTS WITH ADRENAL CORTICAL INSUFFICIENCY (ACI), MEAN AGE The open circles represent the ean threshold responses of the noral volunteers, the black rectangles the ean threshold responses of the patients with AC. The lines extending above and below the sybols represent 1 SEM. The upper liits of the crosshatched area represent the threshold values obtained by VonBekesy (7) and Steinberg and associates (8). The lower liits represent those obtained by Sivian and White (6). The data for the noral volunteers fall approxiately idway between these liits. At each frequency, ean threshold for the patients with ACI was significantly below that of the noral volunteers. cps = cycles per second. below 2 g per 24 hours and did not increase with ACTH, 4 U given intravenously over 8 hours each day for 4 days (except for V.M., whose urinary 17-hydroxycorticosteroids rose to 5. g per 24 hours on the fourth day of ACTH). All patients with anterior pituitary insufficiency had hypothyroidis, hypogonadis, and adrenal cortical insufficiency, with urinary 17-hydroxycorticosteroids below 2.2 g per 24 hours, rising above 1 g per 24 hours after infusion of ACTH, 4 U given intravenously over 8 hours each day for 2 or ore days. Taste and sell thresholds have been reported previously for four of these eight patients (1, 2). All patients reained on an air-conditioned etabolic ward and ate a regular diet, which was well tolerated even when they were not receiving treatent. Sodiu intake was 1 to 2 Eq per day. Body weight, deterined with etabolic scales daily on arising, was used to provide a gross estiate of changes in the volue of body fluids. None of the subjects or patients gave a history of gross hearing loss or acute or chronic ear disease. Otolaryngological exaination revealed no gross abnoralities in any of the noral subjects or patients with ACI. The patients were studied under the following five conditions: a) untreated for 4 or ore days; b) treated with DOCA, 2 g per day, for 1 to 9 days; c) treated with prednisolone, 2 g per day, for 2 to 7 days; d) treated with ACTH, 4 U intravenously over 8 hours, for 4 days; and e) treated with aintenance dosages of 9a-fluorohydrocortisone (.5 to.1 g per day) and of prednisolone (5. to 7.5 g per day) or dexaethasone (.5 g per day). Auditory thresholds were evaluated by easuring each subject's inial sensitivity for a sinusoidal stiulus over a wide range of frequencies. Thresholds were easured independently by two experienters on separate occasions during the afternoon hours. Two of the experienters (R.M., R.D.) participated in the study on a double blind basis. The threshold easureents thus deterined by any two of three observers in both patients and noral volunteers differed by less than 5 decibels (db) within any given subject over the entire range of frequencies tested for any given treatent condition. Threshold deterinations were ade with the subjects and patients cofortably seated alone in an ar chair in an Industrial Acoustic 124 sound chaber. Acoustic signals, provided by a Southwestern Industrial Electronics odel M-2 R-C oscillator, were presented to the subjects over short intervals of tie. The signal was attenuated by a Hewlett Packard odel 35 B attenuator and then presented to the left and right ear of each subject separately through a Knight KN 848 circuaural earphone. We obtained thresholds onoaurally in both ears of each patient utilizing the ethod of liits. Order of presentation to left or right ear was randoized to eliinate order and practice effects. The data reported here are the ean thresholds for the second or better ear tested. Threshold values for noral subjects obtained by these techniques are directly coparable to, and in good agreeent with, those reported by other investigators [(34), Figure 1]. TABLE I Auditory detection thresholds in noral subjects Detection Detection Frequency threshold* threshold* cpst ± ± i ± i ± ± ± 1.8 1, 12.7 ± i 2.1 2, ± 4. 5, 2. ± i 4.4 8, 24.5 ± ± 3.7 1, 3. ± ± , 48.1 ± , 61.4 ± 2.9 Mean range of response (cps) , ,625 Mean age of volunteers (years) Age range (years) Nuber of volunteers 15 1 * Re.2 icrobar; values given are eans ± standard errors. t Cycles per second.

3 AUDITORY THRESHOLDS IN ADRENAL INSUFFICIENCY The eight patients with ACI were found to have a biodal age distribution: four had a ean age of 19.9 years, whereas the other four had a ean age of 48. years. To copare data fro the patients with those fro the noral subjects, it was necessary to select two groups of noral subjects with ages coparable to those of the patients. Thus, 15 younger noral volunteers, ranging in age fro 18 to 26 years, and 1 older ones, ranging in age fro 39 to 61 years, were chosen. In order to ake eaningful coparisons between the patients and the noral volunteers without introducing the effect of age upon hearing thresholds as an uncontrolled variable, we have treated threshold data for the younger and older subjects separately in this paper. Results Auditory thresholds in noral subjects. The ean detection thresholds for each frequency tested in the 15 younger and the 1 older noral volunteers are presented in Table I. The eans deonstrate that the greatest sensitivity of noral hearing is between 1, and 2, cps in both groups. For the younger subjects, the sallest variation occurs at those frequencies where sensitivity tends to be the greatest. For the older subjects, variance is increased at frequencies of 2, cps and above. This greater variation at higher frequencies in the older subjects is presuably a anifestation of the aging effects on the auditory thresholds. The eans deterined for the younger subjects are siilar to those deterined by other investigators, falling between the threshold curves reported by VonBekesy (7) and Steinberg, Montgoery, and Gardner (8) and those reported by Sivian and White (6) (Figure 1). The ean frequency range of responses for these subjects was 5.5 to 15,5 cps. The eans for the older subjects are siilar to those for the younger subjects for frequencies of 7 cps or below, but significantly higher for all frequencies of 1 cps or above. The pattern of responses is siilar to that described by other investigators (9-11). The ean range of frequency responses for these older subjects was 37.5 to 11,625 cps. Thus, not only is there a arked decrease in frequency response in the older, as copared to the younger, subjects at the high end of the frequency spectru, but there is also a slight increase in the frequency response at the lower end of the spectru. Auditory thresholds in patients weith ACI receiving no steroid. The detection threshold for each frequency in each patient with untreated 431 adrenal cortical insufficiency is presented in Table II. The younger patients consist of two with Addison's disease and two with panhypopituitaris (R.E., P.K., E.N., and L.D.). The older patients also consist of two with Addison's disease and two with panhypopituitaris (R.P., V.M., H.L., and E.B.). The detection thresholds for the patients are significantly lower than those for the noral subjects of coparable ages at all frequencies tested between 5 and 1, cps. The greatest increase in sensitivity was found at about 1, to 2, cps, the frequency range in which axial hearing sensitivity is found in noral subjects. At these frequencies, the patients could detect tones that were 11 to 24 db below those detected by coparable noral subjects. In no instance did the range of thresholds observed for the frequencies between 1 and 5, cps overlap the range for coparable noral subjects. Thresholds significantly lower than noral were found at both 12, and 15, cps for the younger patients. However, at the higher frequencies, differences between the older patients and the older subjects becae saller. Mean detection thresholds for the older patients are significantly lower than those of the younger noral subjects at 5, 1,, and 2, cps. This ephasizes the extree sensitivity of the auditory syste in patients with untreated ACI; the older patients are, on the average, 28 years older than the younger noral subjects. The general pattern of hearing responses is the sae in both patients and noral subjects (Figure 1), but the frequency range for both patient groups is arkedly expanded, as copared to that of coparable noral subjects, particularly at the high end of the frequency spectru. The ean frequency range for the younger patients, off treatent, is an average of 21 cps lower at the low end of the frequency spectru and an average of 3,375 cps higher at the high end, as copared to the range for the younger noral subjects. For the older patients, the upper frequency range has been increased by an average of 1,775 cps, as copared to that for the older noral subjects. Auditory thresholds in patients with ACI treated with DOCA. The detection threshold for each frequency in each patient with ACI treated with DOCA alone is presented in Table III. The eans of the detection thresholds for both groups of patients are virtually the sae as those observed

4 432 t3 4. be cd E C4.,. 6 U) NC4 4 U) U) U.-..' W) U U) U) U) -..).) oo HENKIN, McGLONE, DALY, AND BARTTER t o_ boo I I II Id e- "-O U)-) o o eo 4' x NO t- U)e eo)r ' M4 -. z- Z * + B rotso_v- M NO C)~~ ~ < tz oo _) N oo * en -Un'--n)- C.) eo eioo X _U)* a 6~ ~ ~,i,,, O OR I"!, tn C U)U oou oo- 4' ) ) )* F e ie ii R o O o C % - - 4' - - 4'' c-i U) 4')4' Ul) 4' ' 66o U) -i uixoo U)~~~~~~~- -~~~~~~~- U)4'uoL 6)uoxO -ooou c-- e c-c-icu)o o) - U))UU ' to 6 N6 Le;r) o 1 e t- I- I 'O- - ou -ts ' It 'o so o4 r- U e4e ei O Ln c4 Oto U o N - u3.s 4.Q v 4,, : ax w M C-4 ++)-O.. 6 vv li l oo r- U) U) r- U) ) 4' ) U) U) 4' U) U) O.. U) ' *s~uo = b-.' i i H V I C4nt- 1 C4-V +bs o~o * * QY+d*, I I I )UU U) u, _c~o_ o o,5u * ''.%r. ' - vodo o U)v t-.- '4 '-'- U) OR 4 U U).l~ _l 'oi C: C 33). oo w w 4) V o _ in 1-. %- % 4'U) ~~~~~~~> Cl).. - U) ).. * - U2'4'' %")4' ) I- E co U2- (4 - -ciu * W7o' ' - ~~~~ pi 4~~~~~~~~~~~~~ odod~~~~~~~iu~~~~~ ~~cd ) c-.-.-' r- t- U) % -O NO N (Ui _' c-i ofit " kn _4 N- u: w E U P. X..4.J.Q._ 66/ vvq _~ ). o I co la.4.w.. C- _. >2A24 Cd:V o

5 AUDITORY THRESHOLDS IN ADRENAL INSUFFICIENCY off treatent (Table II), despite decreases of seru potassiu concentration and gains in body weight. Auditory thresholds in patients uith ACI treated with prednisolone. The detection threshold for each frequency in each patient with ACI treated only with prednisolone, 2 g per day, for 2 to 4 days, is presented in Table IV. In all patients, the ean detection thresholds returned to noral levels in the lower and iddle frequency ranges after treatent for 2 to 4 days.1 The average outer liits of the frequency range for the younger patients decreased to 47 to 16,75 cps, which are essentially the sae as the liits observed in the younger noral subjects. A siilar decrease was observed in the older patients. This return of threshold to noral occurred also after treatent with aintenance doses of carbohydrate-active steroid alone or with aintenance doses of sodiu-potassiu-active steroid. Siilarly, in those patients with panhypopituitaris and in the patient with ACI with soe reaining adrenal cortical function, treatent with ACTH over 4 days returned hearing thresholds to noral in the sae anner as that observed after treatent with carbohydrate-active steroids (Table IV). Discussion Deterination of detection thresholds for a sinusoidal tone over the entire frequency range of hearing has shown that thresholds for all frequencies tested were lowered in untreated patients with adrenal cortical insufficiency as copared to noral subjects. This increase in sensitivity extends over the entire frequency range but is greatest between 1, and 2, cps, the region of greatest hearing sensitivity in noral subjects. The frequency response pattern of these patients is essentially the sae as that of noral subjects (Figure 1). Treatent of these patients with DOCA alone for as long as 9 days did not alter the abnoral hearing thresholds in any discernible anner. This observation is siilar to those ade previously, in which the increased sensitivity for taste 1 In soe patients, treatent with carbohydrate-active steroids for periods longer than 4 days was required before detection thresholds returned to noral in the higher frequency range (above 1, cps). *)4 C.) C.) A) i*t tj P).- C4 4 oo Co U) a o, 8 Co In U) 8 Co UN ) Cd p4 co CC) o o o4 o to ot-o -. t_ N CS' CCCC 4 4 a O 1 4 Ml I- t W) VI) In.d W) to I o ) CL) Ḣ s1 C2,) 4 % to ie o U) ' C,)Ct) -C-.-' q'- ' N U -SH 44 W) ) 6d'odoS - CS 4 CN H o oi i i IRoe o r-o6 o6 o od oo O o ' C,)C,)OC-C-. CC)C,) -! OO"i) -C -rn CS) _C _4 c sn ' inn)o M 'Or'NŌ _-.- It fw)siat No e to ) W) " O..., c, C, C,) C, C.. t- V C'4 C C-. It )"4 CC) in No 1 No% ld -I C ce to Ild e N ' _ C') to Ct) ~4 za z- _. o4 u O C3C) C') M O McO - C,)Ca 'C- C14e +o Nr COd- ~~~~~~~~6 cd~~ a?co Cd 4C 433, ~~~~~~~~~~~~~~ z Cd. CO la 6 H U:

6 434 and olfaction observed in these patients did not change after treatent with DOCA (1, 2). Treatent of the patients with ACI with carbohydrate-active steroid returned hearing thresholds to noral, as previously shown for the senses of taste and sell. Although taste detection returned to noral 18 to 36 hours after treatent with large doses of prednisolone and sell detection returned to noral after 6 to 16 hours of treatent, auditory detection required at least 24 hours of treatent with 2 g of prednisolone before it returned to noral, and then the return was ainly in the low and iddle frequency ranges. After treatent with carbohydrate-active steroids was discontinued, hearing sensitivity was arkedly increased after 2 to 5 days, a phenoenon siilar to that observed previously for both taste and sell (1, 2). As with taste and sell, the ability to return auditory thresholds to noral is not liited to a single carbohydrate-active steroid, for thresholds have returned to noral after treatent with a variety of carbohydrate-active steroids. Furtherore, excessive aounts of steroid need not be adinistered to return auditory sensitivity to noral. At the tie of adission the patients with ACI were on aintenance doses of carbohydrateactive steroids with or without sodiu-potassiuactive steroids. At that tie, auditory thresholds were siilar to those easured after treatent with prednisolone, 2 g per day, for as long as 7 days. Thresholds observed for the noral subjects in the present study are within the liits observed by any investigators, soe of who used techniques different fro that used here (5-8). The average frequency range observed was fro 5.5 to 15,5 cps. However, other investigators using other types of equipent have shown that noral subjects can respond to an average frequency range of 2 to 2, cps (12, 13). This difference in observed frequency response can be explained by the liitations of energy output of the earphones used in the present study. With these earphones, the frequency response of the patients with untreated ACI was significantly expanded over that of the noral subjects. This indicates that less sound energy was required by the patients with ACI to hear a given frequency than by the noral subjects; the earphone liitation iposed HENKIN, McGLONE, DALY, AND BARTTER upon the noral subjects was not iposed upon the patients until higher or lower frequencies were reached. Investigators have also noted that thresholds for higher frequencies decrease arkedly as subjects becoe older (9-11). In the present study, there are significant differences between the auditory thresholds of the younger and older subjects (Table I). The upper liit of frequency response is arkedly lower in the older subjects copared to the younger ones. However, auditory thresholds in the older patients, off treatent, for tones 5 to 2, cps were significantly lower than even those of the younger noral subjects. The frequency response ranges for the older patients off treatent or on DOCA extended above those found after treatent with prednisolone or those of the older noral subjects by as uch as 1,5 cps. This phenoenon was also observed in the younger patients. Thus, in spite of those changes that occur in the auditory syse with age, e.g., presbycusis, the syste in the older subjects is still responsive to the reoval of carbohydrateactive steroid in the sae qualitative, if not quantitative, anner as that of the younger patients. Since hearing thresholds in the patients studied are significantly lower than noral, it ight be reasonable to assue that they would be ore aware of sounds around the than noral subjects. However, this is not the case, for none of the reported any excessive awareness of noise or gross discofort with noral speech in the usual social setting. When the experienter's voice was transitted through the earphones at intensity levels only slightly above threshold to each patient in the sound chaber, the patients coplained that the voice was rasping and uncofortable. Speech patterns in all patients were grossly noral. The echanis by which this increase in sensitivity to sound occurs or its locus of action in the nervous syste is not known. However, it is clear that this is not a phenoenon confined to the auditory syste, since siilar increases in sensitivity occur for the senses of taste and sell. Siilarly, all three sensory odalities respond in the sae general fashion to replaceent with carbohydrate-active steroids. There ay be a generalized increase in sensitivity to all sensory stiuli in untreated patients with ACT. Thus,

7 AUDITORY THRESHOLDS IN ADRENAL INSUFFICIENCY 435 steroid horones ay well play a significant role in aintaining the level of responsiveness of the sensory syste to incoing stiuli. The anner in which this increase of sensitivity occurs and the behavioral and biocheical anifestations of these changes are presently being investigated (14-16). References 1. Henkin, R. I., J. R. Gill, Jr., and F. C. Bartter. Studies on taste thresholds in noral an and in patients with adrenal cortical insufficiency: the role of adrenal cortical steroids and of seru sodiu concentration. J. cdin. Invest. 1963, 42, Henkin, R. I., and F. C. Bartter. Studies on olfactory thresholds in noral an and in patients with adrenal cortical insufficiency: the role of adrenal cortical steroids and of seru sodiu concentration. J. clin. Invest. 1966, 45, Stein, L., and S. Zerlin. Effect of circuaural earphones and earphone cushions on auditory threshold. J. acoust. Soc. Aer. 1963, 35, Tillan, T. W., and K. D. Gish. Coents on the effect of circuaural earphones on auditory threshold. J. acoust. Soc. Aer. 1964, 36, Davis, H., and F. W. Kranz. The international standard reference zero for pure-tone audioeters and its relation to the evaluation of ipairent of hearing. J. Speech Res. 1964, 7, Sivian, L. J., and S. D. White. On iniu audible sound fields. J. acoust. Soc. Aer. 1933, 4, VonBekesy, G., cited in H. Fletcher, Speech and Hearing in Counication. New York, Van Nostrand, 1953, p Steinberg, J. C., H. C. Montgoery, and M. B. Gardner. Results of the World's Fair hearing tests. J. acoust. Soc. Aer. 194, 12, Glorig, A., and H. Davis. Age, noise and hearing loss. Ann. Otol. (St. Louis) 1961, 7, Nixon, J. C., A. Glorig, and W. S. High. Changes in air and bone conduction thresholds as a function of age. J. Laryng. 1962, 76, Morgan, C. T. Physiological Psychology, 2nd ed. New York, McGrawill, Robinson, D. W., and R. S. Dadson. Threshold of hearing and equal-loudness relations for pure tones, and the loudness function. J. acoust. Soc. Aer. 1957, 29, Davis, H., and S. R. Silveran. Hearing and Deafness. New York, Holt, Rinehart, and Winston, 1964, p Henkin, R. I., R. L. Daly, and G. A. Ojeann. On the action of steroid horones on the central nervous syste in an (abstract). J. clin. Invest. 1966, 45, Henkin, R. I., and F. C. Bartter. The presence of corticosterone and cortisol in the central and peripheral nervous syste of the cat. Progra of the Endocrine Society 48th Meeting, Chicago, Ill., 1966, p Ojeann, G. A., and R. I. Henkin. Steroid dependent changes in huan visual evoked potentials. Life Sci. In press.