THERAPEUTIC DOSES OF radioactive iodine ( 131 I; RAI)

Transcription

1 X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(7): Printed in U.S.A. Copyright 2004 by The Endocrine Society doi: /jc Rapid Rise in Serum Thyrotropin Concentrations after Thyroidectomy or Withdrawal of Suppressive Thyroxine Therapy in Preparation for Radioactive Iodine Administration to Patients with Differentiated Thyroid Cancer DINA I. SERHAL, MONA P. NASRALLAH, AND BAHA M. ARAFAH Division of Clinical and Molecular Endocrinology, University Hospitals of Cleveland and Case Western Reserve University, Cleveland, Ohio Patients with differentiated thyroid cancer are often treated transiently with T 3 in preparation for radioactive iodine (RAI) therapy. We questioned the value of using T 3 transiently in patients requiring RAI therapy. Two groups of patients requiring RAI therapy were investigated. One group included patients studied immediately after thyroidectomy, whereas the other included those withdrawn from chronic suppressive T 4 therapy that followed thyroidectomy and postoperative RAI ablation. Serum TSH were serially measured two to three times weekly until they reached more than 30 mu/liter, after which RAI therapy was administered. Serum TSH reached more than 30 mu/liter THERAPEUTIC DOSES OF radioactive iodine ( 131 I; RAI) are commonly administered to most patients (1, 2) with differentiated thyroid cancers (DTCs). This procedure is typically performed several weeks after thyroidectomy when patients have become hypothyroid. Whereas some patients are given the ablative RAI dose a few weeks after thyroidectomy, others are treated for several weeks or months with T 4 or tri-iodothyronine. Subsequently, thyroid hormone is withdrawn and RAI is administered. Standard monitoring of patients with DTC after thyroidectomy and RAI ablation includes measurements of serum thyroglobulin levels and 131 I whole-body scans (1, 2). A high serum TSH concentration is required to stimulate the release of thyroglobulin and optimize 131 I uptake by cancer cells. High serum TSH were traditionally achieved in patients who had thyroidectomies by withdrawing suppressive thyroid hormone therapy and more recently (3, 4) by the use of recombinant human TSH (rhtsh). Although rhtsh has been widely used in the diagnostic follow-up scanning of patients with DTC, it has not been approved for use alone in preparation for RAI therapy. Thyroid hormone withdrawal is currently required with or without rhtsh before RAI therapy. Abbreviations: DTC, Differentiated thyroid cancer; RAI, radioactive iodine; rh, recombinant human. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community d (mean SD, ) after thyroidectomy or 9 29 ( ) d after T 4 withdrawal. That level of TSH elevation was achieved 18 d after thyroidectomy and 22 d after T 4 withdrawal in more than 95% of patients. Minimal symptoms of hypothyroidism were noted in either group when RAI was administered. Serum TSH increased rapidly without transient therapy with T 3. To minimize symptoms of hypothyroidism, serum TSH levels should be measured twice weekly, starting 10 d after thyroidectomy or T 4 withdrawal. The data cast doubt about the value and benefits from using T 3 in preparing patients for RAI therapy. (J Clin Endocrinol Metab 89: , 2004) The interval between discontinuation of T 4 therapy and the subsequent rise in serum TSH to appropriate levels (25 30 mu/liter) for RAI administration has not been well studied, although intervals of up to 4 6 wk have been established in many centers (5 9). Because T 3 has a shorter half-life than T 4, most endocrinologists switch patients from T 4 to T 3 for several weeks in preparation for RAI therapy. Subsequently, T 3 is withdrawn and RAI therapy is administered whenever the serum TSH concentration reaches the desired value of more than mu/liter. It has been found that the average T 3 withdrawal time is approximately 2 wk (10, 11). Thus, patients would experience shorter periods of hypothyroidism after T 3 withdrawal than they would after discontinuing T 4 therapy. However, a persistent symptomatic period of hypothyroidism despite the above preparation continues to be reported (12). A study by Tamai et al. (13) evaluated thyroid function immediately after thyroidectomy and found that serum TSH reached mu/liter in 9 10 d. A very recent study involving a small number of patients suggested that after thyroid hormone withdrawal serum TSH might reach the desired elevation in a shorter period of time than originally thought (14). In the current investigation, we examined the changes in serum TSH levels in two groups of patients requiring ablative doses of RAI. One group included patients studied immediately after total thyroidectomy, whereas the other included those withdrawn from suppressive T 4 therapy after 3285

2 3286 J Clin Endocrinol Metab, July 2004, 89(7): Serhal et al. Preparation for RAI Administration having had a thyroidectomy and one or more ablative doses of RAI. We postulated that serum TSH increase rapidly after total thyroidectomy and also after withdrawal of suppressive T 4 therapy such that RAI can be administered to patients before they develop significant symptoms of hypothyroidism. Patients and Methods The study comprised consecutive patients with DTC evaluated over a 4-yr period who required therapeutic doses of RAI to treat residual thyroid remnant or metastatic disease. As discussed below, this included patients evaluated immediately after total thyroidectomy as well as others who were on suppressive T 4 therapy after having had a thyroidectomy and at least one therapeutic dose of RAI. The protocol followed at our institution indicates that DTC patients are given RAI after total thyroidectomy if their tumors were more than 1 cm or if they had nodal or distant metastasis. The protocol stipulates that patients who have measurable serum thyroglobulin levels with or without TSH stimulation are given ablative doses of RAI. Documented and sustained elevation of serum TSH concentration is necessary for the proper administration of RAI. Based on studies in the literature, the latter concentration should be greater than mu/liter (12 16). The protocol followed at our institution indicates that the serum TSH concentration should exceed 30 mu/liter at the time of RAI administration to patients with thyroid cancer. All patients included in this report had surgery by either of two experienced thyroid surgeons. Consequently, patients recruited for the current investigation were included in either the thyroidectomy group or the T 4 withdrawal group. The thyroidectomy group (n 42) included patients who were studied immediately after total thyroidectomy and did not receive any form of thyroid hormone therapy until the therapeutic dose of RAI was administered. Nine of the 42 patients had a hemi-thyroidectomy first followed, within a few days, by total thyroidectomy. Once the serum TSH level reached the desired value ( 30 mu/liter), these patients received approximately 100 mci of RAI and were subsequently started on suppressive T 4 therapy. Serum TSH levels were measured before thyroidectomy in 25 of these 42 patients and were normal. The remaining 17 patients in this group were clinically euthyroid, but their serum TSH levels were not measured before thyroidectomy. The T 4 withdrawal group (n 31) included patients who had already had a total thyroidectomy followed by RAI ablation and more than 1 yr of suppressive T 4 therapy to maintain serum less than 0.5 mu/liter. All patients included in this group had documentation of suppressed serum TSH ( 0.5 mu/liter) at the time of thyroid hormone withdrawal. Methods Patients were started on a low-iodine diet immediately after thyroidectomy (thyroidectomy group) or at the time T 4 therapy was discontinued (T 4 withdrawal group). The study design consisted of measuring serum of TSH and free T 4 in all patients every 2 3 d, starting 6 8 d after thyroidectomy or withdrawal of T 4 therapy. This is followed by the administration of therapeutic doses of RAI once serum TSH reach the desired values of more than 30mU/liter. Data on all patients were included in the analysis until RAI was administered, which is usually 1 5 d after the last measured concentration. Patients were examined on the day they received RAI therapy and assessed for clinical hypothyroidism as well as any potential tumor growth. Evaluation of clinical hypothyroidism was based on patients reported symptoms, heart rate, blood pressure measurements, and assessment of their deep tendon reflexes. Clinical evaluation of hypothyroid symptoms in patients was not quantified in detail but was clinically characterized as nonexistent (no signs or symptoms), minimal (some fatigue without any sign), moderate (moderate fatigue, cold intolerance, and some physical findings), or severe (severe symptoms and signs). Generally, patients treated immediately after thyroidectomy were given 100 mci of 131 I, whereas those treated for metastatic or recurrent disease were given mci. A scan was obtained 7 10 d after RAI therapy was administered to identify the areas of uptake. The study was approved by the Institutional Review Board. Serum TSH concentration was measured using the Centaur TSH assay, which is a two-site, ultrasensitive, chemiluminometric sandwich immunoassay. Results were available within 24 h of obtaining the blood sample. The assay has intraassay CV of 7.32, 2.48, and 2.41% and interassay CV of 10.03, 4.12, and 2.05% at three different ranges (0.021, 0.74, and mu/liter) within the assay, respectively. Serum free T 4 concentration was measured using Advia Centaur competitive chemiluminescent immunoassay with a sensitivity range 0.1 ng/dl, intraassay CV of 4.69, 2.31, and 2.22%, and interassay CV of 4.59, 1.95, and 1.58% at three different ranges (0.47, 1.08, and 3.09 ng/dl) within the assay, respectively. Statistical analysis Data are presented as mean sd unless stated otherwise. 2 was used to compare ordinal variables, and Kruskal-Wallis followed by the Mann- Whitney test was used for continuous variables. Results The clinical characteristics of the two groups are shown in Table 1. Among the patients who were studied immediately after thyroidectomy, those who had known baseline serum TSH levels before surgery (n 25) had identical clinical characteristics to those who did not have their levels measured before surgery (n 17). This included similarity in age, gender, tumor type, and stage as well as in the serial measurements of TSH and free T 4 obtained serially after thyroidectomy. Thus, the data on both subgroups were included together to represent patients studied immediately after thyroidectomy (n 42). Other than the expected differences in serum TSH and free T 4, the two groups of patients had similar clinical characteristics (Table 1). As shown in Table 1, serum TSH and free T 4 levels were TABLE 1. Clinical characteristics of two groups of patients with DTC given RAI therapy Thyroidectomy group n 42 T 4 withdrawal group n 31 Age (yr) Gender (F/M) 30/12 23/ Weight (kg) T 4 dose (mg/d) NA N/A Cancer histology (papillary/follicular) 35/7 26/ Baseline serum TSH levels (mu/liter) a Baseline serum free T 4 levels (ng/dl) a Numbers are given as means SD for age, weight, baseline serum TSH, free T 4, and T 4 dose and in absolute numbers for gender and cancer histology. F/M, Females/males. a Baseline serum TSH and free T 4 were measured in 25 of the 42 patients in the thyroidectomy group. To convert serum T 4 levels from ng/dl to pmol/liter, multiply by P value

3 Serhal et al. Preparation for RAI Administration J Clin Endocrinol Metab, July 2004, 89(7): normal before thyroidectomy. The mean ( sd) serum TSH concentration increased to (mu/liter), 9 11 d after thyroidectomy and continued to rise thereafter (Table 2 and Fig. 1). Serum free T 4 decreased gradually after thyroidectomy reaching a mean ( sd) of ng/dl at 9 11 d (Table 2 and Fig. 1). In contrast, serum TSH levels were suppressed and the free T 4 were increased just before suppressive thyroid hormone therapy was discontinued (T 4 withdrawal group). As shown in Table 2, serum TSH increased, whereas the free T 4 decreased gradually after T 4 withdrawal. In these patients, the mean serum TSH concentration, measured 9 11 d after T 4 withdrawal, was mu/liter and rose steadily thereafter. Serum free declined gradually after withdrawal of T 4 therapy, reaching a mean of ng/dl at 9 11 d. Serum TSH were consistently higher in group 1 until d, when the differences between the two groups became statistically insignificant (Fig. 1 and Table 2). Measured serum free T 4 were higher in the T 4 withdrawal group at all times until d when they were similar to those in the thyroidectomy group. The cumulative percentages of patients in both groups who had achieved the desired elevation in serum TSH ( 30 mu/liter) over time are shown in Table 3. Whereas 74% of patients had serum TSH of more than 30 mu/liter when measured 9 11 d after thyroidectomy, only 16% of the patients who were on thyroid hormone therapy had similarly elevated serum TSH values 9 11 d after hormone withdrawal (P 0.001). However, the percentage of patients with serum TSH levels of more than 30 mu/liter increased quickly over time such that no significant differences were noted after 18 d. Over 95% of patients achieved the desired elevation in serum TSH 18 d after thyroidectomy or 22 d after withdrawal of suppressive T 4 therapy. The number of days required to raise the serum TSH concentration to more than 30 mu/liter was calculated in both groups. As shown in Table 3, the mean number of days was after thyroidectomy and was after withdrawal of T 4 therapy (P 0.001). Therapeutic doses of RAI were administered within 1 5 d of the last TSH measurement. By the time they received the therapeutic dose of 131 I, most patients had minimal or no symptoms of hypothyroidism, and none had moderate or severe hypothyroidism. Similarly, none of the patients had measurable changes in evaluable neck disease during that time. Residual uptake in the thyroid bed was noted in 40 of 42 patients given RAI after thyroidectomy, and no uptake was noted in the remaining two. In the latter two patients, serum thyroglobulin levels measured just before RAI therapy were undetectable ( 0.5 ng/ml). Variable uptake was noted in patients given TABLE 2. Serum of free T 4 and TSH (mean SD) in two groups of patients with thyroid cancer measured serially after thyroidectomy or withdrawal of suppressive T 4 therapy Days Serum TSH (mu/liter) Thyroidectomy group Serum free T 4 (ng/dl) Serum TSH (mu/liter) T 4 withdrawal group Serum free T 4 (ng/dl) a a b c a c c c To convert serum thyroxine levels from ng/dl to pmol/liter, multiply by P values as compared with the in the thyroidectomy group: a P 0.001; b P 0.01; c P FIG. 1. Mean and SD of serum TSH (B) and free T 4 (A) in two groups of patients with differentiated thyroid cancer. In one group, serum TSH and free T 4 were measured serially after total thyroidectomy (Tx). In the other group (T 4 withdrawal group), serum TSH and free T 4 were measured after withdrawal of suppressive T 4 therapy (T 4 withdrawal). The latter group already had total thyroidectomy followed by one or more ablative doses of RAI. At baseline (time 0), serum TSH were measured in 25 of 42 patients in the thyroidectomy group. P values are shown for the statistical differences between the two groups at the specified time points as follows: a, P 0.001; b, P 0.01; c, P To convert serum free T 4 from ng/dl to pmol/liter, multiply by

4 3288 J Clin Endocrinol Metab, July 2004, 89(7): Serhal et al. Preparation for RAI Administration TABLE 3. Number of days required to reach the desired serum TSH concentration ( 30 mu/liter) and the cumulative number (percent) of patients achieving that level after thyroidectomy or withdrawal of suppressive T 4 therapy Thyroidectomy group T 4 withdrawal group P value Mean SD Median N/A Range N/A No. (%) of patients with serum TSH 30 mu/liter at: 9 11 d 31/42 (74) 5/31 (16) d 39/42 (93) 24/31 (65) d 40/42 (95) 26/31 (84) d 41/42 (98) 30/31 (97) 1.00 The thyroidectomy group patients were studied immediately after total thyroidectomy. Patients in the T 4 withdrawal group already had total thyroidectomy and one or more therapeutic doses of RAI and were studied after withdrawal of more than 1 yr of suppressive T 4 therapy. RAI therapy to treat residual or recurrent disease (T 4 withdrawal group) more than a year after total thyroidectomy and an initial ablative dose of iodine. Discussion Most patients with invasive DTC are given ablative doses of RAI after thyroidectomy to eradicate normal remnant thyroid tissue or residual cancer. Although in such instances, RAI therapy can be administered shortly after thyroidectomy, it is often delayed for weeks or months. During that time, patients are given either T 4 or T 3 for several weeks before they are withdrawn in preparation for RAI administration. The rationale for the delay is not clear but is reportedly to allow tissue healing and patients recovery after surgery. Considering the advances in surgical techniques and postoperative care, most patients are discharged home within h of having a total thyroidectomy, and most return to near normal activities within d. Although in such instances, RAI therapy can be delayed for logistical reasons or in response to a patient s wishes, there is no known medical reason for delaying such treatment after thyroidectomy. It is common practice to follow a 6-wk protocol in preparing patients for RAI administration (1 3, 5 9). Whereas cessation of T 4 therapy represents one method, the most commonly used approach consists of substituting the more rapidly metabolized T 3 for T 4 for 3 4 wk followed by withdrawal of the former for 2 3 wk. This was based on some studies that demonstrated T 3 withdrawal time to be 2 wk (9 12) compared with the 4 6 wk for T 4 withdrawal (5 7). Several reports have provided alternative approaches, aimed at minimizing the symptoms of hypothyroidism, in preparing patients for RAI therapy (7 15). Although some replace T 4 with T 3 for several weeks, others lower the dose of T 4 by 50% or use rhtsh in addition. Although each of these approaches has been reported to be successful, we believe that our approach is very practical and effective. Our data show that RAI ablation in patients with DTC can be effectively done 2 3 wk after thyroidectomy. It would, therefore, be unnecessary to use T 4 or T 3 transiently in this setting. We noted that serum TSH levels increased rapidly after thyroidectomy such that they were more than 30 miu/ liter in approximately 2 wk. This would be very similar to the reported time required for the rise in serum TSH levels to the same degree after several weeks of T 3 use (7, 10 12). By the time they were ready for RAI therapy, patients had minimal symptoms of hypothyroidism. They tolerated RAI therapy very well and were started on suppressive T 4 therapy immediately thereafter. The scans done 7 10 d after the ablative doses of RAI were administered showed minimal uptake in the thyroid bed in the majority of patients in our study. Being negligible, the latter uptake in the thyroid bed is consistent with the rapid increase in serum TSH levels immediately after thyroidectomy noted in our patients. One limitation to our study is that the assessment of symptoms of hypothyroidism was not blinded and therefore somewhat subjective. However, none of our patients had clinically significant symptoms or signs of hypothyroidism. Furthermore, the study showed that the time required for the serum TSH to reach the desired value of more than 30 mu/liter was very similar to that reported with the transient use of T 3. Over 95% of patients had achieved that degree of elevation in serum TSH at 18 d after thyroidectomy or 22 d after withdrawal of suppressive T 4 therapy. Even though our study did not include a comparative group of patients given T 3, it is important to emphasize the fact that the number of days required to raise serum TSH as reported in our study and by others (13) were very similar to those reported using T 3 transiently. Our data are remarkably similar to those of Tamai et al. (13), who found that serum TSH reached mu/liter 9 10 days after thyroidectomy. In contrast, an earlier report by Edmonds et al. (16) showed that at 2 3 wk after presumed total thyroidectomy, only 20 of 48 patients had elevated serum TSH, whereas the rest had normal or minimally elevated levels associated with normal or near normal serum T 4. It is more than likely that the latter group of patients had significant residual thyroid tissue to account for the difference. Similarly, serum TSH levels increased to more than 30 mu/liter approximately 18 d after discontinuing suppressive T 4 therapy, with nearly 95% of the patients achieving such levels in less than 3 wk. This is remarkably similar to the data reported by Liel (14) who studied eight patients after discontinuing T 4 suppressive therapy and found that the mean interval for serum TSH to be more than 30 miu/liter was 17 d. Considering potential side effects from T 3 use, particularly in elderly patients, the data cast doubt about the necessity for and benefit from the transient use of T 3 before RAI administration. As expected, patients who were withdrawn from T 4 therapy had a slower rise in serum TSH compared with those who had total thyroidectomy. The slower rise in serum TSH after T 4 withdrawal may reflect the delayed recovery of the pituitary-thyroid axis that has been suppressed by exogenous thyroid hormone (17, 18). Thus, the time required to raise serum TSH to more than 30 miu/liter was longer ( d) in the patients who were discontinued T 4 suppressive therapy than in those who had only thyroidectomy ( d). In conclusion, our study shows that serum TSH levels

5 Serhal et al. Preparation for RAI Administration J Clin Endocrinol Metab, July 2004, 89(7): increase rapidly after thyroidectomy or thyroid hormone withdrawal. Most patients reached the high serum TSH required for diagnostic or therapeutic administration of RAI at 2 3 wk after thyroidectomy or withdrawal of suppressive thyroid hormone treatment. To be effective in minimizing symptoms of hypothyroidism, we advocate that serum TSH levels should be measured twice weekly, starting 10 d after elimination of the endogenous (thyroidectomy) or exogenous source of thyroid hormone. Alternatively, serum TSH can be measured at d after either thyroidectomy or withdrawal of T 4 therapy and once or twice weekly thereafter. If a prolonged period of advanced notice is required before the administration of RAI, therapy can be tentatively planned 3 wk after thyroidectomy or T 4 withdrawal, because by that time approximately 95% of patients would have achieved the desired elevation in serum TSH. The schedule can be adjusted to fit the needs and circumstances of individual patients. This will minimize potential tumor growth that might rarely occur during hypothyroxinemia, particularly in patients with aggressive cancer. We also recommend that a low-iodine diet should be instituted at the time of removal of the thyroid hormone source, in preparation for RAI therapy. Even though our study did not include a group of patients given T 3, the data cast doubt about the value and benefits from the transient use of T 3 before RAI administration. Acknowledgments We are indebted to all referring physicians and to Barbara Vaughn and Nancy Ballou of the ambulatory facility nursing staff for their outstanding help in scheduling and obtaining the necessary blood samples. We also thank our colleagues in the Department of Nuclear Medicine for facilitating the study. Received July 3, Accepted March 19, Address all correspondence and requests for reprints to: Baha M. Arafah, M.D., Division of Clinical and Molecular Endocrinology, University Hospitals of Cleveland, Euclid Avenue, Cleveland, Ohio bxa@po.cwru.edu. A preliminary report of the data was presented at the annual meeting of The Endocrine Society in San Francisco, California, June References 1. Mazzaferri EL, Jhiang SM 1994 Long term impact of initial surgery and medical therapy in papillary and follicular thyroid cancer. Am J Med 97: Samaan NA, Schultz PN, Hickey RC, Goepfert H, Haynie TP, Johnston DA, Ordonez NG 1992 The results of various modalities of treatment of well differentiated thyroid carcinoma: a retrospective review of 1599 patients. J Clin Endocrinol Metab 75: Meier CA, Braverman LE, Ebner S, Veronikis I, Daniels GH, Ross DS, Deraska DJ, Davies TF, Valentine M, DeGroot LJ 1994 Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (phase I/II study). J Clin Endocrinol Metab 78: Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI, Cooper DS, Graham KE, Braverman LE, Skarulis MC, Davies TF, De- Groot LJ, Mazzaferri EL, Daniels GH, Ross DS, Luster M, Samuels MH, Becker DV, Maxon 3rd HR, Cavalieri RR, Spencer CA, McEllin K, Weintraub BD, Ridgway EC 1999 A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 84: Stahl TJ, Shapiro B 1973 Use of human thyrotropin radioimmunoassay in the management of patients with thyroid carcinoma. J Nucl Med 14: Varma VM, Beirwaltes WH 1970 Treatment of thyroid cancer. JAMA 214: Hilts SV, Hellman D, Anderson J, Woolfenden J, Van Antwerp J, Patton D 1979 Serial TSH determinations after T 3 withdrawal or thyroidectomy in the therapy of thyroid carcinomas. J Nucl Med 20: Ain KB 2002 Thyroid cancer. In: Rakel RE, Bope ET, eds. Conn s current therapy. Philadelphia: WB Saunders; Mazzaferri EL 2000 Radioiodine and other treatments and outcomes. In: Braverman LE, Utiger RD, Ingbar SH, Werner SC. Werner and Ingbar s the thyroid: a fundamental and clinical textbook, 8th ed. Philadelphia: Lippincott- Williams, Wilkins; Cotton GE, Gorman CA, Mayberry WE 1971 Suppression of thyrotropin (h-tsh) in serums of patients with myxedema of varying etiology treated with thyroid hormones. N Engl J Med 285: Goldman JM, Line BL, Aamodt RL, Robbins J 1980 Influence of triiodothyronine withdrawal time on 131 I uptake postthyroidectomy for thyroid cancer. J Clin Endocrinol Metab 50: Schlumberger MJ 1998 Papillary and follicular thyroid carcinoma. N Engl J Med 338: Tamai H, Suemastu H, Kurokawa N, Esaki M, Ikemi T, Matsuzuka F, Kuma K, Nagataki S 1979 Alterations in circulating thyroid hormones and thyrotropin after complete thyroidectomy. J Clin Endocrinol Metab 48: Liel Y 2002 Preparation for radioactive iodine administration in differentiated thyroid cancer patients. Clin Endocrinol (Oxf) 57: Guimaraes V, DeGroot LJ 1996 Moderate hypothyroidism in preparation for whole 131 I scintiscans and thyroglobulin testing. Thyroid 6: Edmonds CJ, Hayes S 1977 Measurement of serum TSH and thyroid hormones in the management of treatment of thyroid carcinoma with radioiodine. Br J Radiol 50: Vagenakis AG, Braverman LE, Azizi F, Portnay GI, Ingbar SH 1975 Recovery of pituitary thyrotropic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med 293: Burmeister LA, Goumaz MO, Mariash CW, Oppenheimer JH 1992 Levothyroxine dose requirements for thyrotropin suppression in the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab 75: JCEM is published monthly by The Endocrine Society ( the foremost professional society serving the endocrine community.