M S 5 T THYROID-RELEASING HORMONE IN

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1 Age and Ageing 1987; 16: FRAN E. KAISER* St Paul Ramsey Medical VARIABILITY OF RESPOE TO M S 5 T THYROID-RELEASING HORMONE IN Minnesota Hospitals, Minneapolis, Minnesota M i l i Mi 55455, USA NORMAL ELDERLY Summary The present study was undertaken to define the hormonal response to thyroid-releasing hormone (TRH) further in a large, healthy, ambulatory elderly group. Seventy-seven subjects over 60 years old, 30 males (MA) and 47 females (FA), and control subjects, 22 males (MC) and 42 females (FC) were studied. No difference in thyroxine (T4), free thyroxine index (FT 4 I), baseline prolactin, and thyrotropin (TSH) concentrations were found between the four groups. Tri-iodothyronine resin uptake was only different between MC and FA groups. Post-TRH, TSH concentrations were higher in control males and females (MC+FC), compared to their aged counterparts (MA+FA), (P). This was, in part, due to a large number of female controls who exhibited a hyper-response to TRH (A TSH> 3S/iU/ml). A blunted response, defined as a A TSH<6juU/ml, occurred in 36.7% of MA, 29.8% FA, 13.6% MC, and only 4.8% of FC subjects. As expected, there was a significantly higher response of prolactin to TRH in all females (f<0.01) than in males; but no age-related difference among the female population was seen. These data indicate that the response of TSH to TRH declines with age, blunting of the response increases with age, and that TRH use has an extremely limited role as a diagnostic test, especially in an elderly population. INTRODUCTION Thyrotropin-releasing hormone (TRH) has been used to diagnose hyperthyroidism, euthyroid Graves' disease, and mild hypothyroidism, to evaluate thyrotropin (TSH) secretion in patients with hypothalamic pituitary disease, and to test the completeness of suppression of thyroid hormone replacement [1-6]. Blunting of the response to TRH has also been used as an adjunct in the diagnosis of unipolar depression [711]. This blunted response of TSH to TRH, however, may be seen in fasted individuals, patients with uraemia and nonthyroidal illness, as well as in patients with hypothalamic-pituitary disease [12-19]. The difficulties of interpreting the results of TRH testing, especially in the elderly population, have been due to the small numbers of patients studied, the dose of TRH used, and the presence of intercurrent illness. Studies of the effects of ageing on thyroid function and TSH response to TRH have resulted in conflicting data [20-25]. This study was per- Present address: UCLA-San Fernando Valley Program, Olive View Medical Center, Olive View Drive, Sylmar, CA, , USA.

2 346 AGE AND AGEING VOL. 16, NO. 6 formed to explore the response of a healthy population to TRH administration, and clarify the usefulness of this test in the elderly population. Subjects and Methods Seventy-seven elderly subjects (aged years), all of whom were healthy, ambulatory patients whose health care consisted for the most part of yearly physical check-ups were studied, as were 64 younger controls (aged years). The control subjects were 42 females and 22 males who had no history of thyroid disease or other disorders. The aged subjects consisted of 30 males and 47 females with no history of thyroid disease and with the only illness noted to be mild hypertension in 15 of the patients (six elderly males, seven elderly females, one male control, and one female control subject). The only medications taken by this group of patients were antihypertensive agents (hydrochlorothiazide or frusemide). None of the subjects were on any medications known to interfere with thyroid function. Subjects taking oestrogen therapy were excluded, as was any patient suspected of a chronic debilitating disorder. Patients found to be hypothyroid (two subjects) or hyperthyroid (one subject) were also excluded. The subjects were divided into four groups based on sex and age (6U years and above being the entry level into the aged groups, and age below 60 years being considered control group). The groups consisted of male elderly subjects, female elderly subjects, male controls (younger males), and female controls (younger females). Table I contains a profile of the patient population. Informed and written consent was obtained. All blood samples (serum) were obtained between 08h00 and llhoo. Blood was drawn at baseline (time 0) for thyroxine (T 4 ) RIA, T 3 resin uptake (T 3 RU), tri-iodothyronine T 3 RIA, thyrotropin (TSH) and prolactin (PRL). Following the administration of 500/^g of thyrotropin-releasing factor (Thypinone, Abbot Laboratories, North Chicago, IL) given as a bolus injection intravenously, another TSH and PRL were obtained at 30 min. Radio-immunoassays (RIAs) fort 4 (RIA Spac T 4 Kit, Mallinckrodt, St Louis, MO), T 3 (T 3 RIA, Diagnostic Products, Los Angeles, CA), TSH (TSH RIA, Kallestad Labs, Inc., Austin, TX), and PRL (prolactin RIA, Diagnostic Products) were performed using commercially available kits. T 3 RU tests were also done (Tritab T 3 uptake, Nuclear Medical Labs, Dallas, TX), and the free T 4 index was calculated by the method of Bermudez et al. [26]. Normal reference values were: T^, 511 //g/dl; T 3 RU, ; T 3, ng/dl; TSH<1 to 6.5//U/ml and PRL 1-29 ng/ml. The coefficients of variations for the assays were: T 4, 4.9%; T 3 1.3% and TSH, 5.3% (intra-assay variation as specimens were matched). Data for the groups are presented as the mean ±s.e.m. when the population had a normal distribution, or median ± lower and upper quartiles when the population distribution was Age range (years) Mean age (years) No. of patients No. of subjects aged: Table I. Patient population profile MA ± FA ± ± Subjects MC FC ±

3 KAISER: TRH TESTING IN THE ELDERLY 347 skewed. Statistical analyses were performed using Student's two-tailed unpaired t test, analysis of variance and the^f 2 test, Kruskal-Wallis or Wilcoxon rank sum test, where appropriate. RESULTS Basal levels Table II shows basal thyroid hormone concentrations. There was no difference in the serum T 4 levels between the four groups. The T 3 RU was considerably higher in the male controls [ (±s.e.m.)] than in the other three groups (/ > <0.01), but the T 4 index was not different between the groups. T 3 was highest in male controls (133.1 ±4.4 ng/dl) but was only significantly higher in comparison with the FA group (118±3.0 ng/dl, P), and no other comparisons for T 3 within the four groups were statistically significant. The mean serum basal TSH and PRL levels were not different between the four groups (Table III). Stimulation testing with TRH The results of TRH testing in all groups are shown in Table III. The maximum increment of TSH over the baseline value achieved during the course of sampling (A TSH) at 30 min (the increment over baseline values) is shown in Table III. The female controls had the highest A TSH of the four groups and were significantly different from both male groups (P) and from the female aged subjects (P<0.005). Table III shows the response of prolactin to TRH in all four groups. There were, as expected, markedly higher stimulated prolactin levels in both groups of women compared to males, with the prolactin concentrations being somewhat higher and just reaching significance in younger females compared with those of the elderly females (P). Unlike TSH, the prolactin levels attained following TRH appeared much more dependent on gender than on age (Table III). The role of gender in TSH responsivity to TRH can be noted in Table III. Baseline TSH and PRL levels were identical in both males and females but again response to TRH was quite different. The median A TSH was 10.3 /iu/ml in the males and reached a significantly higher concentration in females (12.0, P). T 4 (Mg/d\) T 3 uptake Free thyroxine index T 3 (ng/dl) MA (n=30) 7.9± ± ± ±3.8 Table II. Thyroid functions (mean±s.e.m) FA (n=47) 8.2± ± ± rfc3.Ot MC (n=22) 8.0± ±0.01» 8.5± Refers to the difference between MC and all other groups (P>0.01). t Refers to the difference between FA and MC groups (P). FC (n=42) 8.2± ± ± ±2.9 p MC v. all groups (P<0.01) FA v. MC (P)

4 348 AGE AND AGEING VOL. 16, NO. 6 Quartile MA (n=30) FA (n=47) MC (n=22) FC (n=42) P MAv. FC FA v. FC MC v. FC MAv. MC MAv. FA FA v. MC Baseline Table III. TSH and PRL response to TRH TSH (//U/ml) 30 mm <0.005 <0.01 A TSH* <0.005 " Statistical analysis was performed using the Kruskal-Wallis test. 30 min after 500 fig TRH IV. Quartile Males (n=52) Females (n=89) P Baseline Table IV. TSH and PRL response to TRH: males v. females Baseline min after 500 pg TRH IV. t30 min after 500 /tg TRH IV. TSH GuU/ml) 30 min <0.01 A TSH* Baseline PRL (ng/ml) 30 min PRL (ng/ml) 30 min A PRL* <0.005 APftLf

5 KAISER: TRH TESTING IN THE ELDERLY 349 Table V. The effect of age on TSH response to TRH Quartile Control (n=89) Elderly (n=52) P Baseline min after 500 fig TRH IV. TSH (pu/ml) 30 min <0.01 A. TSH* Similarly, higher levels of prolactin following TRH administration were seen when young and elderly females were compared to young and elderly males (Table IV). Table V shows the ehects of age on TRH stimulation. Despite nearly identical baseline values of TSH in both young and elderly groups, the median A TSH was 9.0 (i\j/m\ with a lower interquartile value of 5.4 and an upper value of 14.8, in the aged group (aged males and females) compared with a higher TSH of 12.6 juu/ml in the control group (lower quartile value 10.1; upper value 17.5). Unlike TRH, however, the prolactin levels attained following TRH appeared more dependent on gender than on age (data not shown). Data regarding the TSH response to TRH within each of the four groups are presented in Table VI. There were no age-related differences within the elderly male group, the male control group or elderly female group. However, the year-old females in the female control group had a A. TSH significantly higher than the year-old, year-old and yearold control females (P). Further examination of the data suggested that the Age (years) Elderly Control Table VI. The effect of sex and age on A TSH (meanls.e.m.) A TSH 7.9± ± ± ± ± ±3.9 Males No P Compared with the other three FC groups. A TSH 16.8± ± ± ± ± ± ±9.6 Females No * P

6 350 AGE AND AGEING VOL. 16, NO. 6 BLUNTED RESPOE TO TRH ( A TSH <8 M U/ml P «0 01 P«OO1- Figure. Percentage of patients with a blunted response to TRH (500 fig intravenous bolus). Black insets in MA and FA groups indicate the percentage of patients with a A TSH<2. MA v. MC/ ) <0.01, FA v. MCP, MAv. FA, MA v. FC/><0.01, FA v. FC/>. number of hyper-responders to TRH was greatest in the female control population, altering the aged versus control TSH responses. Hyper-response to TRH (defined as a A TSH>35//U/ml) [2] was unique to the female population. Four of 47 aged female patients (8.5%) and eight of 42 female control patients (19%), but 0/30 aged males (0%) and 0/22 male controls (0%) had a hyper-response by this criteria (P<0.01 elderly females v. elderly males, elderly female v. young males, female controls v. elderly males). Interestingly, none of these hyper-responsive patients had high basal concentrations of TSH, low levels of thyroxine or tri-iodothyronine, nor was there any clinical evidence of hypothyroidism. When the data were reanalysed to exclude all hyper-responders (only present in the female aged and control populaton), the A TSH for aged males was 9.6//U/ml±1.2, aged females 10.0/^U/ml± 1.1, male controls 11.4^U/ml±1.0 and female controls 13.8 /iu/ml±l.l. Significant differences were found between aged males and female controls (P), and aged females and female controls (P). No other significant differences were found between the groups. This would suggest that there are slight but significant changes in the A TSH with age, at least comparing aged females to female controls, but that the A TSH for elderly males does not significantly diminish when compared to the MC group. Blunted responses to TRH (defined as a A TSH<6 fi\j/m\) [12, 18, 19] occurred in all four groups; 36.7% aged males, 29.8% aged females, 13.6% male controls and 4.8% female controls had a blunted response. This was statistically significant between all groups except for aged males v. aged females (Figure). Using a A TSH of <2 ^U/ml to indicate no response, 6.7% of aged males and 4.3% of aged female patients were nonresponders. None of the male or female control subjects were shown to be nonresponders by this criterion.

7 KAISER: TRH TESTING IN THE ELDERLY 351 DISCUSSION Since the successful identification of TSH in 1969, it has been used as a tool to aid in further defining the disturbances in the hypothalamic-pituitary-thyroid axis. Data, however, regarding the role of ageing on the response to TRH administration are inconclusive. Snyder and Utiger [20] noted in 12 elderly males aged 60=79, that there was a diminution in the TSH response to TRH with age, while in 12 elderly age-matched females, there was no decrease in the TSH response to TRH when each group was compared to young control subjects [21]. However, the T 3 concentrations in that study population of elderly males were also lower than in the other groups studied, perhaps reflecting underlying disease or poor nutritional state. Ohara et al. [23], using even smaller doses of TRH (100 fig and 300 fig), found an increased responsiveness in the elderly to the smaller dose of TRH, with no further incremental response to a dose of 300 fig. This contrasted to the response of their younger cohort who had a further rise of TSH when the dq.se of TRH was increased from 100 to 300 fig. The authors suggested the 'hyper-response' to TRH was a reflection of hypothyroidism in the aged population. Other investigators found a marked diminution in TRH responsivity (with a dose of 500 fig) in women aged (15 patients) but no change in elderly males (60-81, 10 patients), when compared to younger controls [22]. In the largest study of the elderly to date, a small decrease in total T 4 concentration, and a decrease in FT 4 I were noted [25]. In this study of healthy elderly men, basal TSH levels were higher than in their young counterparts. Furthermore, it was suggested that a lack of 'hyper-response' to TRH, despite the slight increase in basal TSH, might indicate a loss of pituitary-thyrotropic function. Clearly, there has been no consensus regarding the response to TRH in the aged population. This study Was undertaken to define further normal thyroid hormone parameters and the response to TRH in a large healthy ambulatory group of both elderly males and females. No difference in thyroxine concentrations or FT^I was found among the four groups studied. The T 3 RU was significantly higher in male controls than in all other groups; the T 3 RIA was significantly higher in male controls than in all other groups; and the T 3 RIA was significantly lower for aged females only in comparison to young males, suggesting that, if any, there is only a minimal change of tri-iodothyronine with age. Basal concentrations of TSH and PRL showed no change with age. Stimulated PRL levels indicated differences only by gender, with no age-related decrement in absolute response found. This finding is in accord with previous studies [27], but disagrees with those of Jacobs et al. [28] and Arnetz et al. [29]. The latter two studies both used small numbers of subjects. The response of TSH to TRH appeared to be both age and gender related. In further delineating these changes, they could all be attributed to the marked response in the older female control subjects to TRH. The percentage of patients who hyperresponded to TRH was highest in this particular group, all of whom had normal basal levels of thyroxine and TSH, and certainly no clinical or chemical evidence of hypothyroidism. Repeat studies performed on a few of these patients as long as one year later showed similar findings, with normal thyroxine concentrations and a normal basal level of TSH.

8 352 AGE AND AGEING VOL. 16, NO. 6 Although it has been suggested that oestrogens play a role in producing the higher responsiveness in females [30], our data showing that the group with the greatest TSH responsiveness to TRH were postmenopausal would argue against this. Androgen, per se, may account for the lower responsivity to TRH in males [31]. Although the response to TRH in women has been noted to be greater than in men [2], the mechanisms underlying the hyper-response seen in this study are unclear. Short-term follow-up showed that the hyper-responsive patients did not become biochemically or clinically hypothyroid; and, therefore, hyper-response cannot and should not be used as an indicator of incipient hypothyroidism. It may be that longer-term longitudinal study would reveal thyroid abnormalities. Of interest was that no male patient, regardless of age, showed any degree of augmented response despite the similarity of T 4 and basal TSH concentrations to the female patients. A blunted response to TRH was seen in some of the patients in each group studied. None of the patients were felt to be clinically depressed or clinically hyperthyroid. The percentage of patients with diminished response was highest in the elderly group, but there was no difference between the elderly males and females. A flat response (A TSH <2 fi\5/m\) was, in fact, seen only in the elderly patients. None of the patients had elevated concentrations of thyroxine or tri-iodothyronine. None of these patients were malnourished (as evidenced by normal serum albumin concentrations), nor did they have acute or chronic illness that might be consistent with a picture of nonthyroidal disease. While the blunted responses seen in this study may be a reflection of the single 30 min time-point of sampling post-trh, there is common clinical usage of this value. Multiple time points may provide increased sensitivity in questionable cases. It may be possible that the increased sensitivity and specificity of newer immunoradiometric assays of TSH could have revealed subclinical hyperthyroidism in some patients, and this test may obviate the need in the future for TRH testing [32]. It would appear that blunting of the TSH response to TRH is not a predictor of thyroid disease in the patients studied. It is possible that the flat response may represent mild hypothalamic pituitary dysfunction in some patients, but no other endocrine abnormalities were found in these patients. Malnutrition can result in a flat TSH response to TRH [4]. Our patients, however, were all well nourished, thus ruling out mild malnutrition as a cause of a flat response. These data suggest that the TRH test has limited clinical usefulness. TRH testing appears to be of help only in excluding a diagnosis of hyperthyroidism if a normal response is obtained. It must be used with extreme caution in confirming endocrine abnormalities, especially in the elderly population. ACKNOWLEDGEMENT This work was supported by a grant from the St Paul-Ramsey foundation (MERF 8303). REFERENCES 1. Sawin CT, Hershman JT. Clinical use of thyrotropin-releasing hormone. Pharmacol Ther (c) 1976;l:

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