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Neonatal thyrotoxicosis
BRIEF CLINICAL A N D LABORATORY OBSERVATIONS
Articles in this section should require less than three JOURNAL pages: text, less than 1,000 words; I or 2 illustrations and/or tables; up to l0 references.
Neonatal thyrotoxicosis J o n a t h a n Singer, M.D., Cincinnati, O h i o
THE MOST COMMON MANIFESTATIONS o f n e o n a t a l h y p e r t h y r o i d i s m h a v e b e e n similar to those seen in older children a n d adults. Most reported cases h a v e occurred in male infants with characteristic features o f goiter, tachypnea, tachycardia, cardiomegaly, hyperkinesis, restlessness, diarrhea, a n d excellent appetite with p o o r weight gain. O t h e r c o m m o n features are flushing, diaphoresis, vomiting, periorbital edema, a n d bilateral e x o p h t h a l m o s . U n u s u a l features described in thyrotoxic infants are hepatosplenomegaly, j a u n d i c e , t h r o m b o c y t o p e n i a , pitting edema, e n l a r g e m e n t o f the reticuloendothelial system, craniosynostosis, a n d the hyperviscosity s y n d r o m e ? -~ This c o m m u n i c a t i o n describes two siblings with n e o n a t a l thyrotoxicosis w h o h a d typical features o f goiter, periorbital edema, tachycardia, respiratory distress, a n d hyperkinesis shortly after birth. T h e first-born infant's s e r u m a n d that o f his m o t h e r c o n t a i n e d long-acting thyroid stimulator. T h e first i n f a n t was m i c r o c e p h a l i c a n d h a d ventricular extrasystoles, b o t h features previously n o t described in n e o n a t a l thyrotoxicosis. CASE REPORT In 1973, Patient J.P. was born spontaneously to a 19-year-old primagravida who had undergone a subtotal thyroidectomy for thyrotoxicosis during the first trimester. Postoperatively, she was clinically euthyroid but had exophthalmos throughout an otherwise uneventful prenatal course. At the thirty-ninth week of gestation, she delivered a meconium-stained male. Physical examination revealed a restless preterm infant, small for gestational age, with mild respiratory difficulty. Weight was From the Department o f Pediatrics, Cincinnati Children's Hospital Medical Center. *Reprint address: Children's Hospital Medical Center, Research Foundation, Elland and Bethesda A yes., Cincinnati, OH 45229.
2,190 gm, length was 45 cm, and occipital frontal circumference was 29 cm, all less than the third percentile. Blood pressure was 90/65, pulse 178, respiration 86, and temperature 37~ The skin was flushed, nonicteric, and had diffuse petechiae. The head was brachycephalic and did not transilluminate; the anterior fontanel was small and nonbulging. There was bilateral periorbital edema with prominent eyes. Results of funduscopic examination were normal. No thyroid gland was palpable and no bruit was heard over the thyroid area. There were minimal intercostal retractions and the lungs were clear. The cardiac examination was unremarkable except for the tachycardia. He was exceptionally jittery, hyperreflexic, and had gross tremors of the extremities with clonus of the lower limh~ Abbreviation used LATS: long-acting thyroid stimulator Laboratory data showed a hemoglobin of 20 gm/dl, a hematocrit of 59.6 volumes/dl, and a leukocyte count of 21,700/ram 3 with a normal differential. Platelets were markedly decreased. The blood sugar concentration was 63 mg/dl and that of calcium, 9.6 mg/dl. The spinal fluid was normal. The chest radiograph showed a normal cardiothymic silhouette with normal pulmonary vascularity. Films of the long bones were normal and the bone age was minimally advanced. The skull films revealed a cranium 4 SD below the mean according to the nonvolumetric cranial indices of Cronqvist, 7 with open sutures, an absence of intracranial calcification and mild cranial lacuna. The electrocardiogram showed multiple unifocal premature ventricular contractions with occasional bigeminy. All cultures were negative for bacteria, Coxsackie virus, and cytomegalovirus. The VDRL was negative. Serologic analysis for antibodies to toxoplasmosis and cytomegalovirus was negative. Rubella hemagglutination inhibition titer of the mother's serum was 1:128, and 1:64 in the infant's. Tachypnea, tachycardia with ventricutar extrasystoles, and extreme hyperactivity continued for the first day. At 24 hours of age, periorbital edema became more prominent and the thyroid gland was palpated for the first time. Thyroid function studies were obtained (Table I). By the third day there was general improvement in the infant's course with decreased irritability and decreased tachypnea; normal sinus rhythm returned. He was discharged at ll days of age weighing 2,280 gin; he appeared somewhat exophthalmic and the thyroid gland was still palpable.
TheJournalofPEDIATRICS
749
750
Brief clinical and laboratory observations
The Journal of Pediatrics November 1977
Table I. Neonatal thyroid function studies
Infant J.P. Protein-bound iodine (/xg/dl) Tri-iodothyronine (ng/dl) Thyroxine ~g/dl) Thyroid-stimulating hormone (/~U/ml) Radioimmunoassay % uptake Long-acting thyroid stimulator response index
[
Normal cord
Normal 5 days old
4-9.5 50.5-58 7.3-i5.3 7-10 45-90 0
7-14 212-226 11-13 7-10 6.6-40 0
At six weeks, he weighed 3,500 gm and appeared normal except for the cranial malformation and mild exophthalmos. The rubella titer was 1:32. LATS was not measurable in the serum. At six months of age the cranial vault was only 2 SD below the mean, and the normal developmental milestones had been attained. At ages one and two years, he had maintained linear growth following the tenth percentile and the cranial vault was at the fiftieth percentile. At three years, he has normal personalsocial behavior and normal motor and language development. The bone age is normal. The results of thyroid function studies are normal. The mother received nine microcuries of 131Iin 1974 and was euthyroid on replacement therapy. LATS was still measurable in her serum. She underwent a second uneventful pregnancy in 1976, spontaneously went into labor at 33 weeks, and delivered an appropriate for gestational age 2,100 gm male who had an immediate onset of profound tachypnea and tachycardia. He had a flushed appearance, exophthalmos, periorbital edema, a palpable thyroid gland, and hyperreflexia. He had a tri-iodothyronine of greater than 400 ng/dl, a thyroxine by radioimmunoassay of 24/~g/ml, a thyroid-stimulating hormone of 0.71/~U/ ml, and LATS was not measurable in the serum. His hypermetabolic state resolved slowly over a two week period of time and he was discharged at 15 days of age,.still exophthalmic. At four weeks and at six months, he was euthyroid on clinical examination.
Day 2
Day 5
Day 8
17 340 > 20 2.05 68 767
performance o f a radionucleotide test during Patient J.P.'s first trimester is not known, but pelvic radiation during pregnancy has been a recognized cause of microcephaly in the fetus? ~ Craniosynostosis and frontal bossing have been the only cranial malformations previously described in neonatal thyrotoxicosis. Since the microcephaly did not persist and there has been no apparent intellectual impairment, the combination of unusual cranial features and growth retardation at birth of this child could have been due to chance association rather than to the metabolic effects of a transplacental transfer of LATS. The occurrence of ventricular extrasystoles has not been previously described in neonatal thyrotoxicosis. Only one instance of paroxysmal atrial tachycardia and a single case of sfiaus arrest have been reported in neonatal thyrotoxicosis, whereas sinus tachycardia and supraventricular tachycardias have been reported commonly in neonates.1 The features of microcephaly and ventricular extrasystoles should be added to the growing constellation of signs recognized as presentations of neonatal thyrotoxicosis.
REFERENCES
DISCUSSION Both sons had an u n c o m m o n l y benign yet "traditional" form of neonatal thyrotoxicosis with spontaneous recovery. Both infants had the most commonly described signs and symptoms; in addition,'Patient J.P. had mild brachycephaly and marked microcephaly. A n occipital frontal circumference of 29 cm falls well below the extremes of head circumference for gestational age, 8 length, 9 and roentgenographic measurements. 7 Prenatally acquired toxoplasmosis, cytomegalic inclusion disease, and rubella were excluded as the etiology of the microcephaly. One cannot exclude cytogenetic abnormalities because chromosomal analysis was not performed, but the patient's clinical appearance was not suggestive of any of the recognized syndromes associated with microcephaly. The significance of the maternal ingestion of iodide or the
1. Javett SN, Senior B, Brando JL, and Heymann S: Neonatal thyrotoxicosis, Pediatrics 24:65, 1959. 2. Skelton MO, and Gans B: Congenital thyrotoxicosis, hepatosplenomegaly and jaundice in two infants of exophthalmic mothers, Arch Dis Child 30:460, 1955. 3. Rosenberg D, Grand MJH, and Silbert D: Neonatal hyperthyroidism, N Engl J Med 268:292, 1963. 4. Mahoney CP, Pyne GE, Stamm SJ, and Bakke JL: Neonatal Graves' disease, Am J Dis Child 107:516, 1964. 5. Hollingsworth DR, and Mabry CC: Congenital Graves' disease, Am J Dis Child 130:148, 1976. 6. Bussman YL, Tillman ML, and Pagliara AS: Neonatal thyrotoxicosis associated with the hyperviscosity syndrome, J P~mATR 90:266, 1977. 7. Austin JHM, and Gooding CA: Roentgenographic measurement of skull size in children, Radiology 99:641, 1971. 8. Lubchenco LO, and Hansman C: Intrauterine growth in length and head circumference as estimated from live births
Volume 91 Number 5
B r i e f cfinical and laboratory observations
at gestational ages from 26 to 42 weeks, Pediatrics 37:403, 1966. Boyd JD: Graphic portrayal of infants' growth with consideration of head size, Am J Dis Child 76:53, 1948.
Gonadotropins and prolactin pituitary reserve in premature thelarche A. Caufriez, M.D.,* R. Woiter, M.D., M. Govaerts, M.D., M. L'Hermite, M.D., and C. Robyn, M.D., Brussels, Belgium
PREMATURE THELARCHE in young girls refers to isolated breast development not accompanied by any other signs of sexual maturation. 1An increased sensitivity of breast tissue to the low levels of estrogens secreted during early childhood has been postulated as the cause of this premature breast development. 1 Normal or slightly increased plasma estradiol and basal gonadotropin (LH and FSH) levels have been reported. ~-7 However, conflicting results concerning gonadotropin responsiveness to synthetic gonadotropin-releasing hormone (LHRH) have been observed. :'-" The purpose of this study was to evaluate the luteinizing hormone and follicle-stimulating hormone response to LH-RH and the prolactin release after thyrotropinreleasing hormone in girls with premature thelarche as compared to normal prepubertal girls of comparable age. PATIENTS
AND METHODS
Fifteen girls (9/12 to 7 years old) with premature thelarche were investigated. The duration of breast development was two weeks to four months at the time of the From the Departments of Pediatrics and o f Obstetrics and Gynecology (Human Reproduction Research Unit), Free University o f Brussels. Supported in part by grants to Prof P.O. Hubinont from the Ford Foundation (USA) and the F.R.S.M. (Belgium). *Reprint address: Laboratoire de Gynbcologie et de Recherches sur la Reproduction Humaine, Hbpital SaintPierre, rue Haute 322, B-IO00 Bruxelles, Belgium.
751
10. Warkany J: Congenital malformations, Chicago, 1971, Yearbook Medical Publishers, Inc., pp 237-239. 11. Riopel DA, and Mullins CE: Thyrotoxicosis and paroxysmal tachycardia, Pediatrics 50:140, 1972.
first physical examination and testing, In all the subjects the breast development disappeared within three to six months after the first physical examination. The bone age was in each case compatible with the chronologic age. Except for uni- or bilateral breast enlargement, no other sign of sexual maturation was present. Vaginal smears did not show any estrogenic stimulation. The control group included 15 girls (1 to 7 years old) hospitalized for evaluation of growth retardation and in whom no endocrine anomalies were evident. Each subject received an intravenous bolus injection of LH-RH (Hoechst, FRG; 25 /~g/m2). Blood samples were withdrawn frequently for 150 minutes through an indwelling venous needle: LH and FSH were measured in all samples by previously described radioimmunoassays 9. 19; results are expressed as m l U / m l of the second International Reference Preparation of human menopausal gonadotropins. In all subjects, routine T4 and TSH determinations by competitive protein-binding assay and radioimmunoassay, respectively, were obtained on blood collected at 8 A~a; 24-hour urine specimens were collected for measurement of 17hydroxycorticosteroids and 17-ketosteroids by the Zimmerman reaction. Abbreviations used LH: luteinizing hormone FSH: follicle-stimulating hormone LH-RH: luteinizing hormone-releasing hormone PRL: prolactin TRH: thyrotropin-releasing hormone T4: thyroxine TSH: thyroid-stimulating hormone Five normal girls and seven with premature thelarche received an intravenous injection of 200 mg TRH (Roche, Belgium) simultaneously to that of LH-RH: serum PRL levels were determined in these samples using a homologous ovine radioimmunoassay. 11PRL levels are expressed in m U / m l of the laboratory standard (a pool of postpartum sera): 1.0 m U / m l of this standard was found to be equivalent to 2.3 mU of the serum research standard 71/ 167 (distributed by the MRC, Holly Hill, London). RESULTS All children had normal values ofT4, TSH, 17-hydroxycorticosteroids, and 17-ketosteroids.
Articles in this section should require less than three JOURNAL pages: text, less than 1,000 words; I or 2 illustrations and/or tables; up to l0 references.
Neonatal thyrotoxicosis J o n a t h a n Singer, M.D., Cincinnati, O h i o
THE MOST COMMON MANIFESTATIONS o f n e o n a t a l h y p e r t h y r o i d i s m h a v e b e e n similar to those seen in older children a n d adults. Most reported cases h a v e occurred in male infants with characteristic features o f goiter, tachypnea, tachycardia, cardiomegaly, hyperkinesis, restlessness, diarrhea, a n d excellent appetite with p o o r weight gain. O t h e r c o m m o n features are flushing, diaphoresis, vomiting, periorbital edema, a n d bilateral e x o p h t h a l m o s . U n u s u a l features described in thyrotoxic infants are hepatosplenomegaly, j a u n d i c e , t h r o m b o c y t o p e n i a , pitting edema, e n l a r g e m e n t o f the reticuloendothelial system, craniosynostosis, a n d the hyperviscosity s y n d r o m e ? -~ This c o m m u n i c a t i o n describes two siblings with n e o n a t a l thyrotoxicosis w h o h a d typical features o f goiter, periorbital edema, tachycardia, respiratory distress, a n d hyperkinesis shortly after birth. T h e first-born infant's s e r u m a n d that o f his m o t h e r c o n t a i n e d long-acting thyroid stimulator. T h e first i n f a n t was m i c r o c e p h a l i c a n d h a d ventricular extrasystoles, b o t h features previously n o t described in n e o n a t a l thyrotoxicosis. CASE REPORT In 1973, Patient J.P. was born spontaneously to a 19-year-old primagravida who had undergone a subtotal thyroidectomy for thyrotoxicosis during the first trimester. Postoperatively, she was clinically euthyroid but had exophthalmos throughout an otherwise uneventful prenatal course. At the thirty-ninth week of gestation, she delivered a meconium-stained male. Physical examination revealed a restless preterm infant, small for gestational age, with mild respiratory difficulty. Weight was From the Department o f Pediatrics, Cincinnati Children's Hospital Medical Center. *Reprint address: Children's Hospital Medical Center, Research Foundation, Elland and Bethesda A yes., Cincinnati, OH 45229.
2,190 gm, length was 45 cm, and occipital frontal circumference was 29 cm, all less than the third percentile. Blood pressure was 90/65, pulse 178, respiration 86, and temperature 37~ The skin was flushed, nonicteric, and had diffuse petechiae. The head was brachycephalic and did not transilluminate; the anterior fontanel was small and nonbulging. There was bilateral periorbital edema with prominent eyes. Results of funduscopic examination were normal. No thyroid gland was palpable and no bruit was heard over the thyroid area. There were minimal intercostal retractions and the lungs were clear. The cardiac examination was unremarkable except for the tachycardia. He was exceptionally jittery, hyperreflexic, and had gross tremors of the extremities with clonus of the lower limh~ Abbreviation used LATS: long-acting thyroid stimulator Laboratory data showed a hemoglobin of 20 gm/dl, a hematocrit of 59.6 volumes/dl, and a leukocyte count of 21,700/ram 3 with a normal differential. Platelets were markedly decreased. The blood sugar concentration was 63 mg/dl and that of calcium, 9.6 mg/dl. The spinal fluid was normal. The chest radiograph showed a normal cardiothymic silhouette with normal pulmonary vascularity. Films of the long bones were normal and the bone age was minimally advanced. The skull films revealed a cranium 4 SD below the mean according to the nonvolumetric cranial indices of Cronqvist, 7 with open sutures, an absence of intracranial calcification and mild cranial lacuna. The electrocardiogram showed multiple unifocal premature ventricular contractions with occasional bigeminy. All cultures were negative for bacteria, Coxsackie virus, and cytomegalovirus. The VDRL was negative. Serologic analysis for antibodies to toxoplasmosis and cytomegalovirus was negative. Rubella hemagglutination inhibition titer of the mother's serum was 1:128, and 1:64 in the infant's. Tachypnea, tachycardia with ventricutar extrasystoles, and extreme hyperactivity continued for the first day. At 24 hours of age, periorbital edema became more prominent and the thyroid gland was palpated for the first time. Thyroid function studies were obtained (Table I). By the third day there was general improvement in the infant's course with decreased irritability and decreased tachypnea; normal sinus rhythm returned. He was discharged at ll days of age weighing 2,280 gin; he appeared somewhat exophthalmic and the thyroid gland was still palpable.
TheJournalofPEDIATRICS
749
750
Brief clinical and laboratory observations
The Journal of Pediatrics November 1977
Table I. Neonatal thyroid function studies
Infant J.P. Protein-bound iodine (/xg/dl) Tri-iodothyronine (ng/dl) Thyroxine ~g/dl) Thyroid-stimulating hormone (/~U/ml) Radioimmunoassay % uptake Long-acting thyroid stimulator response index
[
Normal cord
Normal 5 days old
4-9.5 50.5-58 7.3-i5.3 7-10 45-90 0
7-14 212-226 11-13 7-10 6.6-40 0
At six weeks, he weighed 3,500 gm and appeared normal except for the cranial malformation and mild exophthalmos. The rubella titer was 1:32. LATS was not measurable in the serum. At six months of age the cranial vault was only 2 SD below the mean, and the normal developmental milestones had been attained. At ages one and two years, he had maintained linear growth following the tenth percentile and the cranial vault was at the fiftieth percentile. At three years, he has normal personalsocial behavior and normal motor and language development. The bone age is normal. The results of thyroid function studies are normal. The mother received nine microcuries of 131Iin 1974 and was euthyroid on replacement therapy. LATS was still measurable in her serum. She underwent a second uneventful pregnancy in 1976, spontaneously went into labor at 33 weeks, and delivered an appropriate for gestational age 2,100 gm male who had an immediate onset of profound tachypnea and tachycardia. He had a flushed appearance, exophthalmos, periorbital edema, a palpable thyroid gland, and hyperreflexia. He had a tri-iodothyronine of greater than 400 ng/dl, a thyroxine by radioimmunoassay of 24/~g/ml, a thyroid-stimulating hormone of 0.71/~U/ ml, and LATS was not measurable in the serum. His hypermetabolic state resolved slowly over a two week period of time and he was discharged at 15 days of age,.still exophthalmic. At four weeks and at six months, he was euthyroid on clinical examination.
Day 2
Day 5
Day 8
17 340 > 20 2.05 68 767
performance o f a radionucleotide test during Patient J.P.'s first trimester is not known, but pelvic radiation during pregnancy has been a recognized cause of microcephaly in the fetus? ~ Craniosynostosis and frontal bossing have been the only cranial malformations previously described in neonatal thyrotoxicosis. Since the microcephaly did not persist and there has been no apparent intellectual impairment, the combination of unusual cranial features and growth retardation at birth of this child could have been due to chance association rather than to the metabolic effects of a transplacental transfer of LATS. The occurrence of ventricular extrasystoles has not been previously described in neonatal thyrotoxicosis. Only one instance of paroxysmal atrial tachycardia and a single case of sfiaus arrest have been reported in neonatal thyrotoxicosis, whereas sinus tachycardia and supraventricular tachycardias have been reported commonly in neonates.1 The features of microcephaly and ventricular extrasystoles should be added to the growing constellation of signs recognized as presentations of neonatal thyrotoxicosis.
REFERENCES
DISCUSSION Both sons had an u n c o m m o n l y benign yet "traditional" form of neonatal thyrotoxicosis with spontaneous recovery. Both infants had the most commonly described signs and symptoms; in addition,'Patient J.P. had mild brachycephaly and marked microcephaly. A n occipital frontal circumference of 29 cm falls well below the extremes of head circumference for gestational age, 8 length, 9 and roentgenographic measurements. 7 Prenatally acquired toxoplasmosis, cytomegalic inclusion disease, and rubella were excluded as the etiology of the microcephaly. One cannot exclude cytogenetic abnormalities because chromosomal analysis was not performed, but the patient's clinical appearance was not suggestive of any of the recognized syndromes associated with microcephaly. The significance of the maternal ingestion of iodide or the
1. Javett SN, Senior B, Brando JL, and Heymann S: Neonatal thyrotoxicosis, Pediatrics 24:65, 1959. 2. Skelton MO, and Gans B: Congenital thyrotoxicosis, hepatosplenomegaly and jaundice in two infants of exophthalmic mothers, Arch Dis Child 30:460, 1955. 3. Rosenberg D, Grand MJH, and Silbert D: Neonatal hyperthyroidism, N Engl J Med 268:292, 1963. 4. Mahoney CP, Pyne GE, Stamm SJ, and Bakke JL: Neonatal Graves' disease, Am J Dis Child 107:516, 1964. 5. Hollingsworth DR, and Mabry CC: Congenital Graves' disease, Am J Dis Child 130:148, 1976. 6. Bussman YL, Tillman ML, and Pagliara AS: Neonatal thyrotoxicosis associated with the hyperviscosity syndrome, J P~mATR 90:266, 1977. 7. Austin JHM, and Gooding CA: Roentgenographic measurement of skull size in children, Radiology 99:641, 1971. 8. Lubchenco LO, and Hansman C: Intrauterine growth in length and head circumference as estimated from live births
Volume 91 Number 5
B r i e f cfinical and laboratory observations
at gestational ages from 26 to 42 weeks, Pediatrics 37:403, 1966. Boyd JD: Graphic portrayal of infants' growth with consideration of head size, Am J Dis Child 76:53, 1948.
Gonadotropins and prolactin pituitary reserve in premature thelarche A. Caufriez, M.D.,* R. Woiter, M.D., M. Govaerts, M.D., M. L'Hermite, M.D., and C. Robyn, M.D., Brussels, Belgium
PREMATURE THELARCHE in young girls refers to isolated breast development not accompanied by any other signs of sexual maturation. 1An increased sensitivity of breast tissue to the low levels of estrogens secreted during early childhood has been postulated as the cause of this premature breast development. 1 Normal or slightly increased plasma estradiol and basal gonadotropin (LH and FSH) levels have been reported. ~-7 However, conflicting results concerning gonadotropin responsiveness to synthetic gonadotropin-releasing hormone (LHRH) have been observed. :'-" The purpose of this study was to evaluate the luteinizing hormone and follicle-stimulating hormone response to LH-RH and the prolactin release after thyrotropinreleasing hormone in girls with premature thelarche as compared to normal prepubertal girls of comparable age. PATIENTS
AND METHODS
Fifteen girls (9/12 to 7 years old) with premature thelarche were investigated. The duration of breast development was two weeks to four months at the time of the From the Departments of Pediatrics and o f Obstetrics and Gynecology (Human Reproduction Research Unit), Free University o f Brussels. Supported in part by grants to Prof P.O. Hubinont from the Ford Foundation (USA) and the F.R.S.M. (Belgium). *Reprint address: Laboratoire de Gynbcologie et de Recherches sur la Reproduction Humaine, Hbpital SaintPierre, rue Haute 322, B-IO00 Bruxelles, Belgium.
751
10. Warkany J: Congenital malformations, Chicago, 1971, Yearbook Medical Publishers, Inc., pp 237-239. 11. Riopel DA, and Mullins CE: Thyrotoxicosis and paroxysmal tachycardia, Pediatrics 50:140, 1972.
first physical examination and testing, In all the subjects the breast development disappeared within three to six months after the first physical examination. The bone age was in each case compatible with the chronologic age. Except for uni- or bilateral breast enlargement, no other sign of sexual maturation was present. Vaginal smears did not show any estrogenic stimulation. The control group included 15 girls (1 to 7 years old) hospitalized for evaluation of growth retardation and in whom no endocrine anomalies were evident. Each subject received an intravenous bolus injection of LH-RH (Hoechst, FRG; 25 /~g/m2). Blood samples were withdrawn frequently for 150 minutes through an indwelling venous needle: LH and FSH were measured in all samples by previously described radioimmunoassays 9. 19; results are expressed as m l U / m l of the second International Reference Preparation of human menopausal gonadotropins. In all subjects, routine T4 and TSH determinations by competitive protein-binding assay and radioimmunoassay, respectively, were obtained on blood collected at 8 A~a; 24-hour urine specimens were collected for measurement of 17hydroxycorticosteroids and 17-ketosteroids by the Zimmerman reaction. Abbreviations used LH: luteinizing hormone FSH: follicle-stimulating hormone LH-RH: luteinizing hormone-releasing hormone PRL: prolactin TRH: thyrotropin-releasing hormone T4: thyroxine TSH: thyroid-stimulating hormone Five normal girls and seven with premature thelarche received an intravenous injection of 200 mg TRH (Roche, Belgium) simultaneously to that of LH-RH: serum PRL levels were determined in these samples using a homologous ovine radioimmunoassay. 11PRL levels are expressed in m U / m l of the laboratory standard (a pool of postpartum sera): 1.0 m U / m l of this standard was found to be equivalent to 2.3 mU of the serum research standard 71/ 167 (distributed by the MRC, Holly Hill, London). RESULTS All children had normal values ofT4, TSH, 17-hydroxycorticosteroids, and 17-ketosteroids.