Normal pituitary function and reserve after selective transsphenoidal removal of a thyrotropin-producing pituitary adenoma

Normal Pituitary Function and Reserve After Selective Transsphenoidal Removal of a Thyrotropin-Producing Pituitary Adenoma Antonino

Barbarino,

Laura De Marinis,

A 37-yr-old woman with recurrent hyperthyroidism after partial thyroid ablation was found to have 8n enlarged Sell8 turcica and elevated serum thyrotropin (TSH) and prolactin (PRL) levels measured by radioimmuno8ss8y. Serum growth hormone (GH). luteinking hormone (LH), follicle-stimulating hormone (FSH), and cortisol levels were within normal limits and responded appropriately to provocative stimuli both before and after surgery. preoperatively, the administration of thyrotropin-releasing hormone (TRH) (200 Pg i.v.) and metocLopr8mide (MCP) (10 mg p.0.) induced a more than twofold increase in serum PRL levels, whereas TSH WBS only modestly affected. Sromocriptine (2.5 mg p.o.1 and L-dop8 (500 mg p.0.) suppressed TSH and PRL values to less than 50% of their initial values. After selective transsphenoidal removal of 8 pituitary edenoma. signs and symptoms of hyperthyroidism disappeared and TSH and PRL returned to normal. The postoperative administration of TRH and MCP produced 8 normal response for both PRL and TSH. Postoperatively, bromocriptine induced a parallel decrease in the serum level of both hormones, whereas L-dopa decreased PRL but had no effect on the serum TSH level. This case provides evidence that hyperthyroidism caused by 8 pituitary ad8nOm8 c8n be successfuLLy treated by tr8nssphenoidaL surgery with preservation of normal pituitary function and reserve.

tumors associated with P ITUITARY secretion of TSH and hyperthyroidism

hyperhave been recently reported.‘-” In most of the reported cases, the patients had radiologic evidence of pituitary tumor”’ and absent TSH response to TRH stimulation.2*4’5 Remission of hyperthyroidism after surgery has been reported in four patients.34 However, after treatment all reported patients had either decreased pituitary or diminished pituitary TSH reserve.’ functiona Although more satisfactory results were originally reported with proton-beam therapy in one patient with acromegaly associated with hyperthyroidism,* follow-up studies suggested that this patient was suffering from Graves’ disease rather than pituitary hyperthyroidism.” More recently, Tolis et al.” have reported a patient with pituitary hyperthyroidism in whom thyroid and pituitary function returned to normal following transsphenoidal microsurgery and radiotherapy. We wish to report here a woman in Metabolism,Vol. 29, No. 8 (August), 1980

Carmelo Anile, and Giulio Maira

whom selective transsphenoidal removal of a pituitary adenoma completely alleviated hyperthyroidism while preserving pituitary function and reserve. MATERIALS

AND

METHODS

Serum FSH and LH were measured by specific radioimmunoassays using the double-antibody technic.” The results are expressed as equivalents of the second IRP-HMG in mlIJ/ml serum. The lower limit of sensitivity, calculated as the hormone concentration that corresponded to the 95% confidence lower limit of the buffer control tubes run in each assay, averaged 2.5 mIU second IRP-HMG/ml for LH and 2.2 mIU second IRP-HMG/ml for FSH. Serum PRL levels were measured using a homologous double-antibody radioimmunoassay.’ The sensitivity of assay was 1.5ng/ml, the intraassay variation was 4%. and the interassay variation was 7%. Normal serum PRL levels for the woman ranged from 5 to 20 ng/ml. Serum GH was measured by radioimmunoassay as described previously.” Thyrotropin was determined in serum by radioimmunoassay, using polyethylene glycol (PEG) to separate the bound and free hormone.‘6 The lower limit of sensitivity was 0.2 pU/ml. Serum T1, T, and cortisol were determined by radioimmunoassay as described previously.“,” All samples were assayed in duplicate.

Endocrine Stimulation and Suppression

Tests

TRH stimulation test: 200 pg TRH was injected i.v. Metoclopramide test: IO mg MCP was given orally. Bromocriptine (CB-154) test: 2.5 mg CB-154 was given orally. L-dopa test: 500 mg L-dopa was given orally. Blood samples were drawn at different times before and after the administration of these agents, as indicated in Figs. 1 and 2. A normal TSH and PRL response to TRH and MCP is defined as a greater than twofold increase from the baseline value. A normal TSH and PRL response to CB- 154 and t_-dopa is considered a greater than 50% decrease from the baseline value. LRH stimulation test: 100 fig LRH was injected i.v., and blood was collected at 0, 15, 30, 60, and 120 min for measurement of LH and FSH.

From the Institute of Internal Medicine, Division of Endocrinology, and Institute of Neurosurgery. The Catholic University School of Medicine, Rome, Italy. Receivedfor publication November 2. 1979. Address reprint requests to A. Barbarino. Institute of Internal Medicine. The Catholic University School of Medicine, 00168 Rome, Italy. o 1980 by Grune & Stratton, Inc. 0026-0495/80/2908~007~01.00/0 739

740

BARBARINO ET AL.

Insulin hypoglycemia test: regular insulin (0.15 U/kg body weight) was injected i.v., and blood was drawn as before at 15, 45, 60. and 90 min after the insulin injection. The nadir of blood glucose was 30 mg/ml, 45 min after the insulin injection.

Case Report J.A., a 37-yr-old woman, was admitted to our hospital in January 1978 for evaluation of hyperthyroidism. She was hospitalized in April 1975 because of fatigue, weakness, heat intolerance, marked weight loss, and episodes of tachycardia; neither goiter nor exophthalmos were present. The BMR was +40%. Thyroidal uptake of radioactive iodine was 73% at 6 hr and 82% at 24 hr; the scintiscan showed diffuse enlargement of both thyroid lobes. Serum T, was I8 pg/dl. Methimazole 10 mg daily was begun. After a few months the patient withdrew from antithyroid therapy by her own decision, and symptoms of hyperthyroidism recurred. In October 1975, a subtotal resection of her goiter was performed. Postoperatively, she developed hypoparathyroidism and was given dihydrotachysterol. She appeared euthyroid and her serum T, was 3.9 fig/d]. However, in 1976, she redeveloped symptoms of hyperthyroidism. Therefore, she was admitted to our hospital in 1978 for the first time. On admission she complained of palpitations, excessive sweating, tremor, and nervousness, but she denied menstrual irregularities or galactorrhea. Physical examination revealed a somewhat hyperactive woman with a blood pressure of 130/90 mm Hg. The pulse was regular, with a rate of lOO/min. The skin was moist, and a fine tremor was noted. The thyroid gland was not palpable, and there was no ophthalmopathy. Galactorrhea was not present. Thyroid studies indicated hyperthyroidism with a serum T, of I4 rg/dl, serum T, of 195 ng/dl, and serum TSH of 32 pU/ml. Thyroidal uptake was 54% at 6 hr and 45% at 24 hr; the scintiscan revealed a hyperactive right thyroid lobe. Antithyroglobulin antibodies and thyroid microsomal antibodies were not detectable. Serum calcium and phosphorus levels were within normal limits while she was taking dihydrotachysterol. When the T, suppression test was attempted she developed extreme anxiety and the medication had to be discontinued. Other tests of gonadal and adrenal function were normal. An x-ray of her skull revealed an enlarged sella turcica with double contour. A pneumoencephalogram did not reveal suprasellar extension of the pituitary adenoma.

RESULTS

Preoperative

Endocrine Investigations

Results of serum thyroid and Basal studies. pituitary hormone measurements are reported in Table 1 and Fig. 2. Serum total T4 and T3 concentrations were high and the serum TSH concentration was markedly and inappropriately elevated (24-35 pU/ml) (Fig. 1). The basal serum prolactin level was elevated (40 ng/ml) (Fig. 1). Serum GH, FSH, LH, and cortisol concentrations were within normal limits.

Table 1. Studies of the Secretion of Other Hormones Preooerative

Hormone

Postooerative Basal

Peak 65t

LH (mlU/ml)

5-15*

21.0

70t

22.0

FSH (mllJ/mll

5-20*

6.0

‘Bt

8.0

‘6t

GH (ng/mll Cortisol


0.5

22$

0.5

18%

7.5-20

19.0

33$

14.0

(Irg/dl)

283

lFollicular phase. tAfter LHRH (100 fig i.v.). SAfter insulin (0.15 U/kg i.v.1.

Response to TRH (Fig. 2). The serum TSH concentration increased from 30 /*U/ml to a peak of 48 pU/ml, 20 min after administration of 200 pg TRH. This was accompanied by a rise in serum T, from a baseline level of 175 ng/dl to 240 ng/dl, 120 min after TRH administration. Serum PRL level increased from 40 ng/ml to a peak of 120 ng/ml, 20 min after TRH. Thus, TRH produced a positive PRL response defined as a greater than twofold increase of the baseline value. In contrast, TSH response was not positive as judged by the same standard. Serum GH levels showed a modest increase (< 100%) after TRH administration. Response to MCP (Fig. 2). The serum TSH concentration increased from 25 pU/ml to 40 pU/ml, 150 min after MCP administration. Serum PRL levels increased from 40 ng/ml to 86 ng/ml, 120 min after MCP. Thus, a blunted TSH response to TRH and MCP was noted, whereas a positive PRL response to both stimuli was observed. No change in serum GH concentration was noted. Response to bromocriptine (CB-154) (Fig. 2). Following 2.5 mg bromocriptine, TSH and PRL levels fell in a parallel fashion. However, a normal TSH value was not reached after this single oral dose. The serum GH level did not increase significantly after bromocriptine administration. Response to L-dopa (Fig. 2). TSH and PRL decreased from elevated levels to a nadir 180 min after the L-dopa administration. Serum GH concentration increased from 0.5 ngfml to 5.5 ng/ml, 120 min after L-dopa administration. Provocative tests of other anterior pituitary Tests of LH, FSH, GH, and adrehormones. nocorticotropic reserve gave normal values (Table 1).

741

TSH-PRODUCING PITUITARY ADENOMA

14a

120 106

6a

60

40 - 10.

2.0.’ 5-- ___-_-_----

I 1

I

I 5

1 10

I 20

15

25

30

II I,

35

I 1 240

1

I

400

DAY5

Fig. 1. Serum PRL and TSH levels before and after selective transsphanoidal removal of the adenoma. The broken line represents the upper limit of the normal basal value of both hormones.

Clinical Course

In March 1978 a pituitary adenoma was selectively removed through the transsphenoidal route. The light microscopic investigations revealed a pituitary adenoma with chromophobe cell elements. The electron microscopic picture revealed a cell type with long cell bodies, showing secretory phenomena at the cell membrane.

The granules of these cells were smaller than those in lactotrophic cells, having a diameter of 1O&l 90 nm, and were peripherally located. The patient made an uneventful postoperative recovery, and symptoms of hyperthyroidism rapidly disappeared. One month after surgery, she complained of cold intolerance, some drowsiness, weakness, and fatigue. Thyroid studies suggested the development of mild hypothyroid-

n

/’ \

460 I”.

Fig. 2.

m

120

10

-IO

ae

Y..

Preoperative serum GH. TSH. and PRL response to various stimuli. (See text for explanation.)

4

PO

0

742

BARBARINO ET AL.

Table 2.

Studv

Serum T, (@g/d0 Serum T, (ng/dl) Serum TSH (plJ/ml)

Thyroid Test Results

Normal

JafWWj

February 3,

February 20.

March 17.

April

ValWS

1978

1978

1978

1978

1978

M.-Y 1978

14.4

14.0

14.5

Surgery

2.3

8.5

7.5

8.0

195

190

185

42

67

100

125

28

32

30

2.3

4.0

5.0

4.4

3.5-l

1

60- 180 0.2-5

November

March

1978

1979

Thyroidal 13’1uptake 6 hr (%I 24 hr (%I

5-20

54

10

15-50

45

35

ism (Table 2 and Fig. 2). The patient was not given any therapy and improved spontaneously over the next month, when the thyroid function tests returned to normal. Fifteen months after surgery, while on dihydrotachysterol therapy, her clinical and chemical status remained normal. Postoperative Endocrine Investigations Basal studies. Postoperatively, TSH and PRL levels were within normal limits during the 15 mo of observation (Fig. 1). Serum T, and T, concentrations decreased to hypothyroid levels during the first month following surgery and then returned to normal (Table 2). Results of other pituitary hormone measurements are reported in Table 1. Response to TRH (Fig. 3). The TRH stimulation was performed twice, first 2 mo following surgery (Fig. 3) and again after a period of 8 mo. During both tests, the TSH and PRL levels showed a marked increase after TRH injection. Serum GH level was unchanged. Response to MCP (Fig. 3). Both TSH and PRL concentrations were markedly increased

Fig. 3.

Postoperative

after MCP administration. Serum GH level was unchanged. Response to bromocriptine (CB-154) (Fig. 3). The serum TSH concentration decreased from 2.5 &J/ml to 1.3 pU/ml, 180 min after bromocriptine administration. Serum PRL level decreased from 15 ng/ml to 4 ng/ml, 120 min following CB-154. Serum GH level was unchanged. Response to L-dopa (Fig. 3). After t_-dopa administration, serum TSH level was unchanged and PRL decreased from 13 ng/ml to 5 ng/ml. Serum GH concentration increased to a peak level of 6.0 ng/ml, 60 min after t_-dopa administration. Provocative tests of other anterior pituitary hormones (Table 1). These tests were performed 2 mo after surgery. The patient presented responses similar to those observed before surgery after LRH and insulin. DISCUSSION

This young woman presented with symptoms and signs of recurrent hyperthyroidism after partial thyroid ablation. Thyroid hormones were

serum GH, TSH, and PRL responses to various stimuli. (See text for explanation.)

TSH-PRODUCING

743

PITUITARY ADENOMA

elevated but a measurable elevated serum TSH concentration was found. Her skull x-ray suggested a pituitary tumor that was the most likely site of inappropriate TSH production. The preoperative results of endocrine tests in our patient demonstrated elevated levels of TSH and PRL. The reason for the modestly elevated levels of PRL remains uncertain, since the tumor tissue did not contain lactotrophs. On the other hand, PRL levels have been found to be elevated in patients with different pituitary tumors, such as GH-producing tumors,23 prolactinomas,‘9~22 TSH-producing tumors,4’5 and at least one patient with an ACTH-producing tumor.24 TRH and MCP induced preoperatively a greater than twofold increase in serum PRL, whereas TSH was only modestly affected. This differential response seems to indicate that these hormones were secreted by pituitary cells that responded differently to hypothalamic control. Recently, it has been shown that TRH and MCP might not induce a positive PRL response in patients with PRL-producing tumors.*‘,** Bromocriptine and L-dopa, pharmacologic suppressors of PRL, induced preoperatively a parallel decrease in TSH and PRL. Similar findings were obtained in one patient with a PRL- and TSH-producing adenoma.’ From these data it would appear that TSH-producing tumors are not completely autonomous, since dopamine agonists suppress their secretory activity. The pituitary origin of our patient’s hyperthyroidism was strongly

supported by her clinical response to the selective transsphenoidal removal of the adenoma, after which she became initially mildly hypothyroid and finally regained normal thyroid function. Our patient provided an opportunity to evaluate pituitary function after selective removal of a TSH-producing adenoma with preservation of a large proportion of the pituitary gland. GH, LH, and FSH secretion remained normal postoperatively. Furthermore, following surgery her previously elevated serum TSH and PRL levels returned to normal and showed a normal response to various provocative stimuli. Of some interest are the postoperative changes in serum TSH and PRL levels after CB-154 and L-dopa administration. Bromocriptine induced a parallel decrease in the serum level of both hormones, whereas L-dopa decreased PRL and had no effect on serum TSH. These data are in agreement with the findings obtained in normal subjects. Orally administered L-dopa has been reported to have no effect on TSH secretion in normal subjects.25.26 On the contrary, it has been shown that bromocriptine is capable of decreasing normal TSH and PRL levels.*’ From the clinical and hormonal studies performed in this patient it can be concluded that (1) her hyperthyroidism was due to excessive TSH production from a pituitary adenoma, and (2) both pituitary function and reserve were restored to normal after the surgical procedure.

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21. Barbarino A, De Marinis L, Maira G, et al: Serum prolactin response to thyrotropin-releasing hormone and metoclopramide in patients with prolactin-secreting tumors before and after transsphenoidal surgery. J Clin Endocrinol Metab47:1148-1151, 1978 22. Barbarino A. De Marinis L, Menini E. et al: Prolactin-secreting pituitary adenomas: Prolactin dynamics before and after transsphenoidal surgery. Acta Endocrinol 91:397409, 1979 23. Franks S, Jacobs HS, Nabarro JDN: Prolactin concentrations in patients with acromegaly: Clinical significance and response to surgery. Clin Endocrinol 5:63-79. 1976 24. Bigos ST, Robert F, Pelletier G, et al: Cure of Cushing’s disease by transsphenoidal removal of a microadenoma from a pituitary gland despite a radiographically normal sella turcica. J Clin Endocrinol Metab 45:12511260, 1977 25. Eddy RL, Jones AL, Chakmakjian ZH, et al: Effect of levodopa (r-dopa) on human hypophyseal trophic hormone release. J Clin Endocrinol Metab 33:7099712. 1971 26. Refetoff S. Fang VS, Rapaport B, et al: lnterrelationships in the regulation of TSH and prolactin secretion in man. Elfects of t_-dopa, TRH and thyroid hormone in various combinations. J Clin Endocrinol Metab 38:450-457, 1974 27. Ferrari C, Beck-Peccoz P, Paracchi A, et al: Controllo monaminergico della secrezione della prolattina e dell’ormone tireotropo, in XVI Congress0 Nazionale di Endocrinologia, Bari 18-21 Maggio 1976, pp 103-121