Primary hypothyroidism, empty sella, and hypopituitarism

Primary hypothyroidism, empty sella, and hypopituitarism

CLINICAL AND LABORATORY OBSERVATIONS Primary hypothyroidism, empty sella, and hypopituitarism Stephen H. LaFranchi, M.D., Cheryl E. Hanna, M.D., and ...

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Primary hypothyroidism, empty sella, and hypopituitarism Stephen H. LaFranchi, M.D., Cheryl E. Hanna, M.D., and Patricia L. Krainz, M.D. From the Department of Pediatrics, Oregon Health Sciences University, Portland

P r i m a r y hypothyroidism may be associated with enlargem e n t of the sella turcica, t h o u g h t to represent h y p e r t r o p h y a n d hyperplasia of the pituitary gland in response to lack of negative feedback of thyroid h o r m o n e s ) Thyroid ablation in mice a n d rats produces a progressive sequence of pituitary hyperplasia, enlargement, nodularity, a n d adenoma, which can be prevented by thyroid h o r m o n e treatment. 2 Subtle visual field defects resulting from pituitary e n l a r g e m e n t have been documented in a majority of patients with primary hypothyroidism3; severe visual field loss and blindness have also been reported. 4's T h e s e changes m a y b e reversible with thyroid h o r m o n e replacem e n t : a l t h o u g h in some cases craniotomy has been necessary.4,5 As m i g h t be expected, p i t u i t a r y h o r m o n e alterations have also been documented in primary hypothyroidism, 7 a n d hypopituitarism, both transient 8 and p e r m a n e n t : has been reported. A n empty sella is a reported outcome in some of these p a t i e n t s ) ~ H W e report a n l 1-year-old boy with p r i m a r y hypothyroidism associated with e n l a r g e m e n t of t h e sella a n d pituitary gland, in w h o m an empty sella and hypopituitarism developed after thyroid h o r m o n e t r e a t m e n t . To our knowledge, this is the first child reported with this sequence of changes documented by C T scan findings. CASE REPORT This adolescent boy was first seen at age 11.1 years with complaints of tiredness, dizziness, and increasing weight gain, which the family attributed to immobilization after a fracture of the femur at age 9 years. He also complained of occasional bitemporal headaches. On physical examination, his height was at the 20th percentile, and weight >97th percentile; his recent growth rate had slowed to 3.6 cm/yr. He had dry, pasty skin, coarse hair, and an area of vitiligo on the shoulder; puffiness

Submitted for publication July 19, 1985; accepted Oct. 17, 1985. Reprint requests: Stephen H. LaFranchi, M.D., Department of Pediatrics, Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, OR 97201.

around the eyes was noted. Visual acuity was 20/20 in both eyes, and funduscopic findings, including the appearance of the optic discs, were normal; formal visual field testing was not performed. No goiter was palpable. The genitalia were Tanner stage I. The return of the ankle reflexes was delayed. All hormone measurements (Table) were performed by radioimmunoassay. Initial tests showed primary hypothyroidism caused by chronic lymphocytic thyroiditis; an anti-microsomal antibody titer was positive at 1:400, and an anti-thyroglobulin antibody titer was negative. Serum prolactin concentration was 14.9 ng/ml (0 to 15 ng/ml). A lateral skull radiograph showed an intact but enlarged sella turcica (Figure); this study was obtained by the referring pediatrician while the thyroid test results were pending because of his concern regarding the patient's short stature and headaches. After discovering the sella turcica enlargement, he ordered a CT scan of the head, which showed enlarge-

See related article, p. 540.


Adrenocorticotropin Computed tomography Follicle-stimulating hormone Luteinizing hormone Thyroxine Thyroid-stimulating hormone

ment of the pituitary gland with suprasellar extension (Figure). Following thyroxine replacement, 0.1 mg/day, the patient reported improvement in his initial complaints; he lost 5.0 kg, and his serum T, level normalized. However, after 8 months of treatment he had grown only 2.2 cm, a rate of 3.3 era/yr. Genitalia ~2were still Tanner stage I. A repeat CT scan now showed the sella filled with fluid of CSF density, interpreted as an empty setla (Figure). At age 11.9 years, serum LH and FSH values were below the limits of sensitivity of the assay, and there was subnormal hGH response to L-dopa stimulation. After priming with testosterone, the patient underwent sequential insulin-hypoglycemia and arginine stimulation with hGH sampling every 15 minutes for 150 minutes; peak hGH concentrations were again subnormal (Table). The basal cortisol level was normal, but no increase was seen with hypoglycemia (Table). There were no symptoms of diabetes insipidus, and urine specific gravity was 1.017. At age 12.4 years,



Clinical and laboratory observations

The Journal of Pediatrics April 1986

Figure. A, Lateral skull radiograph taken before thyroxine replacement shows enlargement of sella turcica. B, CT scan (coronal section) before thyroxine replacement shows enlargement of pituitary gland with suprasellar extension (arrow). Cavum septum pellucidum is also present. C, CT scan (coronal section) after 8 months of thyroxine therapy shows pituitary ~land replaced by fluid of CSF density (arrow), interpreted to be empty sella.

Table, Results of laboratory studies over time

Chronologic age (yr) 11.1 11.9 (T 4

Bone age (yr) 7

T4 (~g/dl)

TSH (#U/ml)





LH (mlU/ml)

FSH (mlU/ml)



dose 0.1 rag) 12.0

12.4 (T4 dose increased to 0.125 mg) Normal range

10 6.3




serum T4 fell and TSH level rose, and thyroxine dosage was increased to 0.125 mg/day (Table). Treatment with human growth hormone has not yet been initiated. DISCUSSION Previous reports of adults describe primary hypothyroidism associated with pituitary enlargement followed by development of an empty sella 1~12; pituitary enlargement 789 followed by hypopituitarism,, ; pituitary enlargement and visual deficits 4,5,6; or a normal sella followed by empty sella and hypopituitarism. TM~2Our patient underwent the unique sequence of primary hypothyroidism associated with pituitary enlargement with suprasellar extension documented on C T scan, followed after 8 months of thyroxine therapy by development of an empty sella associated with clinical and biochemical evidence of abnormal pituitary function.



hGH (ng/ml) L-Dopa 60 min 90 min Insulin hypoglycemia Arginine


Cortisol (~g/dl)

3.0 1.0 2.0 2.2

0 min 16.6 60 min 9.8


Studies documented h G H deficiency and low gonadotropin levels for age (although at a bone age of 10 years gonadotropin deficiency cannot be determined with certainty). The normal basal cortisol level with failure to increase with hypoglycemia suggests partial A C T H deficiency as well. The elevated T S H concentration during low thyroxine replacement indicates preservation of thyrotroph function. Pituitary enlargement in this setting is often associated with visual distrubances; our patient had no evidence for this, although a subtle visual field deficit cannot be ruled out. The mechanism of development of the empty sella remains unknown. Marked pituitary enlargement may lead to a tenuous blood supply and predispose it to infarction. Alternatively, pituitary enlargement and suprasellar extension may damage the diaphragma sellae; thy-

Volume 108 Number 4

roid hormone replacement then may cause thyrotroph regression and expose the pituitary gland and sella to C S F pressure or arachnoid pulsations, which may produce an empty sella. 13 In general, only a minority of patients with empty sella develop pituitary hormone deficiencies, 14 so additional damage to the pituitary gland must occur in some individuals. One might wonder whether slower thyroxine treatment (e.g., less than full replacement dosage) might have altered the development of an empty sella and hypopituitarism. This has been suggested by McVie, ~3 although we know of no studies to support this recommendation. Our patient was initially given a relatively 10w dose of thyroxine, 1.67 /~g/kg body weight, and subsequently required increased dosage. Evidence is accumulating that pituitary enlargement and subtle visual field defects and pituitary alterations occur more commonly with primary hypothyroidism than previously appreciated. Our case report outlines the full spectrum of these changes during childhood, when the development of h G H deficiency has more impact. The initial C T scan was obtained somewhat serendipitously; with the diagnosis of primary hypothyroidism, we would recommend C T scan of the brain only if the patient has signs of increased intracranial pressure or visual field deficits. With pituitary enlargement or mild visual field defects, we believe a conservative approach with thyroxine therapy and close observation is warranted. If the expected clinical response is not seen (in particular, failure to return to normal or catch-up growth rate), the clinician must consider the development of hypopituitarism, which may be associated with an empty sella. We thank Douglas Livermore, M.D., for referring the patient.

Clinical and laboratory observations



1. Yamada T, Tsukui T, Ikejiri K, et al. Volume of sella turcica in normal subjects and in patients wiht wimary hypothyroidism and hyperthyroidism. J Clin Endocrinol Metab 1976;42:817. 2. Clifton KH. Experimental hypophyseal neoplasia: a review of recent results. Aeta Int Cancer 1962;18:293. 3. Yamamoto K, Saito K, Takai T, et al. Visual field defects and pituitary enlargement in primary hypothyroidism. J Clin Endocrinol Metab 1983;57:283. 4. Caughey JE, Lester MJ. Hypothyroidism and pituitary tumors. NZ Med J 1961;60:486. 5. Melnyk CS, Greer MA. Functional pituitary tumor in an adult possibly secondary to long-standing myxedema. J Clin Endocrinol t965;25:761. 6. Skanse B, Ar6n A: Disappearance of bi-temporal hcmianopsia following correction of myxedema in a case of ehromophobe pituitary tumor. Acta Endocrinol 1956;23:289. 7. Bigos ST, Ridgway C, Kourides l, Maloof F. Spectrum of pituitary alterations with mild and severe thyroid impairment. J Clin Endocrinol Metab 1978;46:317. 8. Leiba S, Landau B, Ber A. Target gland insufficiency and pituitary tumours. Acta Endocrinol 1960;60:112. 9. Vagenakis AG, Dub K, Braverman LE. Pituitary enlargement, pituitary failure, and primary hypothyroidism. Ann Intern Med 1976;85:195. 10. Jawadi MH, Ballonoff LB, Stears JC, Katz FH. Primary hypothyroidism and pituitary enlargement. Arch Intern Med 1978;138:1555. 11. Luboshitzky R, Barzilai D. Primary empty sella syndrome and hypopituitarism associated with primary hypothyroidism. J Endocrinol Invest 1981;4:213. 12. Lawrence AM, Wilber JF, Hagan TC. The pituitary and primary hypothyroidism. Arch Intern Med 1973;132:327. 13. McVie R. Abnormal TSH regulation, psuedotumor cerebri, and empty sella after replacement therapy in juvenile hypothyroidism. J PEDIATR 1984;105:768. 14. Brisman K, Efendic S. Pituitary function in the empty sella syndrome. Neuroendocrinology 1981;32:70.

Transient neonatal hypothyroidism probably related to immaturity of thyroidal iodine organification O. Nose, M.D., T. Harada, M.D., K. Miyai, MD., N. Hata, M.D., M. O g a w a , M.D., I. Maki, M.D., S. Kanaya, M.D., S. Kimura, M.D., K. Shimizu, M.D., a n d H. Yabuuchi, M.D. From the Departments of Pediatrics and Laboratory Medicine, Osaka UniversitySchool of Medicine, Osaka, Japan

Supported in part by grants from the Ministry of Health and Welfare and the Ministry of Education, Science and Culture of Japan. Submitted for publication Aug. 12, 1985; accepted Oct. 3, 1985.

Reprint requests: Osamu Nose, M.D., Department of Pediatrics, Osaka University School of Medicine, Fukushima-ku, Osaka 553, Japan.