A rare form of hypothyroidism. (Case Histories).

ABSTRACT: Secondary hypothyroidism is extremely rare. In the majority of cases, there is a genetic (gene mutations) or structural (mass effect or infiltration) basis for central hypothyroidism, and there is simultaneous deficiency of other adenohypophysial hormones. Isolated deficiency of thyrotropin is even rarer. This report features the case of a woman who had isolated thyrotropin deficiency, with the remainder of the anterior pituitary hormones being normal. The various causes of central hypothyroidism and the role of the thyrotropinreleasing hormone test are briefly described.

**********

THE PREVALENCE of secondary hypothyroidism is extremely low. The majority of the cases have either a genetic or structural basis for central hypothyroidism. The majority of these patients are also deficient in other anterior pituitary hormones. Isolated thyrotropin deficiency represents the rarest form of secondary hypothyroidism. This report describes a symptomatic woman with idiopathic isolated thyrotropin deficiency. The patient improved significantly with thyroxine replacement.

CASE REPORT

A 46-year-old woman was referred to the endocrine clinic for evaluation of suppressed thyrotropin level. The patient had been well until 4 months earlier, when she began to have fatigue and lethargy along with cold intolerance and dry skin. She denied any history of heat intolerance, weight loss, change in neck size, or eye or skin changes. Her primary physician obtained thyroid function tests, which yielded the following values: thyrotropin <0.05 mU/L (normal, 0.5 to 4.5 mU/L), thyroxine ([T.sub.4]) 6.0 [micro]g/dL (4.5 to 11.5 [micro]g/dL), triiodothyronine ([T.sub.3]) 1.00 [micro]g/mL (0.8 to 2.0 ng/mL), free [T.sub.4] index (FTI) 6.6 (4.5 to 11.5), and [T.sub.4] uptake 1.1 (0.8 to 1.3). The patient was referred to our clinic for further workup.

The patient denied any history of headaches, peripheral vision changes, or head trauma. Her medical history included unipolar depression, which was under excellent control. Total abdominal hysterectomy and bilateral salpingo-oophorectomy had been done 4 years earlier because of uterine fibroids. She was not receiving hormone replacement therapy. There was a family history of hyperthyroidism in an aunt and a niece. She denied any addictions, and her medications included sertraline, trazodone, and clonazepam.

Physical examination revealed normal vital signs. Extraocular movements and the visual fields with direct confrontation were normal. The thyroid gland was normal in size, shape, and texture. Skin and hair were dry, and deep tendon reflexes were normal. Significant laboratory values were as follows: thyrotropin 0.11 mU/L, [T.sub.3] 0.74 ng/mL, [T.sub.4] 5.2 [micro]g/dL, FTI 5.2, [T.sub.4] uptake 1.0, free [T.sub.4] 0.5 ng/dL (0.7 to 1.6 ng/dL), cortisol 19.9 [micro]g/dL, prolactin 6.9 ng/mL (normal, 0 to 18), corticotropin (ACTH) 21.7 pg/mL, luteinizing hormone (LH) 43.3 mIU/mL, follicle-stimulating hormone (FSH) 90.2 mIU/mL, and insulin-like growth factor I (IGF-I) 157 ng/mL. The serum cortisol level was measured at 8 AM. Magnetic resonance imaging (MRI) with gadolinium showed a normal pituitary gland with normal enhancement.

Since the patient's thyroid function tests were consistent with central hypothyroidism and all the other anterior pituitary hormones and MRI were normal, the possibility of isolated thyrotropin deficiency (secondary hypothyroidism) or thyrotropin-releasing hormone (TRH) deficiency (tertiary hypothyroidism) was entertained. To distinguish between these two distinct entities, TRH stimulation test was done. The results are shown in Table 1.

The TRH test showed a blunted thyrotropin response suggesting secondary hypothyroidism (thyrotropin deficiency), and thyroxine replacement therapy was started. At 2-month follow-up, the patient had less cold intolerance, fatigue, and lethargy. Thyroid function values were thyrotropin 0.09 mU/L, [T.sub.3] 1.02 ng/mL, and free [T.sub.4] 1.0 ng/mL.

DISCUSSION

Central hypothyroidism is a rare disorder with a prevalence of 0.0002% to 0.005%. (1) Most commonly, it is encountered along with multiple pituitary hormone deficiencies resulting from pituitary surgery, apoplexy, radiation exposure, pituitary and other intracranial tumors, infiltrative systemic diseases. or autoimmune conditions such as lymphocytic hypophysitis. (2) Comprehensive laboratory evaluation in our patient showed normal levels of all the other pituitary hormones. Although a normal IGF-I level does not exclude the diagnosis of growth hormone (GH) deficiency, provocative tests for GH secretion were not done.

Isolated thyrotropin deficiency is extremely rare.(3) It is seen equally in both sexes and has a bimodal peak. The first peak is seen in childhood and the second in adults between the ages of 30 and 60 years. In children, mutations in Pit-i gene, Prop-i gene, and thyrotropin beta subunit gene can result in cretinism.(4) However, these mutations usually result in multiple pituitary hormone deficiencies. The causes of isolated thyrotropin deficiency in adults include mutations in TRH receptor, increased somatostatinergic or dopaminergic tone, and an increase in cerebral opioids activity. The role of opioids is further substantiated by the fact that pretreatment with naloxone increases thyrotropin response to TRH stimulation. (5)

As compared with euthyroid subjects, patients with central hypothyroidism show a decrease in nocturnal surge of thyrotropin secretion. (6) In many patients, thyrotropin may be in the normal range or even slightly elevated with a frankly low free [T.sub.4] level. It is believed that this thyrotropin is biologically inactive because of abnormal glycosylation of the molecule. (7)

Patients with isolated central hypothyroidism have symptoms similar to those in patients with primary hypothyroidism. However, the presence of a nonpalpable thyroid gland is a clue to the diagnosis of central hypothyroidism. The laboratory values generally confirm the diagnosis. Regardless of the severity of symptoms, imaging of the pituitary gland is mandatory, and MRI with gadolinium is the preferred imaging modality.

The TRH stimulation test helps to distinguish secondary from tertiary hypothyroidism. (8) In the former, there is absence or blunting of thyrotropin response to TRH, since there is no thyrotropin reserve in. the pituitary. In hypothalamic disease, there is a delayed and exaggerated response to TRH because the thyrotrophs take some time to "wake up" after a prolonged lack of stimulation by endogenous TRH. In euthyroid subjects, the thyrotropin peak is usually seen 15 to 20 minutes after TRH injection. Since TRH also results in stimulation of prolactin secretion, prolactin is used as a control against the thyrotropin response. (9) The absence of response of both these hormones points toward consideration of multiple pituitary hormone deficiencies. As a rule, the normal response of prolactin is several-fold higher in magnitude than the normal thyrotropin response. The prolactin response to TRH is higher in women because of the influence of estrogen. The thyrotropin response also declines with aging. (10) Table 2 illustrates the pattern of response of thyrotropin to TRH.

Patients should be given replacement doses of L-thyroxine. There is no role for thyrotropin monitoring in judging the adequacy of replacement dose. This should be assessed by monitoring free [T.sub.4] levels. The level of free [T.sub.4] should be kept in the normal range, and the dose should be titrated to avoid side effects. It is important to rule out adrenal insufficiency before thyroxine replacement is initiated since it can result in adrenal crisis in patients with partial or absolute cortisol deficiency.

A variety of drugs can cause alterations in thyroid function tests. Our patient was taking two antidepressants that were serotonin reuptake inhibitors. Although the case of an adolescent who was taking sertraline and had a low total [T.sub.4] value has been reported, free [T.sub.4] and thyrotropin levels were normal, as were results of the TRH test.(11) The low total [T.sub.4] in that patient was attributed to a competition for TBG binding between the drug and thyroid hormone. Similarly, many other antidepressants have been shown to decrease TRH synthesis in rat hypothalamic neurons. (12) Even if we assume that this mechanism applies to humans, the response to TRH test should be exaggerated, implying tertiary hypothyroidism. Our patient had low thyrotropin and low free [T.sub.4] levels, and results of the TRH test were consistent with secondary hypothyroidism.

CONCLUSION

This case of a middle-aged woman with isolated secondary hypothyroidism illustrates that symptoms of hypothyroidism and absence of a goiter are important clues to the diagnosis. Magnetic resonance imaging with gadolinium is mandatory in all patients with secondary or tertiary hypothyroidism to rule out tumor. Free [T.sub.4] levels should be measured in the follow-up of these patients.

TABLE 1.

Results of Thyrotropin-Releasing Hormone Stimulation

                          Test
             Baseline  15 minutes  30 minutes  45 minutes

Thyrotropin    0.35       3.57        4.32        2.97
Prolactin      12.4       99.9        92.4        47.4
TABLE 2.

Response of Thyrotropin to Thyrotropin-Releasing Hormone

             Thyrotopin
Pattern       (mU/L)

Normal       Men 7-9
             Women 15-18
Absent       Men and women <1.0
Blunted      Men 1.0-4.0
             Women 1.0-6.0
Exaggerated  Men >15
             Women >25

References

(1.) Faglia G: Tile Thyroid. Philadelphia, Lippincott Publications, 1996

(2.) Samuels MH, Ridgway EC: Central hypothyroidism. Endocrinol Metab Clin North Am 1992;21:903-919

(3.) Sawin CT, McHugh JE: Isolated lack of thyrotropin in man. J Clin Endocrinol Metab 1966;26:955-959

(4.) Tatsumi K, Miyai K, Amino N: Genetic basis of congenital hypothyroidism: abnormalities in the TSH beta gene, the PITI gene, and the NIS gene. Clin Chem Lab Med 1998; 36:659-662

(5.) Rolandi E, Marabini A, Magnani G, et al: Influence of low doses of naloxone on pituitary secretion in man. Eur J Clin Pharmacol 1982; 22:213-216

(6.) Caron PJ, Nieman LK, Rose SR, et al: Deficient nocturnal surge of thyrotropin in central hypothyroidism. J Clin Endocrinol Metab 1986; 62:960-964

(7.) Faglia G, Bitensky L, Pinchera A, et al: Thyrotropin secretion in patients with central hypothyroidism: evidence for reduced biological activity of immunoreactive thyrotropin. J Clin Endocrinol Metab 1979; 48:989-998

(8.) Faglia G: The clinical impact of the thyrotropin-releasing hormone test. Thyroid 1998; 8:903-908

(9.) Snyder PJ, Jacobs LS, Rabello MM, et al: Diagnostic value of thyrotrophin-releasing hormone in pituitary and hypothalamic diseases, assessment of thyrotrophin and prolactin secretion in 100 patients. Ann Intern Med 1974; 81:751-757

(10.) Snyder PJ, Utiger RD: Response to thyrotropin releasing hormone (TRH) in normal man. J Clin Endocrinol Metab 1972; 34:380-385

(11.) Harel Z, Biro FM, Tedford WL: Effects of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent. J Adolesc Health 1995; 16:232-234

(12.) Jackson IM, Luo LG: Antidepressants inhibit the glucocorticoid stimulation of thyrotropin releasing hormone expression in cultured hypothalamic neurons. J Invest Med 1998;46:470-474

RELATED ARTICLE: KEY POINTS

* Secondary hypothyroidism due to isolated thyrotropin deficiency is rare.

* Although the symptoms in primary or secondary hypothyroidism are similar, the absence of a goiter is a clue to central etiology.

* Once the biochemical diagnosis of central hypothyroidism is confirmed, then regardless of the patient's symptoms, magnetic resonance imaging of the pituitary is mandatory.

* Adequacy of the replacement dose of levothyroxine should be assessed by monitoring free [T.sub.4] levels.

* Free [T.sub.4] levels should be kept in the upper normal range.

From the Divisions of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Md; and the University of Parana, Guritiba, Brazil.

Reprint requests to Shehzad Basaria, MD, Johns Hopkins University School of Medicine, Division of Endocrinology and Metabolism, 4940 Eastern Ave, A-E-5, Suite 503, Baltimore, MD 21224.