Influence of Age and Sex in Modulating TSH Level in Primary Hypothyroidism
From the Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh.
MM Hammami, B Al-Saihati, S Al-Ahmari, Influence of Age and Sex in Modulating TSH Level in Primary Hypothyroidism. 1995; 15(6): 575-578
Abstract
Previous studies addressing the interaction of age and sex with the function of the hypothalamic-pituitary-thyrotrophs axis yielded conflicting results, due in part to inability to control for the effect of variable free thyroid hormone levels. We studied the effect of age and sex on TSH levels in patients with severe primary hypothyroidism who have essentially undetectable plasma thyroid hormone levels. The TSH levels were measured in 116 thyroid cancer patients four weeks after the withdrawal of thyroxine therapy in preparation for radioiodine scan/treatment. All patients had a TSH ≥30 mU/L (normal = 0.2-5) and a free T4 <6 pmol/L (normal = 10-25). Thirty males and 86 females with a mean age (± SD) of 40 ± 16 (range 6-89 years) were studied on up to four hypothyroid episodes, with a total of 191 episodes. The TSH level during the first hypothyroid episode correlated significantly with the TSH level during subsequent episodes (first episode versus second episode, r = 0.7, P - 0.0001; first versus third episode, r = 0.6, P = 0.03). There was a significant negative correlation between age and TSH level (r = -0.24, P = 0.0009) that persisted when only the first hypothyroid episode was considered (r = -0.23, P = 0.01), or when only males (r = -0.32, P = 0.02) or only females (r = -0.23, P = 0.005) were considered. Means of TSH levels in males and females were not significantly different (130 versus 114 mU/L, respectively; P = 0.28). We conclude that age but not sex may modulate the sensitivity/responsiveness of the hypothalamic-pituitary thyrotroph axis to primary hypothyroidism. Ann Saudi Med 1995;15(6):575-578.
An age-related diminution in thyrotrophs function has been found by most, but not all, investigators. In response to an injection of a bolus of thyrotropin-releasing hormone (TRH), a decrease in thyroid-stimulating hormone (TSH) release was shown in elderly males and females,1-3 in elderly males,4 in elderly females,5 and in elderly males but not in elderly females.6-10 Further, the expected increase in TSH level in response to the inhibition of T4 deiodination by oral iopanoic acid was not observed in healthy elderly volunteers.11 However, TSH response to a four-hour infusion of TRH was similar in the elderly compared to young male volunteers, although there was a small but significant increase in basal TSH concentration in the elderly.12
The effect of sex on thyrotroph function is even more controversial. Significantly lower TSH response to TRH in young males compared to young females was found in some studies,8,13,14 but not in others.6,7,10,15 On the other hand, significantly diminished TSH response to TRH was found in elderly males compared to elderly females.16,17
A diminished TSH response to TRH could be due to: 1) decreased thyrotrophs capacity to secrete TSH (or decreased thyrotrophs sensitivity to TRH), and/or 2) increased sensitivity of the thyrotrophs to the negative feedback of circulating thyroid hormones. This is further complicated by the potential effects of drugs and chronic illnesses, which are not uncommon in the elderly, and of sex hormones on thyroid hormone binding proteins and free thyroid hormone levels. In order to further define the interaction of age and sex with thyrotrophs function, a model is needed where the modulation of TSH secretion by thyroid hormones is eliminated. Studying TSH levels in patients of different ages and sexes who have had essentially undetectable thyroid hormone levels for a determined period provides such a model.
We examined the effect of age and sex on TSH levels in patients with primary hypothyroidism that resulted from thyroidectomy and radioiodine ablation for differentiated thyroid cancer, four weeks after the withdrawal of thyroxine therapy.
Patients and Methods
The medical records of all thyroid cancer patients who had radioiodine thyroid scans at King Faisal Specialist Hospital and Research Centre during the three months before the start of the study were reviewed. All patients (116) who had a TSH level of ≥30 mU/L were included in the study. In some of these patients, TSH and FT4 levels were also available in euthyroid/mild hyperthyroid states that followed or preceded the hypothyroid episodes. The mild hyperthyroid state was the result of thyroxine therapy. All patients had131I and/or surgical thyroid ablation and were on thyroxine therapy until about four weeks before the determination of the TSH level. Each of the 116 patients had one to four hypothyroid episodes (total episodes = 191). The mean age ± SD of patients was 40 ± 16 with a range of six to 89 years. There were 86 females and 30 males. One hundred and twelve patients had papillary, three had follicular and one had Hürthle cell thyroid cancer. Eight patients had essential hypertension, nine had diabetes mellitus, and two had both; all were on treatment with good to fair control.
TSH assay: TSH levels were determined using Amerlite TSH assay kit obtained from Amersham, UK. The assay was performed in our clinical laboratory according to the manufacturer's recommendation. The normal range for TSH is 0.2 - 5.0 mU/L (using Saudi male blood donors). The intra- and interassay coefficients of variation (CV) are 4%.
Statistical Analysis: Data is presented as mean (± SD). Statistical significance of the data was analyzed using the chi-squared test, t-test or Pearson correlation as indicated, and a standard statistical package (statgraphics/SAS). P value of <0.05 was considered significant.
Results
One hundred and sixteen patients were studied for up to four hypothyroid episodes. Fourteen patients had one hypothyroid episode, 55 had two, 13 had three and seven had four, for total hypothyroid episodes of 191. TSH levels ranged from 30 to 630 mU/L with a mean ± SD of 125 ± 94.
Correlation between TSH levels of different hypothyroid episodes: TSH levels during the first hypothyroid episode correlated significantly with the TSH levels during the second episode (r = 0.7, P - 0.0001, Figure 1) and with the TSH level during the third episode (r = 0.6, P = 0.03).
TSH level and age: As shown in Figure 2, considering all hypothyroid episodes, the TSH level correlated negatively with age (r = -0.24, P = 0.0009). The correlation persisted when only the first hypothyroid episode (r = -0.23, P = 0.01), only males (r = -0.32, P =0.02) or only females (r = -0.23, P = 0.005) were considered. Since TSH level in the hypothyroid state can be affected by the degree of TSH suppression in the period immediately before stopping thyroxine therapy, we compared TSH and FT4 levels that were available in the euthyroid/mild hyperthyroid state in patients ≤40 years old to those in older patients. The euthyroid/mild hyperthyroid state followed or preceded the hypothyroid episodes. Four patients in each group had an undetectable TSH level. Mean TSH and FT4 evels in the euthyroid/mild hyperthyroid state were similar in patients ≤40 years old compared to older patients (TSH 1.91 [n = 35] versus 2.01 [n = 31] mU/L, respectively and FT4 18.7 [n = 40] versus 18.8 [n = 29] pmol/L, respectively].
TSH level and sex: The TSH level was not significantly different in males compared to females (130 ± 116 versus 114 ± 94 mU/L, respectively). There was also no significant difference in the TSH level between males (n = 13) and females (n = 52) ≤ 40 years old (172 ± 160 versus 125 ± 108 mU/L, respectively, P = 0.21), or between males (n = 17) and females (n = 34) >40 years old (97 ± 37 versus 97 ± 64 mU/L, respectively).
Discussion
Our study demonstrates that: 1) there is remarkable individual variation of TSH levels in patients with primary hypothyroidism of more or less similar duration and severity; 2) the magnitude of the TSH response to primary hypothyroidism is rather reproducible in a given individual; 3) the magnitude of the TSH response correlates negatively with age in both males and females; and 4) the magnitude of the TSH response is not significantly different between males and females.
The negative correlation between TSH level and age suggests that the TSH level is modulated by age in primary hypothyroidism. However, it is possible that older patients stopped thyroxine therapy for a relatively shorter period of time or were on relatively higher doses of thyroxine. Either of these possibilities may result in a lower TSH level after stopping thyroxine therapy. Because of the retrospective nature of this study, the actual duration of discontinuing thyroid hormone treatment could not be determined. However, all patients were given the same instructions. Further, the significant correlation between TSH levels on separate hypothyroid episodes of the same patient suggests that the majority of the patients were rather constant in the period for which they discontinued thyroxine therapy. Furthermore, there is no reason to suspect that younger patients stopped thyroxine therapy for longer periods than the older patients. The possibility that on average the elderly were receiving relatively higher doses of thyroxine, which may have resulted in more prolonged suppressive effect on the TSH level, is also unlikely. Although TSH and FT4 levels on thyroxine treatment immediately before the hypothyroid episodes were not obtained in all patients, available levels were not different between patients ≤40 years old and older patients.
Several studies have examined the effect of age and sex on the hypothalamic-pituitary-thyrotrophs axis by analyzing the TSH response to TRH injection1-10,12-17 or to inhibitors of peripheral T3 production.11 Although the results were conflicting, most studies showed a diminished TSH response in the elderly and in males. Since TSH secretion is modulated positively by TRH and negatively by free thyroid hormones, these studies could not determine whether the diminished TSH response to TRH was due to decreased thyrotrophs sensitivity to TRH or to increased thyrotrophs sensitivity to thyroid hormones, or both. In our study, the effect of thyroid hormones was eliminated, since all patients had thyroidectomy ± ablative radioiodine treatment.
A lower TSH level in primary hypothyroidism in the elderly could be due to increased clearance or decreased secretion of TSH. The latter can be due to decreased responsiveness of the hypothalamus and/or the thyrotrophs to hypothyroidism. Our study did not address these different possibilities; however, the observation that TSH response to TRH may be decreased in the elderly,1-10 and that the metabolic clearance rate of TSH in rats is decreased rather than increased by aging,18 localizes the defect to the thyrotrophs.
Finally, our patients had severe primary hypothyroidism (TSH ≥30 mU/L) and were on thyroxine therapy before the hypothyroid episodes. Our findings, therefore, may or may not apply to patients with less severe hypothyroidism or to hypothyroidism that is not preceded by thyroxine therapy.
In summary, our study confirms previous studies which showed that age modulates thyrotrophs sensitivity and responsiveness to TRH by demonstrating significant negative correlation between age and TSH levels in primary hypothyroidism. However, we found no significant effect of sex on TSH levels. Finally, although the TSH level is invaluable in diagnosing primary hypothyroidism, it may not accurately reflect the severity of hypothyroidism in geriatric patients.
Acknowledgments
We would like to extend our gratitude to Ms Judith Lansi Sosa and Ms Editha Nera Bernardino for their excellent secretarial assistance in the preparation of this manuscript.
References
1. Ohara H, Kobayashi T, Shiraishi M, Wada T. Thyroid function of the aged as viewed from the pituitary thyroid system. Endocrinol Jpn; 1974;21:377-82.
2. Cuttelod S, Lemarchard-Beraud T, Magnenat P, Perret C, Poli S, Vannoti A. Effect of age and role of kidneys and liver on thyrotropin turnover in man. Metabolism 1974;23:101-11.
3. Hantouche E, Piketty ML, Poirier MF, Brochier T, Olie JP. Obsessive-compulsive disorder and the study of thyroid function. Encephale 1991;17:493-6.
4. Wahby VS, Ibrahim GA, Giller EL, et al. Relationship of age to TSH response to TRH in depressed males. Acta-Psychiatr-Scand 1988;78:283-8.
5. Wenzel KW, Meinhold H, Herpich M, Adelkofer F, Schleusner H. TRH-stimulatioqs test mit alters - und geschlechtsabhangigem TSH anstieg bei normal personen. Klin Wochenschr 1974;52:722-7.
6. Snyder PJ, Utiger RD. Response to thyrotropin-releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 1972;34:380-5.
7. Snyder PJ, Utiger RD. Thyrotropin response to thyrotropin-releasing hormone in normal females over forty. J Clin Endocrinol Metab 1972;34:1096-8.
8. Azizi RF, Vagenakis AG, Portnay GI, Rapoport B, Ingbar SH, Braverman LE. Pituitary-thyroid responsiveness to intramuscular thyrotropin-releasing hormone based on analyses of serum thyroxine, triiodothyronine and thyrotropin concentrations. N Engl J Med 1975;292:273-7.
9. Banki CM, Arato M, Papp Z. Thyroid stimulation test in healthy subjects and psychiatric patients. Acta Psychiatry Scand 1984;70:295-303.
10. Erfurth EM, Norden NE, Hender P, Nilsson A, Ek L. Normal reference interval for thyrotropin response to thyroliberin: dependence on age, sex, free thyroxin index, and basal concentrations of thyrotropin. Clin Chem 1984;30:196-9.
11. Szabolcs I, Kovacs Z, Vertes L, Goth M, Szilagyi G. Pituitary thyrotroph hypofunction in aged euthyroid subjects as assayed by the administration of iopanoic acid. ZFA 1988;43:289-93.
12. Harman SM, Wehmann RE, Blackman MR. Pituitary thyroid hormone economy in healthy aging males: basal indices of thyroid function and thyrotropin responses to constant infusions of thyrotropin-releasing hormone. J Clin Endocrinol Metab 1984;58:320-6.
13. Ormston BJ, Garry R, Cryer RJ, Besser GM, Hall R. Thyrotropin-releasing hormone as a thyroid function test. Lancet 1971;2:10-4.
14. Noel GL, Dimond RC, Wartofsky L, Earll JM, Frantz AG. Studies of prolactin and TSH secretion by continuous infusion of small amounts of thyrotropin-releasing hormone (TRH). J Clin Endocrinol Metab 1974;39:6-17.
15. Rabello MM, Snyder PJ, Utiger RD. Effects on the pituitary-thyroid axis and prolactin secretion of single and repetitive oral doses of thyrotropin-releasing hormone (TRH). J Clin Endocrinol Metab 1974;39:571-8.
16. Targum SD, Marshall LE, Magac-Harris K, Martin D. TRH tests in a healthy elderly population. Demonstration of gender differences. J Am Geriatric Soc 1989;37:533-6.
17. Targum SD, Marshall LE, Fischman P. Variability of TRH test responses in depressed and normal elderly subjects. Biol Psychiatry 1992;31:787-93.
18. Connors JM, De Vito WJ, Hedge GA. The effects of the duration of severe hypothyroidism and aging on the metabolic clearance rate of thyrotropin (TSH) and the pituitary TSH response to TSH-releasing hormone. Endocrinol 1984;114:1930-7.
Print version 
Plain text 
