Metabolic Clearance and Blood Production Rates of Estradiol in Hyperthyroidism E. CHESTER RIDGWAY, CHRISTOPHER LONGCOPE, AND FARAHE MALOOF Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and the Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545 ABSTRACT. The metabolic clearance rate of 17/3estradiol (MCR2), the plasma levels of 17/3-estradiol (E2)1, sex-steroid binding globulin (SSBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured in 10 hyperthyroid subjects (7 men and 3 women). The blood production rate of 17/3-estradiol (PB2) was calculated for all subjects. Nine of the 10 hyperthyroid subjects had a decreased MCR2 which returned towards normal in 5 of the 6 subjects restudied following therapy. In all 10 subjects the levels of SSBG were increased when they were hyperthyroid and returned toward normal with therapy. It is concluded that the decrease in MCR2 is largely due to the increased binding of 17/3-estradiol to SSBG.
I
N hyperthyroidism there is a shift in the normal pattern of urinary steroid metabolites. Increased excretion of 11-oxo and 5ametabolites of cortisol1 at the expense of 11/3-hydroxy and 5/3-metabolites have been noted (1,2). The 5a-metabolites of testosterone are excreted in increased amounts compared to the 5/3-metabolites (3), and for the urinary metabolites of 17/3-estradiol, the amounts of 2-methoxy compounds are increased while the amounts of estriol are decreased (4,5). While the changes noted in the urinary metabolites of cortisol and testosterone are somewhat similar, the changes which occur in the metabolism of the unconjugated steroids in the blood are markedly dissimilar. The metabolic clearance and proReceived December 27, 1974. Please address reprint requests to Dr. C. Longcope, Worcester Foundation, Shrewsbury, Mass. 01545. 1 The following trivial names are used: 17/3-estradiol for estra-l,3,5(10)-triene-3,17/3-diol; estrone for 3hydroxyestra-l,3,5(10)-trien-17-one; testosterone for 17/3-hydroxyandrost-4-en-3-one; cortisol for 11/3, 17,21-trihydroxypregn-4-ene-3,20-dione.
In 7 of the 10 hyperthyroid the plasma E2 concentrations were normal whereas 3 had slightly elevated levels. In 8 of the 10 hyperthyroid the PB2 was within the normal range. Only 2 hyperthyroid subjects had slightly elevated PB2. In the 6 subjects who were restudied after therapy, there was no consistent change in PB2 which remained in the normal range in all cases. It is concluded that the MCR2 is decreased in most subjects with hyperthyroidism in association with an increase of SSBG. Despite this change in MCR2 there is no significant change in PB2. The increase in SSBG levels in hyperthyroidism appears to be a direct effect of the elevation of thyroid hormone activity and is not mediated through estrogen. (J Clin Endocrinol Metab 41: 491, 1975)
duction rates of cortisol are increased (6) while the plasma cortisol concentration remains essentially normal. For testosterone however, the plasma concentration is generally elevated (7), the metabolic clearance rate is decreased (8,9) and the blood production rate remains normal (9). It is not certain whether the dynamics of 17/3-estradiol metabolism resemble more closely those of cortisol or testosterone. Chopra et al. (10) and Chopra and Tulchinsky (11) reported that the plasma 17/3estradiol concentration was elevated in men while they were hyperthyroid. Ruder et al. (12) reported, however, that the metabolic clearance rate of 17/3-estradiol (MCR2) did not change in 2 of 3 subjects who were made hyperthyroid with L-triiodothyronine. On the basis of these two studies, it was felt that hyperthyroid individuals would have an increased blood production rate of 17/3estradiol (10). In an attempt to elucidate further these problems, we have determined the MCR2, plasma concentrations and production rate of 17/3-estradiol in individuals with hyperthyroidism. 491
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492
JCE & M • 1975 Vol41» No 3
RIDGWAY, LONGCOPE AND MALOOF
Materials and Methods Patients. Ten hyperthyroid patients (age 27-69) were studied on the Metabolic Research Ward of the Massachusetts General Hospital and informed consent was obtained prior to all procedures. The patients (7 men and 3 women) presented with classical clinical and laboratory criteria for the diagnosis including nervousness, weight loss, heat intolerance, tremor, an enlarged thyroid gland and elevated indices of thyroid function. None of the patients was taking estrogen or androgen medication. Laboratory assessment of thyroid function including total thyroxine (T4D), free thyroxine (FT4), total triiodothyronine (T3D), radioiodine uptake (RAI uptake), serum thyrotropin (TSH), basal metabolic rate (BMR) were all performed by previously described methods (13). Plasma 17/3-estradiol (E2) was measured by the method of Nagai and Longcope (14); plasma testosterone (T) and the sex-steroid binding globulin (SSBG) were measured by Inter Science Institute, Los Angeles, Calif, using the methods of Furuyama et al. (15) and Nugent et al. (16) respectively. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured by radioimmunoassay using the methods of Odell et al. (17,18). Both LH and FSH are expressed in ng LER-907 per ml. Metabolic clearance rates (MCR2) of estradiol were performed utilizing the constant infusion method (19). 6,7-3H-17/3-Estradiol (42 mCi/mmol) was obtained from New England Nuclear Corporation; 4-14C-17/3-estradiol (31.7 mCi/ mmol) and 4-14C-estrone (33.7 mCi/mmol) were obtained from Amersham-Searle Corporation. All radioactive steroids were purified prior to use (20) and administered in an eight percent ethanol in saline solution. All infusions were carried out between 8 and 11:30 AM with the subjects supine and fasting. At zero time baseline samples were collected for 17/3-estradiol, testosterone, sex steroid binding globulin, LH and FSH. Then each subject received intravenously 4 /xCi of 3H-estradiol in 10 ml of solution and 30 minutes later a constant infusion of 6 /aCi of 3 H-17/3-estradiol in 15 ml of solution was started and continued at a constant rate for 180 min. Blood samples were collected from the opposite arm at 120, 150,180 min of the infusion. The samples were centrifuged and the plasma stored at 4 C until they were analyzed for radio-
activity as unconjugated 17/3-estradiol and estrone as previously described (20). The metabolic clearance rates (MCR2) and production rates (PB2) of 17/3-estradiol were then calculated by previously described methods (19). It should be noted that the MCR2 was determined in the supine position and the concentration of E2 was determined on a specimen of blood obtained between 7:30-8:00 AM. The PB2 calculated from these data are essentially estimates in any one individual but the mean data would be comparable to our normal group. Of the 7 hyperthyroid men, 5 were treated with radioactive iodine and followed until significant clinical improvement occurred; 1 (#5) was treated with propylthiouracil and 1 (#6) had a subtotal thyroidectomy. Subjects 1 and 9 both had slightly elevated TSH levels but were clinically euthyroid when restudied. These two patients have been followed an additional year and continue to be clinically euthyroid with normal TSH levels. All three hyperthyroid females were treated with radioactive iodine. Following therapy with radioactive iodine 3 men and 3 women were restudied several months after significant improvement in thyroid function had been achieved.
Results
The thyroid function studies on the 10 patients are given in Table 1. The 10 patients (7 men and 3 women) were hyperthyroid as documented by elevated RAI uptakes, T4D, FT4 and T3D. Only 2 of the hyperthyroid men had gynecomastia and the 1 reproductive-aged woman had regular menstrual cycles. The results of the estrogen studies are given in Table 2. The 7 men when hyperthyroid had a mean ± SE MCR2 of 650 ± 125 liter/day/m2 which is significantly less (P < 0.01) than the mean of 915 ± 30 liters/ day/m2 found in 24 normal men in our laboratory (20-23). The age range of the normals was similar to that of the subjects. The 2 postmenopausal hyperthyroid women had MCR2 of 480 and 500 liters/day/m2, each of which is at the lower limit of our normal of 500 liters/day/m2 found in 8 postmenopausal women (23,24). The 1 premenopausal
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ESTRADIOL PRODUCTION IN HYPERTHYROIDISM
493
TABLE 1. Thyroid function on individual patients Subject #
Age/Sex
BMR %
T4D Mg%
FT4 ng %
T3D ng%
Rail %
TSH uU/ml
Clinical diagnosis
1
38/M
ND ND
11.5 3.0
3.0 0.6
380 135
60 33
I
N hyperthyroidism there is a shift in the normal pattern of urinary steroid metabolites. Increased excretion of 11-oxo and 5ametabolites of cortisol1 at the expense of 11/3-hydroxy and 5/3-metabolites have been noted (1,2). The 5a-metabolites of testosterone are excreted in increased amounts compared to the 5/3-metabolites (3), and for the urinary metabolites of 17/3-estradiol, the amounts of 2-methoxy compounds are increased while the amounts of estriol are decreased (4,5). While the changes noted in the urinary metabolites of cortisol and testosterone are somewhat similar, the changes which occur in the metabolism of the unconjugated steroids in the blood are markedly dissimilar. The metabolic clearance and proReceived December 27, 1974. Please address reprint requests to Dr. C. Longcope, Worcester Foundation, Shrewsbury, Mass. 01545. 1 The following trivial names are used: 17/3-estradiol for estra-l,3,5(10)-triene-3,17/3-diol; estrone for 3hydroxyestra-l,3,5(10)-trien-17-one; testosterone for 17/3-hydroxyandrost-4-en-3-one; cortisol for 11/3, 17,21-trihydroxypregn-4-ene-3,20-dione.
In 7 of the 10 hyperthyroid the plasma E2 concentrations were normal whereas 3 had slightly elevated levels. In 8 of the 10 hyperthyroid the PB2 was within the normal range. Only 2 hyperthyroid subjects had slightly elevated PB2. In the 6 subjects who were restudied after therapy, there was no consistent change in PB2 which remained in the normal range in all cases. It is concluded that the MCR2 is decreased in most subjects with hyperthyroidism in association with an increase of SSBG. Despite this change in MCR2 there is no significant change in PB2. The increase in SSBG levels in hyperthyroidism appears to be a direct effect of the elevation of thyroid hormone activity and is not mediated through estrogen. (J Clin Endocrinol Metab 41: 491, 1975)
duction rates of cortisol are increased (6) while the plasma cortisol concentration remains essentially normal. For testosterone however, the plasma concentration is generally elevated (7), the metabolic clearance rate is decreased (8,9) and the blood production rate remains normal (9). It is not certain whether the dynamics of 17/3-estradiol metabolism resemble more closely those of cortisol or testosterone. Chopra et al. (10) and Chopra and Tulchinsky (11) reported that the plasma 17/3estradiol concentration was elevated in men while they were hyperthyroid. Ruder et al. (12) reported, however, that the metabolic clearance rate of 17/3-estradiol (MCR2) did not change in 2 of 3 subjects who were made hyperthyroid with L-triiodothyronine. On the basis of these two studies, it was felt that hyperthyroid individuals would have an increased blood production rate of 17/3estradiol (10). In an attempt to elucidate further these problems, we have determined the MCR2, plasma concentrations and production rate of 17/3-estradiol in individuals with hyperthyroidism. 491
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 28 September 2015. at 18:59 For personal use only. No other uses without permission. . All rights reserved.
492
JCE & M • 1975 Vol41» No 3
RIDGWAY, LONGCOPE AND MALOOF
Materials and Methods Patients. Ten hyperthyroid patients (age 27-69) were studied on the Metabolic Research Ward of the Massachusetts General Hospital and informed consent was obtained prior to all procedures. The patients (7 men and 3 women) presented with classical clinical and laboratory criteria for the diagnosis including nervousness, weight loss, heat intolerance, tremor, an enlarged thyroid gland and elevated indices of thyroid function. None of the patients was taking estrogen or androgen medication. Laboratory assessment of thyroid function including total thyroxine (T4D), free thyroxine (FT4), total triiodothyronine (T3D), radioiodine uptake (RAI uptake), serum thyrotropin (TSH), basal metabolic rate (BMR) were all performed by previously described methods (13). Plasma 17/3-estradiol (E2) was measured by the method of Nagai and Longcope (14); plasma testosterone (T) and the sex-steroid binding globulin (SSBG) were measured by Inter Science Institute, Los Angeles, Calif, using the methods of Furuyama et al. (15) and Nugent et al. (16) respectively. Serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured by radioimmunoassay using the methods of Odell et al. (17,18). Both LH and FSH are expressed in ng LER-907 per ml. Metabolic clearance rates (MCR2) of estradiol were performed utilizing the constant infusion method (19). 6,7-3H-17/3-Estradiol (42 mCi/mmol) was obtained from New England Nuclear Corporation; 4-14C-17/3-estradiol (31.7 mCi/ mmol) and 4-14C-estrone (33.7 mCi/mmol) were obtained from Amersham-Searle Corporation. All radioactive steroids were purified prior to use (20) and administered in an eight percent ethanol in saline solution. All infusions were carried out between 8 and 11:30 AM with the subjects supine and fasting. At zero time baseline samples were collected for 17/3-estradiol, testosterone, sex steroid binding globulin, LH and FSH. Then each subject received intravenously 4 /xCi of 3H-estradiol in 10 ml of solution and 30 minutes later a constant infusion of 6 /aCi of 3 H-17/3-estradiol in 15 ml of solution was started and continued at a constant rate for 180 min. Blood samples were collected from the opposite arm at 120, 150,180 min of the infusion. The samples were centrifuged and the plasma stored at 4 C until they were analyzed for radio-
activity as unconjugated 17/3-estradiol and estrone as previously described (20). The metabolic clearance rates (MCR2) and production rates (PB2) of 17/3-estradiol were then calculated by previously described methods (19). It should be noted that the MCR2 was determined in the supine position and the concentration of E2 was determined on a specimen of blood obtained between 7:30-8:00 AM. The PB2 calculated from these data are essentially estimates in any one individual but the mean data would be comparable to our normal group. Of the 7 hyperthyroid men, 5 were treated with radioactive iodine and followed until significant clinical improvement occurred; 1 (#5) was treated with propylthiouracil and 1 (#6) had a subtotal thyroidectomy. Subjects 1 and 9 both had slightly elevated TSH levels but were clinically euthyroid when restudied. These two patients have been followed an additional year and continue to be clinically euthyroid with normal TSH levels. All three hyperthyroid females were treated with radioactive iodine. Following therapy with radioactive iodine 3 men and 3 women were restudied several months after significant improvement in thyroid function had been achieved.
Results
The thyroid function studies on the 10 patients are given in Table 1. The 10 patients (7 men and 3 women) were hyperthyroid as documented by elevated RAI uptakes, T4D, FT4 and T3D. Only 2 of the hyperthyroid men had gynecomastia and the 1 reproductive-aged woman had regular menstrual cycles. The results of the estrogen studies are given in Table 2. The 7 men when hyperthyroid had a mean ± SE MCR2 of 650 ± 125 liter/day/m2 which is significantly less (P < 0.01) than the mean of 915 ± 30 liters/ day/m2 found in 24 normal men in our laboratory (20-23). The age range of the normals was similar to that of the subjects. The 2 postmenopausal hyperthyroid women had MCR2 of 480 and 500 liters/day/m2, each of which is at the lower limit of our normal of 500 liters/day/m2 found in 8 postmenopausal women (23,24). The 1 premenopausal
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 28 September 2015. at 18:59 For personal use only. No other uses without permission. . All rights reserved.
ESTRADIOL PRODUCTION IN HYPERTHYROIDISM
493
TABLE 1. Thyroid function on individual patients Subject #
Age/Sex
BMR %
T4D Mg%
FT4 ng %
T3D ng%
Rail %
TSH uU/ml
Clinical diagnosis
1
38/M
ND ND
11.5 3.0
3.0 0.6
380 135
60 33
