THE EFFECTS OF THYROID HORMONES ON THE METABOLISM OF STEROIDS
T. F. Gallagher, Leon Hellman, H. Leon Bradlow, B. Zumoff, David K. Fukushima
Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Annals of the New York Academy of Sciences, 86: 605-611. (1960)
This study is concerned with observations on the influence of thyroid hormones on the peripheral transformation of steroids in human subjects. The interrelation of these hormones was suggested by the fact that patients with untreated myxedema exhibited an extreme diminution in androsterone formation when compared with normal subjects. Furthermore, it was found that triiodothyronine could increase the production of androsterone in euthyroid subjects as well as in patients with myxedema.[1]
The studies to be described fall into three groups: (1) the definition of the quantity and kind of endogenous androgen metabolites in myxedematous, euthyroid, and hyperthyroid subjects; (2) the effect of deficiency or excess of thyroid hormone on the metabolism of exogenous androgen; and (3) investigation of the “thyromimetic” effect of androsterone.
The steroid hormone metabolites that have been examined in this study are shown in FIGURE 1. Both of the compounds formulated, androsterone and etiocholanolone, are major end-products of androgen metabolism in man. They are structurally identical except for the orientation of the hydrogen atom attached to C-5, which is a in androsterone and /3 in etiocholanolone. This might seem to be a minor chemical difference; it actually represents a very significant change in the shape of the molecule. Because of this structural dissimilarity each compound has a profoundly different biological activity. Three major potential precursors of these metabolites are also shown in FIGURE 1, and it should be emphasized that these hormones are secreted both by the adrenal gland and by the testes.
In this presentation we are concerned primarily with the quantitative relationship between these two products of androgen metabolism. In order to clarify this relationship we have employed the term androsterone fraction. This value represents the percentage of the total amount of androsterone plus etiocholanolone that is comprised by androsterone alone.
The effect of hypothyroidism on androgen metabolism is shown in FIGURE 2. We have compared a group of control subjects matched, in so far as possible, as to age and sex with a group of patients with myxedema. We have studied the endogenous production of these metabolites from their precursors in each group by chromatographic methods that have been well standardized and used for many years in our laboratories.[2][3] We have studied similarly both groups of patients with respect to their ability to metabolize a tracer dose of parenterally administered testosterone-4-C14. For this purpose the radioactive hormone was administered intravenously, and complete urine collections were obtained for 48 hours following the dose. After hydrolysis of the conjugates the two metabolites, androsterone and etiocholanolone, were isolated by the technique of reverse isotopic dilution.[4] This procedure gives a very precise measure of the amount of each of these compounds produced from the tracer dose of hormone. In the control group the average production of the 2 metabolites, androsterone and etiocholanolone, in 9 subjects showed an androsterone fraction of about 40 per cent. Seven of these subjects received tracer doses of testosterone-4-C14, and the results with this exogenous hormone were almost identical with the endogenous production; that is, the androsterone fraction again was about 40 per cent, while the etiocholanolone amounted to about 60 per cent of the total of these two substances. It is clear from these results that the tracer dose of exogenously administered radioactive hormone faithfully reflected the metabolism of the hormone produced from glandular sources. Thus the metabolic sequences concerned in the production of the metabolites can be measured either from endogenously produced hormone or from labeled testosterone.
It is immediately evident from FIGURE 2 that the patients with myxedema exhibited a sharp difference in hormone metabolism from both endogenous and exogenous sources. In either case the androsterone fraction was 15 per cent or less with, of course, a concomitant increase in etiocholanolone. It is evident, then, that deficiency in thyroid hormone production is associated with a very considerable decrease in the production of androsterone.
FIGURE 3 demonstrates the effect of triiodothyronine administration on androgen metabolism both from endogenous glandular sources and from exogenous testosterone-4-C14. As noted above, the exogenous testosterone-4-C14 is metabolized identically with the endogenously produced hormones in that each showed an androsterone fraction of approximately 30 per cent. When these same subjects were treated with triiodothyronine there was a marked change in the metabolism of androgen from endogenous glandular secretion, as well as from intravenously administered testosterone-4-C14, since the androsterone fractions from each of these precursors rose to more than 50 per cent under the influence of the thyroid hormone.
The influence of hyperthyroidism on endogenous androgen metabolism is illustrated in FIGURE 4. Five patients were studied, and in each instance the androsterone fraction was 50 per cent or greater. Three of these subjects were elderly, and one had been castrated for cancer of the prostate. In the light of other results[5] the very high androsterone fractions in these individuals is striking, but is quite in accord with the concept that has been developed in this study of the interrelationship of functional thyroid level and androgen metabolism.
The effect of hyperthyroidism on exogenous testosterone metabolism in four of these same patients is shown in FIGURE 5. Again it is evident that the androsterone fraction derived from testosterone-4-C14 was large in each instance. FIGURE 6 shows the effect of treatment of the hyperthyroidism on the metabolism of androgens. Two patients were studied before and after their hyperthyroidism had been corrected. It is evident that there was a very significant diminution in the androsterone fraction in the euthyroid state as compared with the untreated hyperthyroidism.
These results are all consistent with the view that androgen metabolism is interrelated with the level of thyroid function. These findings led us to make the hypothesis that some of the recognizable effects of thyroid deficiency or excess might be mediated by the availability of androsterone in the body. One of the most evident biochemical alterations associated with thyroxine excess or deficiency is the change in the level of serum cholesterol. For this reason, we investigated the effect of androsterone on the serum cholesterol concentration in 4 patients with myxedema, in 7 patients with hypercholesterolemia, and in 5 normocholesteremic subjects. The steroid was given in a daily dose of 50 mg. intramuscularly; a representative result is shown in FIGURE 7. It is evident that androsterone caused a sharp and significant fall in the level of serum cholesterol and that, following withdrawal of the steroid, the serum cholesterol returned to the pretreatment level. The composite data from 16 individuals treated with androsterone are charted in FIGURE 8. It is evident that there was a consistent and significant influence of this steroid hormone metabolite in lowering the serum cholesterol in the 3 classes of patients studied.
The data on which these summaries are based have been published.[6] It is noteworthy that the androgenic hormones from which androsterone is derived have often been associated with hyperlipemic states, especially because of the increased incidence of atherosclerosis in men. Since androsterone production normally declines with age,[2][5] and in view of the influence this metabolite exerts on the cholesterol level as shown in this study, it seems reasonable to suggest that these events may be causally associated. Obviously, androsterone is not the sole factor concerned with the level of serum cholesterol; nevertheless, a deficiency of this substance may well be one of the mechanisms involved in the pathogenesis of hypercholesteremia and, perhaps, of atherosclerosis.
The most important conclusion that emerges from these studies is that metabolites of hormones may have an independent physiological function that is in no necessary way related to that of the glandular secretory products from which they are derived. We have recently demonstrated that etiocholanolone, the other major androgen metabolite, is a pyrogen in man? This hitherto unsuspected property may have physiological significance, as suggested from the findings of Bondy and his associates: who have indicated that a disturbance of etiocholanolone metabolism could be associated with the presence of fever in periodic disease. It is thus strongly suggested that metabolites are not simply inactive end products of a spent hormone, but may have their own important functions. There is a significant corollary to this conclusion. The present studies done in vivo and with human subjects have not as yet been reproduced in experimental animals. Thus androsterone does not lower the hypercholesterolemia of cholesterol-fed rabbits, and Kappas (personal communication) has shown that steroids that are pyrogens in man do not produce fever in other species. Since the metabolism of steroid hormones in man is appreciably different from that of the common laboratory animals, it is evident that studies in other species may not disclose the biological activity characteristic of the hormonal metabolites produced by the human.
Summary
Thyroid hormone level altered steroid hormone metabolism.
Some effects of the thyroid may be mediated through steroids.
Androsterone, a steroid metabolite, lowered elevated serum cholesterol.
Steroid metabolites have biological action separate from hormones and may be specifically related to disease.
References
[1] BRADLOW, H. L., L. HELLMAN & T. F. GALLAGHER. 1956. Interaction of hormonal effects: influence of triiodothyronine on androgen metabolism. Science. 124: 1206.
[2] KAPPAS, A. & T. F. GALLAGHER. 1955. Studies in steroid metabolism. XXVIII. The α-ketosteroid excretion pattern in normal females and the response to ACTH. J.Clin. Invest. 34: 1566.
[3] GALLAGHER, T. F. 1958. Adrenocortical carcinoma in man: the effect of amphenone on individual ketosteroids. J. Clin. Endocrinol. and Metabolism. 18: 937.
[4] BRADLOW, H. L. & T. F. GALLAGHER. 1957. Metabolism of 11β-hydroxy-Δ4-androstene- 3,17-dione in man. J. Biol. Chem. 229: 505.
[5] DOBRINER, K., A. KAPPAS, C. P. RHOADS & T. F. GALLAGHER. 1953. Studies in steroid metabolism. XIX. The α-ketosteroid excretion pattern in normal males. J. Clin. Invest. 32: 940.
[6] HELLMAN, L., H. L. BRADLOW, B. ZUMOFF, D. K. FUKUSHIMA & T. F. GALLAGHER. 1959. Thyroid-androgen interrelations and the hypocholesteremic effect of androsterone. J. Clin. Endocrinol. and Metabolism. 19: 936.
[7] KAPPAS, A., L. HELLMAN, D. K. FUKUSHIMA & T. F. GALLAGHER. 1958. The thermogenic effect and metabolic fate of etiocholanolone in man. J. Clin. Endocrinol. and Metabolism. 18: 1043.
[8] BONDY, P., K. G. L. COHN, W. HERRMANN & K. R. CRISPELL. 1958. The possible relationship of etiocholanolone to periodic fever. Yale J. Biol. and Med. 30:395.
T. F. Gallagher, Leon Hellman, H. Leon Bradlow, B. Zumoff, David K. Fukushima
Sloan-Kettering Institute for Cancer Research, New York, N. Y.
Annals of the New York Academy of Sciences, 86: 605-611. (1960)
This study is concerned with observations on the influence of thyroid hormones on the peripheral transformation of steroids in human subjects. The interrelation of these hormones was suggested by the fact that patients with untreated myxedema exhibited an extreme diminution in androsterone formation when compared with normal subjects. Furthermore, it was found that triiodothyronine could increase the production of androsterone in euthyroid subjects as well as in patients with myxedema.[1]
The studies to be described fall into three groups: (1) the definition of the quantity and kind of endogenous androgen metabolites in myxedematous, euthyroid, and hyperthyroid subjects; (2) the effect of deficiency or excess of thyroid hormone on the metabolism of exogenous androgen; and (3) investigation of the “thyromimetic” effect of androsterone.
The steroid hormone metabolites that have been examined in this study are shown in FIGURE 1. Both of the compounds formulated, androsterone and etiocholanolone, are major end-products of androgen metabolism in man. They are structurally identical except for the orientation of the hydrogen atom attached to C-5, which is a in androsterone and /3 in etiocholanolone. This might seem to be a minor chemical difference; it actually represents a very significant change in the shape of the molecule. Because of this structural dissimilarity each compound has a profoundly different biological activity. Three major potential precursors of these metabolites are also shown in FIGURE 1, and it should be emphasized that these hormones are secreted both by the adrenal gland and by the testes.
In this presentation we are concerned primarily with the quantitative relationship between these two products of androgen metabolism. In order to clarify this relationship we have employed the term androsterone fraction. This value represents the percentage of the total amount of androsterone plus etiocholanolone that is comprised by androsterone alone.
The effect of hypothyroidism on androgen metabolism is shown in FIGURE 2. We have compared a group of control subjects matched, in so far as possible, as to age and sex with a group of patients with myxedema. We have studied the endogenous production of these metabolites from their precursors in each group by chromatographic methods that have been well standardized and used for many years in our laboratories.[2][3] We have studied similarly both groups of patients with respect to their ability to metabolize a tracer dose of parenterally administered testosterone-4-C14. For this purpose the radioactive hormone was administered intravenously, and complete urine collections were obtained for 48 hours following the dose. After hydrolysis of the conjugates the two metabolites, androsterone and etiocholanolone, were isolated by the technique of reverse isotopic dilution.[4] This procedure gives a very precise measure of the amount of each of these compounds produced from the tracer dose of hormone. In the control group the average production of the 2 metabolites, androsterone and etiocholanolone, in 9 subjects showed an androsterone fraction of about 40 per cent. Seven of these subjects received tracer doses of testosterone-4-C14, and the results with this exogenous hormone were almost identical with the endogenous production; that is, the androsterone fraction again was about 40 per cent, while the etiocholanolone amounted to about 60 per cent of the total of these two substances. It is clear from these results that the tracer dose of exogenously administered radioactive hormone faithfully reflected the metabolism of the hormone produced from glandular sources. Thus the metabolic sequences concerned in the production of the metabolites can be measured either from endogenously produced hormone or from labeled testosterone.
It is immediately evident from FIGURE 2 that the patients with myxedema exhibited a sharp difference in hormone metabolism from both endogenous and exogenous sources. In either case the androsterone fraction was 15 per cent or less with, of course, a concomitant increase in etiocholanolone. It is evident, then, that deficiency in thyroid hormone production is associated with a very considerable decrease in the production of androsterone.
FIGURE 3 demonstrates the effect of triiodothyronine administration on androgen metabolism both from endogenous glandular sources and from exogenous testosterone-4-C14. As noted above, the exogenous testosterone-4-C14 is metabolized identically with the endogenously produced hormones in that each showed an androsterone fraction of approximately 30 per cent. When these same subjects were treated with triiodothyronine there was a marked change in the metabolism of androgen from endogenous glandular secretion, as well as from intravenously administered testosterone-4-C14, since the androsterone fractions from each of these precursors rose to more than 50 per cent under the influence of the thyroid hormone.
The influence of hyperthyroidism on endogenous androgen metabolism is illustrated in FIGURE 4. Five patients were studied, and in each instance the androsterone fraction was 50 per cent or greater. Three of these subjects were elderly, and one had been castrated for cancer of the prostate. In the light of other results[5] the very high androsterone fractions in these individuals is striking, but is quite in accord with the concept that has been developed in this study of the interrelationship of functional thyroid level and androgen metabolism.
The effect of hyperthyroidism on exogenous testosterone metabolism in four of these same patients is shown in FIGURE 5. Again it is evident that the androsterone fraction derived from testosterone-4-C14 was large in each instance. FIGURE 6 shows the effect of treatment of the hyperthyroidism on the metabolism of androgens. Two patients were studied before and after their hyperthyroidism had been corrected. It is evident that there was a very significant diminution in the androsterone fraction in the euthyroid state as compared with the untreated hyperthyroidism.
These results are all consistent with the view that androgen metabolism is interrelated with the level of thyroid function. These findings led us to make the hypothesis that some of the recognizable effects of thyroid deficiency or excess might be mediated by the availability of androsterone in the body. One of the most evident biochemical alterations associated with thyroxine excess or deficiency is the change in the level of serum cholesterol. For this reason, we investigated the effect of androsterone on the serum cholesterol concentration in 4 patients with myxedema, in 7 patients with hypercholesterolemia, and in 5 normocholesteremic subjects. The steroid was given in a daily dose of 50 mg. intramuscularly; a representative result is shown in FIGURE 7. It is evident that androsterone caused a sharp and significant fall in the level of serum cholesterol and that, following withdrawal of the steroid, the serum cholesterol returned to the pretreatment level. The composite data from 16 individuals treated with androsterone are charted in FIGURE 8. It is evident that there was a consistent and significant influence of this steroid hormone metabolite in lowering the serum cholesterol in the 3 classes of patients studied.
The data on which these summaries are based have been published.[6] It is noteworthy that the androgenic hormones from which androsterone is derived have often been associated with hyperlipemic states, especially because of the increased incidence of atherosclerosis in men. Since androsterone production normally declines with age,[2][5] and in view of the influence this metabolite exerts on the cholesterol level as shown in this study, it seems reasonable to suggest that these events may be causally associated. Obviously, androsterone is not the sole factor concerned with the level of serum cholesterol; nevertheless, a deficiency of this substance may well be one of the mechanisms involved in the pathogenesis of hypercholesteremia and, perhaps, of atherosclerosis.
The most important conclusion that emerges from these studies is that metabolites of hormones may have an independent physiological function that is in no necessary way related to that of the glandular secretory products from which they are derived. We have recently demonstrated that etiocholanolone, the other major androgen metabolite, is a pyrogen in man? This hitherto unsuspected property may have physiological significance, as suggested from the findings of Bondy and his associates: who have indicated that a disturbance of etiocholanolone metabolism could be associated with the presence of fever in periodic disease. It is thus strongly suggested that metabolites are not simply inactive end products of a spent hormone, but may have their own important functions. There is a significant corollary to this conclusion. The present studies done in vivo and with human subjects have not as yet been reproduced in experimental animals. Thus androsterone does not lower the hypercholesterolemia of cholesterol-fed rabbits, and Kappas (personal communication) has shown that steroids that are pyrogens in man do not produce fever in other species. Since the metabolism of steroid hormones in man is appreciably different from that of the common laboratory animals, it is evident that studies in other species may not disclose the biological activity characteristic of the hormonal metabolites produced by the human.
Summary
Thyroid hormone level altered steroid hormone metabolism.
Some effects of the thyroid may be mediated through steroids.
Androsterone, a steroid metabolite, lowered elevated serum cholesterol.
Steroid metabolites have biological action separate from hormones and may be specifically related to disease.
References
[1] BRADLOW, H. L., L. HELLMAN & T. F. GALLAGHER. 1956. Interaction of hormonal effects: influence of triiodothyronine on androgen metabolism. Science. 124: 1206.
[2] KAPPAS, A. & T. F. GALLAGHER. 1955. Studies in steroid metabolism. XXVIII. The α-ketosteroid excretion pattern in normal females and the response to ACTH. J.Clin. Invest. 34: 1566.
[3] GALLAGHER, T. F. 1958. Adrenocortical carcinoma in man: the effect of amphenone on individual ketosteroids. J. Clin. Endocrinol. and Metabolism. 18: 937.
[4] BRADLOW, H. L. & T. F. GALLAGHER. 1957. Metabolism of 11β-hydroxy-Δ4-androstene- 3,17-dione in man. J. Biol. Chem. 229: 505.
[5] DOBRINER, K., A. KAPPAS, C. P. RHOADS & T. F. GALLAGHER. 1953. Studies in steroid metabolism. XIX. The α-ketosteroid excretion pattern in normal males. J. Clin. Invest. 32: 940.
[6] HELLMAN, L., H. L. BRADLOW, B. ZUMOFF, D. K. FUKUSHIMA & T. F. GALLAGHER. 1959. Thyroid-androgen interrelations and the hypocholesteremic effect of androsterone. J. Clin. Endocrinol. and Metabolism. 19: 936.
[7] KAPPAS, A., L. HELLMAN, D. K. FUKUSHIMA & T. F. GALLAGHER. 1958. The thermogenic effect and metabolic fate of etiocholanolone in man. J. Clin. Endocrinol. and Metabolism. 18: 1043.
[8] BONDY, P., K. G. L. COHN, W. HERRMANN & K. R. CRISPELL. 1958. The possible relationship of etiocholanolone to periodic fever. Yale J. Biol. and Med. 30:395.
