Vol. 75, Na. 1 Prmted III 113 A
Bromocriptine due to Pituitary ANTHONY MAYLENE
and Triac Therapy for Hyperthyroidism Resistance to Thyroid Hormone*
J. DULGEROFF, MITCHELL E. GEFFNER, WONG, AND JEROME M. HERSHMAN
SANKAR
N. KOYAL,
Endocrinology and Metabolism Division, West Los Angeles Veterans Administration Medical Center, Los Angeles, California 90073; and the Departments of Medicine and Pediatrics, University of California School of Medicine, Los Angeles, California 90024 ABSTRACT
Brc therapy (12.5 mg/day), heart rate decreased (108 to 72/min), TSH decreased (5.7 to 1.2 mu/L), T:, decreased (9.9 to 1.7 nmol/L), free T, decreased (205 to 21 pmol/L), ST1 lengthened (left ventricular ejection time, 0.389 to 0.405 s), and VO, did not change (164 to 162 mL/min). We found no significant clinical improvement with a maximal dose of Triac (2.1 mg/day), only minimal reduction in goiter size; mild decreases in TR (9.9 to 6.7 nmol/L), free T, (205 to 113 pmol/L), and TSH (5.7 to 5.4 mu/L); no change in ST1 (left ventricular ejection time, 0.389 to 0.401 set); and an increase in 0, consumption (VO,, 164 to 209 mL/min). Thus, the results favor Brc as effective therapy for this patient with PRTH. (J Clin Endocrinol Metab 75: 1071-1075, 1992)
Although a number of patients with generalized resistance to thyroid hormone have been treated with bromocriptine (Brc), only one previously reported patient with nontumoral TSH-mediated hyperthyroidism, presumably due to pituitary resistance to thyroid hormone (PRTH), has been successfully treated with bromocriptine (Brc). In addition, several studies suggested that the T, analog 3,5,3’-triiodothyroacetic acid (Triac) may control hyperthyroidism in patients with PRTH. In the current study a patient with PRTH diagnosed at age 15 yr underwent separate therapeutic trials with Brc and Triac, during which time physical parameters, thyroid function tests, systolic time intervals (STI), and oxygen consumption (VO,) were measured. On
R
ESISTANCE to thyroid hormone is characterized by the diminished responseof target tissuesto an adequate or increasedamount of thyroid hormone (1). Patients are identified by persistently elevated serum levels of T, and T3 in the absence of intercurrent illnesses,medication usage, or alterations of thyroid hormone binding to serum proteins. At the sametime, serum TSH levels are inappropriately normal or elevated, and the TSH responseto TRH is not suppressed despite high circulating levels of free thyroid hormone. Generalized resistance to thyroid hormone (GRTH) affects all thyroid hormone-responsive tissuesto varying degrees.Patients with this disorder are clinically euthyroid or hypothyroid (1, 2). Pituitary resistance to thyroid hormone (PRTH) primarily affects the regulation of TSH secretion; supranorma1thyroid hormone levels do not inhibit TSH secretion (1, 2). In both cases, the defect is thought to be partial, as complete resistance would probably be incompatible with life (1). GRTH is inherited in an autosomal dominant fashion and has been linked to single base substitutions on the cerbA0 thyroid hormone receptor gene in several kindreds and a deletion of c-erbA@ receptor gene in the original kindred (3). The inheritance pattern of PRTH has not been delineated. Dopamine has been shown to inhibit TSH secretion (4, 5), and bromocriptine (Brc) is a dopamine agonist that inhibits TSH secretion in some patients with inappropriate TSH Received November 25, 1991. Address requests for reprints to: Jerome M. Hershman, M.D., Endocrinology Wll lD, West Los Angeles Veterans Administration Medical Center, Los Angeles, California 90073. * This work was supported by V.A. Medical Research Funds.
secretion due to tumoral secretion, GRTH, and PRTH (6-8). 3,5,3’-Triiodothyroacetic acid (Triac) is a T3 analog that binds to nuclear receptors with higher affinity than T3 and has a very short residencetime on the nuclear receptor in comparison with T3 (9). The metabolic effects of Triac are alleged to be small in magnitude and short-lived. When Triac was given to normal or thyroidectomized patients, it suppressedbasal TSH levels and the TSH responseto TRH without changing heart rate, weight, or Achilles tendon reflex time (10). This suppressionof TSH secretion with minimal peripheral metabolic effects makes Triac a potential treatment for patients with PRTH. Triac has reportedly been used successfully in eight patients and unsuccessfully in two patients with PRTH to relieve symptoms of hyperthyroidism (2, 11-15). In this study we treated a patient with PRTH diagnosed at age 15 yr with separate coursesof Brc and Triac to determine their effects on her hyperthyroidism. Materials
and Methods
Serum T, and free T, (FT,) were measured by RIA using commercial kits (Diagnostic Products Corp., Los Angeles, CA); the normal ranges are: TX, 1.3-2.7 nmol/L; and FTI, 9-27 pmol/L. There was a 25% crossreaction of Triac in the T, RIA. TSH was measured by a sensitive immunoradiometric assay (Hybritech, HS-IRMA, La Jolla, CA; normal range, 0.4-5.3 mu/L). TRH tests were performed by giving 500 rg synthetic TRH, iv; TSH measurements were obtained at -15, 0, 15, 30, 45, and 60 min. Systolic time intervals (STI) were determined from aortic flow velocity signals recorded with continuous wave doppler ultrasound. Left ventricular ejection time (LVET) was defined from the onset to the end of the aortic velocity spectrum. QT was measured as the interval from the Q wave on the simultaneously recorded electrocardiogram to the end of LVET. The preejection period (PEP) was the difference between LVET
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The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 22 October 2015. at 19:15 For personal use only. No other uses without permission. . All rights reserved.
DULGEROFF
1072
and QT (PEP = QT - LVET). Three cardiac cycles were measured from each of three observations made during each clinical visit (each observation made after 20 min of recumbency). LVET and PEP were corrected for heart rate (HR) using Tseng’s formulas: LVETc = LVET + 0.6 X HR; PEPc = PEP + 0.4 x HR (16). The intraobserver error was calculated from the mean and so of all observations and is expressed as a mean coefficient of variation. Oxygen consumption was measured by a SensorMedics Horizon Metabolic System (model 4400, Yorba Linda, CA) employing a minute by minute analysis of cardiorespiratory variables [minute ventilation, tidal volume, and oxygen consumption (VO,)]. Data were gathered for 3-10 min until a steady state was observed, after which the measurements were recorded. Means of all results were calculated. Brc was provided by Sandoz (Englewood, NJ). Triac was supplied in 0.35.mg tablets by ANA SA Laboratories (Neuilly-Sur-Seine, France). The experimental protocol was approved by our Human Subject Research Committee. The patient and her mother gave informed consent.
Case Report The patient is now a 17-yr-old black female who presented in June 1986 at the age of 12 yr with complaints of weight loss, nervousnes, heat intolerance, and tremor for 6-12 months. She had no nausea, diarrhea, or headaches, Her past medical history was remarkable for sickle cell trait and a heart murmur. Her blood pressure was 145/80, heart rate was 118 beats/min, respiratory rate was 15/min, height was 158 cm (75th percentile), and weight was 36 kg (25th percentile). She had no exophthalmos. Her thyroid gland was enlarged and measured 5 X 3 cm on the right and 5 x 2 cm on the left, and the consistency was firm with no irregularities. She had a II/VI systolic ejection murmur, a fine tremor, hyperkinesis, and brisk tendon reflexes, Her serum T, level was 498 nmoI/L (normal, 64-167 nmoI/L), FT, index was 753 (normal, 64-l 67), T3 was 11.5 nmoI/L, and TSH was 5.1 mu/L. Antithyroglobulin and antimicrosomal antibody were negative, and thyroid-stimulating immunoglobulins were 128% (normal,
Bromocriptine due to Pituitary ANTHONY MAYLENE
and Triac Therapy for Hyperthyroidism Resistance to Thyroid Hormone*
J. DULGEROFF, MITCHELL E. GEFFNER, WONG, AND JEROME M. HERSHMAN
SANKAR
N. KOYAL,
Endocrinology and Metabolism Division, West Los Angeles Veterans Administration Medical Center, Los Angeles, California 90073; and the Departments of Medicine and Pediatrics, University of California School of Medicine, Los Angeles, California 90024 ABSTRACT
Brc therapy (12.5 mg/day), heart rate decreased (108 to 72/min), TSH decreased (5.7 to 1.2 mu/L), T:, decreased (9.9 to 1.7 nmol/L), free T, decreased (205 to 21 pmol/L), ST1 lengthened (left ventricular ejection time, 0.389 to 0.405 s), and VO, did not change (164 to 162 mL/min). We found no significant clinical improvement with a maximal dose of Triac (2.1 mg/day), only minimal reduction in goiter size; mild decreases in TR (9.9 to 6.7 nmol/L), free T, (205 to 113 pmol/L), and TSH (5.7 to 5.4 mu/L); no change in ST1 (left ventricular ejection time, 0.389 to 0.401 set); and an increase in 0, consumption (VO,, 164 to 209 mL/min). Thus, the results favor Brc as effective therapy for this patient with PRTH. (J Clin Endocrinol Metab 75: 1071-1075, 1992)
Although a number of patients with generalized resistance to thyroid hormone have been treated with bromocriptine (Brc), only one previously reported patient with nontumoral TSH-mediated hyperthyroidism, presumably due to pituitary resistance to thyroid hormone (PRTH), has been successfully treated with bromocriptine (Brc). In addition, several studies suggested that the T, analog 3,5,3’-triiodothyroacetic acid (Triac) may control hyperthyroidism in patients with PRTH. In the current study a patient with PRTH diagnosed at age 15 yr underwent separate therapeutic trials with Brc and Triac, during which time physical parameters, thyroid function tests, systolic time intervals (STI), and oxygen consumption (VO,) were measured. On
R
ESISTANCE to thyroid hormone is characterized by the diminished responseof target tissuesto an adequate or increasedamount of thyroid hormone (1). Patients are identified by persistently elevated serum levels of T, and T3 in the absence of intercurrent illnesses,medication usage, or alterations of thyroid hormone binding to serum proteins. At the sametime, serum TSH levels are inappropriately normal or elevated, and the TSH responseto TRH is not suppressed despite high circulating levels of free thyroid hormone. Generalized resistance to thyroid hormone (GRTH) affects all thyroid hormone-responsive tissuesto varying degrees.Patients with this disorder are clinically euthyroid or hypothyroid (1, 2). Pituitary resistance to thyroid hormone (PRTH) primarily affects the regulation of TSH secretion; supranorma1thyroid hormone levels do not inhibit TSH secretion (1, 2). In both cases, the defect is thought to be partial, as complete resistance would probably be incompatible with life (1). GRTH is inherited in an autosomal dominant fashion and has been linked to single base substitutions on the cerbA0 thyroid hormone receptor gene in several kindreds and a deletion of c-erbA@ receptor gene in the original kindred (3). The inheritance pattern of PRTH has not been delineated. Dopamine has been shown to inhibit TSH secretion (4, 5), and bromocriptine (Brc) is a dopamine agonist that inhibits TSH secretion in some patients with inappropriate TSH Received November 25, 1991. Address requests for reprints to: Jerome M. Hershman, M.D., Endocrinology Wll lD, West Los Angeles Veterans Administration Medical Center, Los Angeles, California 90073. * This work was supported by V.A. Medical Research Funds.
secretion due to tumoral secretion, GRTH, and PRTH (6-8). 3,5,3’-Triiodothyroacetic acid (Triac) is a T3 analog that binds to nuclear receptors with higher affinity than T3 and has a very short residencetime on the nuclear receptor in comparison with T3 (9). The metabolic effects of Triac are alleged to be small in magnitude and short-lived. When Triac was given to normal or thyroidectomized patients, it suppressedbasal TSH levels and the TSH responseto TRH without changing heart rate, weight, or Achilles tendon reflex time (10). This suppressionof TSH secretion with minimal peripheral metabolic effects makes Triac a potential treatment for patients with PRTH. Triac has reportedly been used successfully in eight patients and unsuccessfully in two patients with PRTH to relieve symptoms of hyperthyroidism (2, 11-15). In this study we treated a patient with PRTH diagnosed at age 15 yr with separate coursesof Brc and Triac to determine their effects on her hyperthyroidism. Materials
and Methods
Serum T, and free T, (FT,) were measured by RIA using commercial kits (Diagnostic Products Corp., Los Angeles, CA); the normal ranges are: TX, 1.3-2.7 nmol/L; and FTI, 9-27 pmol/L. There was a 25% crossreaction of Triac in the T, RIA. TSH was measured by a sensitive immunoradiometric assay (Hybritech, HS-IRMA, La Jolla, CA; normal range, 0.4-5.3 mu/L). TRH tests were performed by giving 500 rg synthetic TRH, iv; TSH measurements were obtained at -15, 0, 15, 30, 45, and 60 min. Systolic time intervals (STI) were determined from aortic flow velocity signals recorded with continuous wave doppler ultrasound. Left ventricular ejection time (LVET) was defined from the onset to the end of the aortic velocity spectrum. QT was measured as the interval from the Q wave on the simultaneously recorded electrocardiogram to the end of LVET. The preejection period (PEP) was the difference between LVET
1071
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 22 October 2015. at 19:15 For personal use only. No other uses without permission. . All rights reserved.
DULGEROFF
1072
and QT (PEP = QT - LVET). Three cardiac cycles were measured from each of three observations made during each clinical visit (each observation made after 20 min of recumbency). LVET and PEP were corrected for heart rate (HR) using Tseng’s formulas: LVETc = LVET + 0.6 X HR; PEPc = PEP + 0.4 x HR (16). The intraobserver error was calculated from the mean and so of all observations and is expressed as a mean coefficient of variation. Oxygen consumption was measured by a SensorMedics Horizon Metabolic System (model 4400, Yorba Linda, CA) employing a minute by minute analysis of cardiorespiratory variables [minute ventilation, tidal volume, and oxygen consumption (VO,)]. Data were gathered for 3-10 min until a steady state was observed, after which the measurements were recorded. Means of all results were calculated. Brc was provided by Sandoz (Englewood, NJ). Triac was supplied in 0.35.mg tablets by ANA SA Laboratories (Neuilly-Sur-Seine, France). The experimental protocol was approved by our Human Subject Research Committee. The patient and her mother gave informed consent.
Case Report The patient is now a 17-yr-old black female who presented in June 1986 at the age of 12 yr with complaints of weight loss, nervousnes, heat intolerance, and tremor for 6-12 months. She had no nausea, diarrhea, or headaches, Her past medical history was remarkable for sickle cell trait and a heart murmur. Her blood pressure was 145/80, heart rate was 118 beats/min, respiratory rate was 15/min, height was 158 cm (75th percentile), and weight was 36 kg (25th percentile). She had no exophthalmos. Her thyroid gland was enlarged and measured 5 X 3 cm on the right and 5 x 2 cm on the left, and the consistency was firm with no irregularities. She had a II/VI systolic ejection murmur, a fine tremor, hyperkinesis, and brisk tendon reflexes, Her serum T, level was 498 nmoI/L (normal, 64-167 nmoI/L), FT, index was 753 (normal, 64-l 67), T3 was 11.5 nmoI/L, and TSH was 5.1 mu/L. Antithyroglobulin and antimicrosomal antibody were negative, and thyroid-stimulating immunoglobulins were 128% (normal,
