A Case of Cushing Syndrome with Both Secondary Hypothyroidism and Hypercalcemia Due to Postoperative Adrenal Insufficiency

Endocrine Journal 2004, 51 (1), 105–113

NOTE

MASAHITO KATAHIRA, TSUTOMU YAMADA* AND MASAHIKO KAWAI*

Department of Internal Medicine, Kyoritsu General Hospital, Nagoya 456-8611, Japan *Division of Endocrinology, Department of Internal Medicine, Okazaki City Hospital, Okazaki 444-8553, Japan

Abstract. A 48-year-old woman was referred to our hospital because of secondary hypothyroidism. Upon admission a left adrenal tumor was also detected using computed tomography. Laboratory data and adrenal scintigraphy were compatible with Cushing syndrome due to the left adrenocortical adenoma, although she showed no response to the TRH stimulation test. Hypercortisolism resulting in secondary hypothyroidism was diagnosed. After a left adrenalectomy, hydrocortisone administration was begun and the dose was reduced gradually. After discharge on the 23rd postoperative day, she began to suffer from anorexia. ACTH level remained low, and serum cortisol, free thyroxine and TSH levels were within the normal range. Since her condition became worse, she was re-admitted on the 107th postoperative day at which time serum calcium level was high (15.6 mg/dl). Both ACTH response to the CRH stimulation test and TSH response to the TRH stimulation test were restored to almost normal levels, but there was no response of cortisol to CRH stimulation test. We diagnosed that the hypercalcemia was due to adrenal insufficiency. Although the serum calcium level decreased to normal after hydrocortisone was increased (35 mg/day), secondary hypothyroidism recurred. It was suggested that sufficient glucocorticoids suppressed TSH secretion mainly at the pituitary level, which resulted in secondary (corticogenic) hypothyroidism. However, both postoperative glucocorticoid deficiency and adequate amounts of thyroxine due to the elimination of inhibition of TSH secretion by glucocorticoids might cause hypercalcemia possibly through increased bone reabsorption of calcium.

Key words: Cushing syndrome, Corticogenic hypothyroidism, Hypercalcemia, Hydrocortisone withdrawal, Thyroxine (Endocrine Journal 51: 105–113, 2004)

CUSHING syndrome has been known to occur in with a prevalence of 6% in primary adrenal insuffi- association with secondary hypothyroidism [1, 2]. It is ciency. Some investigators reported a case of hyper- known that both natural and synthetic glucocorticoids calcemia after surgical treatment of Cushing syndrome inhibit thyroid function by suppressing TSH secretion [13, 14]. However, to our knowledge, a case of both at the suprahypophysial level [3–7] and/or at the pitui- Cushing syndrome with secondary hypothyroidism tary level [6–9]. Such secondary hypothyroidism is and hypercalcemia due to adrenal insufficiency after called “corticogenic hypothyroidism” [10]. On the surgical treatment of Cushing syndrome has not been other hand, hypercalcemia in association with hypo- reported to date. We report here the first case of Cush- adrenalism was first described in 1932 [11]. Nerup ing syndrome resulting in secondary hypothyroidism, [12] reported that hypercalcemia was demonstrated which was complicated by hypercalcemia in hydrocortisone withdrawal.

Received: January 15, 2003 Accepted: October 17, 2003 Correspondence to: Masahito KATAHIRA, M.D., Department of Case Report Internal Medicine, Kyoritsu General Hospital, 4-33 Goban-cho, Atsuta-ku, Nagoya 456-8611, Japan A 48-year-old woman had suffered from irritation 106 KATAHIRA et al. and anxiety since 1998, when her menstrual cycle be- hypertension. Her mother had diabetes mellitus and came irregular. After 1995 her weight increased from arrhythmia. 68 kg to 73 kg in 2000 and began to decrease there- Physical examination showed the following findings: after. She also began to suffer from tremors, resulting height 154.6 cm, weight 64.2 kg, body mass index in her admission to a psychiatric hospital on July 25, 26.9 kg/m2, blood pressure 147/97 mmHg, pulse rate 2001. She had a small goiter and decreased levels of 70 beats/min and temperature 37.0ºC. Conjunctivae free thyroxine (FT4) and TSH (0.67 ng/dl and 0.13 were not anemic. Pulmonary, cardiac, abdominal and U/ml, respectively). Hypokalemia (3.13 mmol/l) neurological examinations were unremarkable. The was also detected and potassium was administered. goiter was small, and the tremors had already dimin- She was referred and admitted to our hospital on ished. She had normal hircus and pubic hair, but had September 21, 2001 because of secondary hypothy- moon face and buffalo hump as well as striae cutis roidism and hypokalemia. She has been administered distensae and peripheral edema. hypotensors and diuretics since 1991 because of hyper- Laboratory data on first admission are shown in tension and edema. Her father and sister also had Table 1. White blood count was normal, but eosinocyte

Table 1. Laboratory findings on first admission

Urinalysis Endocrinology Protein (–) Free triiodothyronine 1.98 pg/ml Glucose (–) Free thyroxine 0.53 ng/dl Occult blood (–) TSH 0.02 U/ml TGPA (–) Blood cell count MCPA (–) White blood cell 4400/ l Eosinocyte 0% ACTH <5 pg/ml Red blood cell 341×104/ l DHEA-S 306 ng/ml Hemoglobin 10.1 g/dl Cortisol (serum) 23.2 g/dl Hematocrit 31.4% (urine) 153–255 g/day Platelet 21.6×104/ l Urinary 17-KS 3.4–3.7 mg/day Urinary 17-OHCS 9.9–12.6 mg/day Blood chemistry GH 0.26 ng/ml Total protein 5.9 g/dl Somatomedin-C 140 ng/ml Albumin 60.7% PRL 35 ng/ml

1-globulin 2.8% LH 1.3 mIU/ml 2-globulin 8.6% FSH 5.0 mIU/ml -globulin 12.2% Serum estradiol 44.7 pg/ml -globulin 15.7% Serum adrenaline <5 pg/ml Aspartate aminotransferase 26 IU/l Serum noradrenaline 106 pg/ml Alanine aminotransferase 58 IU/l Serum dopamine <5 pg/ml Lactate dehydrogenase 378 IU/l Plasma renin concentration 6.5 pg/ml Alkaline phosphatase 189 IU/l Serum aldosterone 16 pg/ml Sodium 144 mmol/l Potassium 3.2 mmol/l Anti-pituitary cell antibody (–) Chloride 106 mmol/l (indirect fluorescent antibody technique) Calcium 9.4 mg/dl Phosphate 3.6 mg/dl Daily variation Blood urea nitrogen 13 mg/dl Time ACTH (pg/ml) Serum cortisol ( g/dl) Creatinine 0.50 mg/dl 0600 h <5 17.7 Total cholesterol 204 mg/dl 1200 h <5 24.7 Fasting plasma glucose 79 mg/dl 1800 h <5 21.3 Hemoglobin A 5.1% 1c 2400 h <5 22.9 TGPA: anti-thyrogloblin particle agglutination, MCPA: anti-thyroid microsomal particle agglutination, DHEA-S: dehydroepiandrosterone sulfate, 17-KS: 17-ketosteroid, 17-OHCS: 17-hydroxycorticosteroid GLUCOCORTICOID REGULATION OF TSH AND CALCIUM 107 was not detected. Total protein level (normal range: Table 2. Results from the endocrinological examination on 6.2–7.8 g/dl) was slightly low, and plasma protein first admission fraction was normal. Alanine aminotransferase and CRH stimulation test (CRH 100 g iv) lactate dehydrogenase levels were high. Serum potas- Time (min) 0 30 60 90 120 sium level was low. Free triiodothyronine (FT3), FT4 ACTH (pg/ml) 5 <5 <5 <5 <5 and TSH levels (normal range: 3.14–4.93 pg/ml, 0.82– Serum cortisol ( g/dl) 18.8 17.4 17.1 16.0 16.7 1.59 ng/dl, and 0.43–3.94 U/ml, respectively) were TRH stimulation test (TRH 500 g iv) low. PRL level was high. Plasma ACTH level was Time (min) 0 30 60 90 120 suppressed, while serum cortisol, urinary cortisol and TSH ( U/ml) 0.020.030.040.020.02 urinary 17-hydroxycorticosteroid (17-OHCS) levels PRL (ng/ml) 32 55 49 45 39 were high. Daily variations in plasma ACTH and cor- GRH stimulation test (GRH 100 g iv) tisol levels were not observed. Results from the endo- Time (min) 0 30 60 90 120 crinological examination on first admission are shown GH (ng/ml) 0.20 1.21 0.04 0.73 0.49 in Table 2. ACTH did not respond to 100 g CRH LH-RH stimulation test (LH-RH 100 g iv) stimulation, whereas the serum cortisol level remained Time (min) 0 30 60 90 120 high. In addition, TSH did not respond to 500 g TRH LH (mIU/ml) 2.5 9.6 14 16 20 stimulation. Basal PRL had increased, while PRL FSH (mIU/ml) 5.9 9.9 12 15 19

Fig. 1. Clinical imaging on first admission. (A) Abdominal computed tomography. Arrows indicate an adrenal tumor in the left adrenal gland. (B) 131I-adosterol scintigram demonstrated a greater uptake in the left adrenal gland. (C) Magnetic resonance image of the head revealed no mass. 108 KATAHIRA et al. response to TRH had slightly decreased. GH response immediately after the surgical treatment and the dose to GRH had also decreased. Responses of LH and was reduced gradually from 200 mg/day. Potassium FSH to LH-RH were delayed. Computed tomography was discontinued on November 6, 2001. The patient (CT) of the abdomen revealed a distinct solitary mass was discharged with replacement of hydrocortisone (3.5 cm in diameter) on the left adrenal gland (Fig. 1A). 131I-adosterol scintigraphy revealed a hot uptake around the left adrenal gland (Fig. 1B). In contrast, magnetic resonance image (MRI) of the head revealed no mass (Fig. 1C). Based on these findings, the disease was diagnosed as Cushing syndrome due to left adrenal tumor. Administration of levothyroxine (50 g/day) was begun and potassium was increased from 3.6 mEq/day to 16 mEq/day. Although there had been no menstrual bleeding since August 2001, it started on October 13, 2001. After FT4 and serum potassium levels reached the normal ranges, the left adrenal tumor was removed on October 17, 2001. Fine granular cells proliferated and atypical nuclei were not found, histologically suggesting that the adrenal tumor was an adenoma Fig. 2. Histopathological examination of the left adrenal gland. (Fig. 2). Hydrocortisone administration was begun (Hematoxylin-eosin staining, original magnification ×200)

Fig. 3. Clinical course in 2001. 17-OHCS: 17-hydroxycorticosteroid, FT4: free thyroxine. GLUCOCORTICOID REGULATION OF TSH AND CALCIUM 109

(15 mg/day) and levothyroxine (25 g/day) on No- Table 3. A hemogram was normal. Serum creatinine vember 8, 2001. However, she began to suffer from and uric acid levels were high, but serum potassium anorexia. Plasma ACTH level remained low (6–8 pg/ level was low. Serum calcium level was high, but ml), and serum cortisol, FT4 and TSH levels were intact PTH level was low. PTH-related peptide and within normal range. Levothyroxine was discontinued angiotensin converting enzyme levels were normal. on December 17, 2001 and hydrocortisone was Urinary calcium level was almost normal. On the reduced gradually to 5 mg/day (Fig. 3). However, other hand, while ACTH level was normal, serum the patient began to suffer from hypotonia, tremors, cortisol, urinary cortisol and urinary 17-OHCS levels nausea and vomiting after January 2002. In order to were low. Results from endocrinological examinations examine the causes of her symptoms, she was re- on second admission are shown in Table 4. Although admitted to our hospital on January 31, 2002. both ACTH response to 100 g CRH stimulation and Laboratory data on second admission are shown in TSH response to 500 g TRH stimulation were almost

Table 3. Laboratory findings on second admission

Urinalysis Blood chemistry Protein (+) Total protein 6.3 g/dl Glucose (–) Albumin 55.8%

Occult blood (+/–) 1-globulin 4.4%

2-globulin 9.4% Blood cell count -globulin 10.9% White blood cell 4500/ l -globulin 19.5% Neutrophil 51.9% Aspartate aminotransferase 28 IU/l Basocyte 0.4% Alanine aminotransferase 12 IU/l Eosinocyte 4.0% Lactate dehydrogenase 169 IU/l Monocyte 8.7% Alkaline phosphatase 89 IU/l Lymphocyte 35.0% Creatine kinase 35 IU/l Red blood cell 342×104/ l Sodium 145 mmol/l Hemoglobin 9.7 g/dl Potassium 3.3 mmol/l Hematocrit 30.6% Chloride 105 mmol/l Platelet 32.5×104/ l Calcium 15.6 mg/dl Phosphate 2.6 mg/dl Endocrinology Blood urea nitrogen 19 mg/dl Creatinine 2.71 mg/dl Free triiodothyronine 5.39 pg/ml Uric acid 8.2 mg/dl Free thyroxine 1.75 ng/dl CRP 5.2 mg/dl TSH 1.67 U/ml CEA <2.5 ng/ml ACTH 31 pg/ml CA19-9 22 U/ml DHEA-S 71 ng/ml Fasting plasma glucose 83 mg/dl Cortisol (serum) 2.4 g/dl ACE 13.5 IU/l (urinary) <9.5 g/day Urinary 17-KS 2.3 mg/day Urine chemistry Urinary 17-OHCS 2.7 mg/day GH 2.16 ng/ml Sodium 228 mmol/day Soamtomedin-C 180 ng/ml Potassium 44.3 mmol/day LH 10 mIU/ml Chloride 224 mmol/day FSH 68 mIU/ml Calcium 275.5 mg/day Serum estradiol <10.0 pg/ml Phosphate 191.9 mg/day Intact PTH 8 pg/ml Creatinine 511.1 mg/day PTH (radioimmunoassay) 230 pg/ml Volume 1900 ml/day PTH-related protein 0.3 pmol/l

1,25(OH)2vitaminD 17.7 pg/ml

DHEA-S: dehydroepiandrosterone sulfate, 17-KS: 17-ketosteroid, 17-OHCS: 17-hydroxycorticosteroid, CRP: C- reactive protein, CEA: carcinoembryonic antigen, ACE: angiotensin converting enzyme 110 KATAHIRA et al.

Table 4. Results from the endocrinological examination on normal, serum cortisol did not respond to 100 g CRH second admission stimulation. However, urinary cortisol and 17-OHCS CRH stimulation test (CRH 100 g iv) responded to prolonged ACTH stimulation (1 mg, 3 Time (min) 0 30 60 90 120 days). CT scans revealed no tumor. These findings ACTH (pg/ml) 20 56 54 47 51 suggested that adrenal insufficiency due to acute Serum cortisol ( g/dl) <1.0 1.3 1.5 1.4 <1.0 withdrawal of hydrocortisone after surgical treatment TRH stimulation test (TRH 500 g iv) caused hypercalcemia in this patient. Time (min) 0 30 60 90 120 Administration of saline (2,000 ml/day), elcatonin TSH ( U/ml) 2.018.107.476.076.63 (80 units/day) and pamidronate disodium (30 mg/day) PRL (ng/ml) 60 98 96 88 91 was begun, and serum calcium level decreased but Prolonged ACTH stimulation test did not reach normal range. Hydrocortisone was also Day 1234 increased after CRH stimulation test on February 7, 17-OHCS (mg/day) 2.0 3.8 4.9 8.9 2002. Serum calcium level decreased to normal range Urinary cortisol ( g/day) <11.4 <14.8 25.7 78.3 while urinary calcium level decreased to below normal ACTH stimulation (1 mg im) III range. Since serum calcium level decreased to below 17-OHCS: 17-hydroxycorticosteroid normal range, vitamin D was temporarily administered

Fig. 4. Clinical course in 2002. 17-OHCS: 17-hydroxycorticosteroid, FT4: free thyroxine. GLUCOCORTICOID REGULATION OF TSH AND CALCIUM 111 from February 14 to March 7, 2002. The patient calcemia. In the present case, these diseases were not recovered from anorexia and tremors by February likely to cause hypercalcemia since the PTH level was 25, 2002. Since FT4 and TSH levels decreased after low. On the other hand, PTH secretion is appropriately hydrocortisone was increased, levothyroxine adminis- suppressed in parathyroid-independent hypercalcemia, tration (25 g/day) was restarted on March 8, 2002. which involves neoplasms, excess vitamin D, thyro- Although there had been no menstrual bleeding since toxicosis, adrenal insufficiency, renal failure, immobi- October 2001, it started again on March 24, 2002. In lization, Jansen’s disease and drugs. Neoplasms were the end, the patient was discharged with replacement not found in the present case. Vitamin D intoxication, of hydrocortisone (35 mg/day) and levothyroxine on sarcoidosis and other granulomatous diseases and March 25, 2002 (Fig. 4). Williams’ syndrome cause excess vitamin D. In the present case, these diseases were not likely to cause hypercalcemia since the level of 1,25 (OH)2 vitamin D Discussion was low. Although the levels of FT3 and FT4 were slightly high, the TSH level was normal. The blood The elevation in serum cortisol in Cushing syn- calcium level of this patient was too high for hyper- drome is accompanied by a reciprocal decrease in calcemia induced by thyrotoxicosis [19]. While there serum TSH concentration [1, 2]. In contrast, TSH was renal failure on second admission, this renal fail- secretion is enhanced in the presence of glucocorticoid ure seems to not cause but result from hypercalcemia deficiency resulting from adrenalectomy [15] or since the serum creatinine level was almost normal primary adrenocortical insufficiency [16, 17]. In until January 2002. The patient did not suffer from this case, both TSH and FT4 levels were low and diseases resulting in immobilization such as spinal cord levothyroxine replacement was required to maintain injury or extensive casting after fractures. Jansen’s thyroid function before the operation. After the opera- disease and drugs were not likely to cause hypercal- tion, they rose without levothyroxine replacement. cemia since the patient had a normal stature and was However, they were suppressed again after hydrocorti- not taking vitamin A, thiazide diuretics, theophylline sone was increased. Based on these findings, TSH or any drugs resulting in milk-alkali syndrome. In the secretion was obviously suppressed by glucocorticoids present case, the serum calcium level decreased to the in this case. Some investigators [3–5] postulated that normal range after hydrocortisone was increased and this suppressive effect might occur with inhibition of remained normal under adequate hydrocortisone re- the secretion of TRH from the hypothalamus. In con- placement even after saline, elcatonin and pamidronate trast, Otsuki et al. [6] suggested that TSH secretion disodium were discontinued, suggesting that hypercal- might be inhibited not only at the suprahypophyseal cemia was due to adrenal insufficiency after surgical level but also at the pituitary level. Taylor et al. [18] treatment of Cushing syndrome. examined the inhibitory effects of dexamethasone on Walser et al. [20] demonstrated that increased calci- the secretion of TSH in vitro by using the rat anterior um absorption from the gut would not appear to be an pituitary gland. In the present case, TSH did not important factor in the development of hypercalcemia. respond to TRH stimulation before the operation. How- A second possible mechanism involves the reduction ever, TSH response to TRH stimulation was almost in the glomerular filtration rate occurring as a result of normal in the presence of glucocorticoid deficiency af- hypovolemia, which in turn results in an increase in ter the operation, suggesting that TSH secretion might proximal tubular reabsorption of sodium with concur- be inhibited mainly at the pituitary level in this case. rent calcium reabsorption. These mechanisms were There are two categories of hypercalcemia: that suggested to be secondary to the consequent volume associated with dysfunction of the parathyroid cell depletion and correctable by rehydration of the patient. (parathyroid-dependent hypercalcemia) and that in However, the present patient was hypovolemic on which hypercalcemia occurs despite appropriate para- second admission, but the hypercalcemia responded thyroid suppression (parathyroid-independent hyper- partially to intravenous saline infusion. Moreover, calcemia) [19]. Parathyroid-dependent hypercalcemia total 24-h urinary calcium output was decreased com- involves primary hyperparathyroidism, familial hypo- paratively with corticosteroid treatment. Therefore, an calciuric hypercalcemia and lithium-induced hyper- increase in proximal tubular reabsorption of calcium 112 KATAHIRA et al. did not necessarily cause hypercalcemia in this patient. levels returned to normal without levothyroxine re- A third possible mechanism involves the increased placement after the operation and she eventually did calcium absorption from bone. Montoli et al. [21] not recover from the psychiatric symptoms until demonstrated that a glucocorticoid deficiency might February 25, 2002. Taken together, it might have been appear to induce calcium mobilization from bone inappropriate to administer levothyroxine before the stores by mechanisms unrelated to the bone remodel- operation. ing processes. Jowsey and Simons [22] investigated The last problem is hyperprolactinemia. There the contribution of increased bone reabsorption of was neither prolactinoma nor other pituitary or sellar calcium, particularly with respect to the associated tumors based on the imaging findings in the present effects of thyroxine. In their study, dogs subjected to case. The loss of thyroxine replacement might result both adrenalectomy and parathyroidectomy displayed in the elevation of the PRL level on second admission. precipitous increases in calcium levels. On the other Since the basal PRL level was moderately high but sta- hand, dogs subjected to both adrenalectomy and ble during the course, treatments such as thyroxine, thyroidectomy displayed no significant increases in other drugs and adrenal surgery seemed to be inde- calcium; administration of thyroxine produced a pendent of hyperprolactinemia. PRL release inhibiting marked hypercalcemia. These findings appear to be factor (PIF) is supposed to play an important role in comparable to the situation of the current patient. regulation of PRL secretion. Therefore, the suppres- Among other aspects in the current case, the first sion of PIF may cause a hypersecretion of PRL. problem is tremors. Although tremors are a sign of Hashimoto [23] suggested that hyperprolactinemia in hyperthyroidism, they occurred in a hypothyroid state Cushing disease might be due to the suppressive effect before first admission and in a euthyroid and slightly of cortisol on PIF. However, the present patient hyperthyroid state before second admission. There- showed high basal levels and subnormal rises of PRL fore, the tremors seem to be independent of thyroid both in hypercorticoidism and in hypocorticoidism. function in the present patient and instead seem to be The patient did not have systemic disorders resulting part of the psychiatric symptoms due to hypercortiso- in hyperprolactinemia such as chronic renal failure and lism and hypercalcemia. The second problem is the polycystic ovarian disease. In the end, the elevated hypokalemia on second admission. Generally speaking, PRL level in this patient in whom no cause could be hyperkalemia occurs in adrenal insufficiency. Find- identified was considered to be idiopathic [24]. ings in the present case suggested that vomiting due to In summary, sufficient glucocorticoids suppressed adrenal insufficiency and hypercalcemia resulted in TSH secretion mainly at the pituitary level in the hypokalemia. The third problem is the menstrual present case, which resulted in insufficient thyroxine. phase when LH, FSH, estradiol and results of an LH- Even after thyroxine replacement, hypercalcemia did RH stimulation test were examined, which was diffi- not occur because of sufficient glucocorticoids due to cult to determine since the patient’s menstrual cycle Cushing syndrome. However, both glucocorticoid de- was irregular. However, it might have been either the ficiency after the operation and adequate amounts of follicular phase or the luteal phase since the secretions thyroxine due to the elimination of inhibition of TSH of LH and FSH were suppressed on first admission secretion by glucocorticoids might have caused hyper- and elevated on second admission by negative feed- calcemia possibly through increased bone reabsorption back of estradiol. The fourth problem is levothyroxine of calcium. This case appears to be important since it replacement before the operation. Levothyroxine was demonstrates the relationship between glucocorticoids administered to improve the psychiatric symptoms due and TSH secretion and also between glucocorticoids, to hypothyroidism and to avoid unexpected events dur- thyroxine and calcium homeostasis. ing and after the operation. However, FT4 and TSH

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