Endocrinol.Japon.1989,36(4), 459-464

Isolated ACTH Deficiency Associated with TransientThyrotoxicosis and Hyperprolactinemia

YOSHIFUMI KANEMARU, TOSHIKAZU NOGUCHI AND TOSHIMASA ONAYA

The Third Department of Internal Medicine, Universityof Yamanashi Medical School, Tamaho, Yamanashi 409-38, Japan

Abstract

A 43-year-old woman with isolated ACTH deficiency in association withtransient thyrotoxicosis is reported. The initial evaluation revealed that plasmaACTH and cortisol did not respond to corticotropin-releasing hormone (CRH)in the presence of hyperthyroxinemia and hyperprolactinemia. During thereplacement therapy with dexamethasone, she developed transient hypothyroxi-nemia with persistent hyperprolactinemia. Although thyroid open biopsy didnot show any evidence of autoimmune thyroiditis or subacute thyroiditis, thedata appear to provide other evidence of a possible relationship betweenacute adrenal insufficiency and transient thyroid dysfunction.

Isolated ACTH deficiency is a rare causeof adrenocortical insufficiency, which is notfrequently associated with other endocrineabnormalities. There have been severalreports of isolated ACTH deficiency inassociation with some thyroid dysfunctionssuggesting that an autoimmune process maybe directed against both the pituitary andthe thyroid gland (Richtsmeier et al., 1980).On the other hand, we have previouslyreported two cases of transient thyrotoxicosisafter unilateral adrenalectomy due to

Cushing's syndrome (Haraguchi, et al. 1984).In this paper we report a case of isolatedACTH deficiency associated with transientthyrotoxicosis and hyperprolactinemia.

Materials and Methods

Plasma ACTH was measured by RIA usingthe CIS ACTH radioimmunoassay kit (AtomicEnergy Laboratory of Biomedical Products,France). The sensitivity of the assay of ACTHwas 10pg/ml. Prolactin (PRL), LH, FSH, GH,triiodothyronine (T3), thyroxine (T4) and cortisollevels were determined by RIA. TSH wasmeasured by highly sensitive TSH immuno-radiometric assay with a commercially availablekit. Urinary 17-OHCS was measured by theSilber-Porter reaction and 17-KS by the Zim-mermann reaction. Anti-TSH receptor antibodywas determined with a Smith's kit. Autoanti-bodies for anterior pituitary cell surface mem-brane (PitCSA) were assayed by an immuno-fluorescence method with GH3 ce11 (rat GH and

prolactin secreting cell) and AtT-20 cells (mouseadrenocorticotropic hormone secreting cell) asantigens. Briefly, the diluted sera and cell sus-pension were mixed. After adding FITC-labelledanti-human IgG solution, the cell suspensionwas examined under an incident fluorescence

Received October 4, 1988

Requests for reprints should be addressed to

YOSHIFUMI KANEMARU.

460 KANEMARU et al.Endocrinol. Japon.August 1989

microscope (Sugiura et al., 1987). Anti-adrenalantibody was determined by a tissue substrate-indirect immunofluorescence method. Briefly,cryostat sections of adrenal gland were reactedwith dilutions of patient's serum, rinsed andreacted with fluoresceinated anti-human immuno-

globulin conjugate. Patterns were compared tocontrols (Bigazzi PE et al., 1968).

ACTH-Z and lysine vasopressin were ad-ministered intramuscularly. Insulin (0.1unit/kg),corticotropin-releasing hormone (CRH, 100pg) ,LH-releasing hormone (LH-RH, 100pg) , andthyrotropin-releasing hormone (TRH, 500mg)were injected intravenously. CRH was gener-ously donated by Dr. Shibazaki, Department ofMedicine, Tokyo Women's Medical college .

Case Report and Results

A 43-year-old housewife was admitted

to the hospital in May, 1987 complaining

chiefly of nausea, vomiting, and headache

that had persisted for 3 weeks. She also

complained of general weakness and diz-

ziness. Without any medication, these

symptoms disappeared spontaneously. The

family history and the past history were

noncontributory. Her menses had been

regular. She was married at the age of 24

and had two children after normal preg-

nancies without any abnormal postpartum

galactorrhea. She had never been on medi-cine until this admission.

On admission, she was asthenic, but

conscious. She was 151.6cm tall and

weighed 47.6kg. No pigmentation was

Table 1. Thyroid function and PRL be-fore and after administrationof dexamethasone (0.5mg/day)

observed in the skin or mucous membranes.

There was a normal distribution of body

hair, and the goiter was not palpable with-

out tenderness. The blood pressure was

88/60mmHg, pulse rate 108/min, and body

temperature 37.2•Ž.

Laboratory data (blood) were as follows:

Erythrocyte sedimentation rate, 35mm/h;

glucose, 115mg/dl; total serum protein,

6.2g/dl; ZTT, 8.8 units; TTT, 3.8 units;

total bilirubin, 0.65mg/dl; total cholesterol,

99 mg/dl; urea nitrogen, 16.8mg/dl; crea-

tinine, 0.5mg/dl; GOT, 206 units/1; GPT,

223 units/1; LDH, 554 units/1; ALP, 289

units/1; r-GTP, 59 units/1; sodium 139.5

mEq/l; potassium, 3.9 mEq/1 ; chloride,

104.8 mEq/1; cortisol, less than 1.0pg/dl

(normal 3.7-13.0); ACTH, less than 10

pg/ml (less than 50); T4, 13.9pg/dl (4.5-

13.0); T3, 2.5ng/ml (0.8-1.8); free T4 was

3.54ng/dl (0.85-2.15); free T3, 8.8pg/ml

(3.0-5.8); TSH, less than 0.1pU/ml (0.6-

5.1); PRL, 130ng/ml (less than 30); serum

thyroglobulin, 13ng/ml (less than 30); and

thyroxine binding globulin, 19 pg/ml (11-

27). Antithyroid, anti-TSH receptor and

antiadrenal antibodies were negative. Al-

though autoantibodies to GH3 cells were

negative, autoantibodies to AtT-20 cells were

positive.

Corticosteroid replacement therapy (dex-

amethasone, 0.5mg/day, orally) has resulted

in the complete elimination of the clinical

symptoms with normalization of liver func-

tion abnormalities although thyroid function

Table 2. Response to ACTH-Z.

Vol.36, No.4 ACTH DEFICIENCY AND THYROTOXICOSIS 461

has fluctuated. T4, T3 and free T4 levels

decreased from 13.9ƒÊg/dl, 2.5ng/ml and

3.54ng/dl to 2.6ƒÊg/dl, 0.5ng/ml and 0.59

ng/dl, respectively, after dexamethasone

administration (0.5mg/day) for 4 weeks

(Table 1). 123I-Uptake after 4 weeks'

dexamethasone replacement (0.5mg/day)

was 5.5% and 21.3%, at 3h, and 24h,

respectively. Eight weeks later, thyroid

function also normalized without T4 re-

placement (T4, 6.1ƒÊg/dl; T3, 0.9ng/ml;

free T4, 0.9ng/dl; TSH, 4.2ƒÊU/ml). Plasma

PRL also decreased 2 weeks after dexame-

thasone administration (0.5mg/day) but

still showed an excessive response to TRH

(Tables 1 and 4).

The pituitary fossa appeared normal in

size, and intact in plain skull radiographs.

High resolution CT and magnetic resonance

imaging (MRI) showed no abnormality in

the skull or sella turcica.

Basal urinary 17-OHCS, 17-KS and

plasma cortisol were subnormal but showed

good responses to the daily administration

of ACTH-Z (Table 2). No response of

Table 3. ACTH response to various tests.

plasma ACTH to im injection of lysine

vasopressin, insulin-induced hypoglycemia

and iv infusion of CRF were observed,

whereas serum GH response to insulin-

induced hypoglycemia was normal (Table

3). Serum LH and FSH responded normally

to LH-RH (Table 4). Serum TSH showed

different responses to TRH during dexa-

methasone replacement therapy (0.5mg/day).

Serum TSH remained very low during hy-

perthyroxinemia, while serum TSH showed

a slightly exaggerated response to TRH

during hypothyroxinemia. Although the

basal value for PRL fell, PRL still showed

an excessive response to TRH (Table 4).

The thyroid open biopsy was carried out

50 days after dexamethasone administration

(0.5mg/day) during the euthyroid state (T4,

5.6ƒÊg/dl; T3, 1.0ng/ml; free T4, 0.83

ng/dl; TSH, 4.2ƒÊU/ml). Histological exa-

mination showed the thyroid follicles to be

small and irregular in size. There was no

fibrosis of the interstices or infiltration of

neutrophils and lymphocytes. These findings

were compatible neither with those of

Table 4. Response to LH-RH and TRH.

462 KANEMARU et al.Endocrinol. Japon.August 1989

Fig. 1. Biopsy specimen of the thyroid gland. The thyroid follicles were small and irregular

in size. There was no fibrosis of the interstices or infiltration of lymphocytes (Hematoxylin

and eosin; magnification,•~200.

Hashimoto's thyroiditis nor subacute thy-roiditis. (Fig. 1)

Discussion

Impairment of adrenocortical functionin ACTH deficiency is often due to pituitaryinvolvement by tumor or non-neoplasticinfiltration, and is frequently accompaniedby deficiencies of other pituitary hormones.

In this case, the headache, fever anddizziness for a couple of weeks beforeadmission may indicate pituitary apoplexy,a condition known to cause empty sellaand hypopituitarism, including isolatedACTH deficiency (Pelkonen et al., 1978).The patient had hyperprolactinemia, whichcould be due to an infarcted tumor, or

primary empty sella (Gharib et al., 1983).CT and MRI, however, showed no ab-normality in the skull and sella turcica.

Several studies have shown that both basaland induced PRL response in man andanimals can be inhibited by the administra-tion of glucocorticoid (Copinschi et al., 1975;Sowers et al., 1977; Lantigua et al., 1980).In addition, Shibutani et al. (1988) recentlyreported that the increased basal PRL andPRL hyperresponsiveness in a case of isolatedACTH deficiency returned to normal afterglucocorticoid replacement.

The possible etiological associations withisolated ACTH deficiency include primaryhypothyroidism (Yamamoto et al., 1976;Miller et al., 1982), insulin-dependent dia-betes mellitus (Abramson et al., 1968), andpolyglandular 'failure (thyroiditis, diabetes,hypoparathyroidism)(Kojima et al., 1982),all of which suggest a possible autoimmunemechanism. Richtsmeier et al. (1980) havedescribed selective ACTH deficiency as apart of an autoimmune syndrome whichcomprises lymphoid hypophysitis and thy-

Vol.36, No.4 ACTH DEFICIENCY AND THYROTOXICOSIS 463

roiditis. In their case, the patient had silent

thyroiditis with postpartum thyrotoxicosis,

a probable variant of chronic lymphocytic

thyroiditis.

In the present case, isolated ACTH de-

ficiency was accompanied bytransient thy-

rotoxicosis and liver dysfunction. Boththyroid and liver functions normalized with

glucocorticoid replacement therapy. Anti-thyroid, anti-TSH receptor and antiadrenalantibodies were negative. Although auto-antibodies to GH3 cells were negative, thoseto AtT-20 cells were positive. Sugiura etal. (1987) have described the incidence ofautoantibodies to AtT-20 cells among 5ACTH deficient patients. In their cases,all of the sera were positive for antibodiesto AtT-20 cells. Although the precise re-lationship between transient thyrotoxicosisand hypocorticalism is unclear, there areseveral lines of evidence showing that acute-ly altered adrenal function can elicit transientthyrotoxicosis (Maruyama et al., 1982,Haraguchi et al., 1984). Maruyama et al.(1982) reported a transient thyrotoxicosiswhich occurred after the cessation of steroidtherapy in a patient with autoimmunethyroiditis and rheumatoid arthritis. Hara-

guchi et al. (1984) reported transient thy-rotoxicosis in two patients with Cushing'ssymdrome who had undergone unilateraladrenalectony. They suggested that im-munological changes enhanced by a reduc-tion in the steroid hormone concentrationmight be closely related to the occurrenceof transient thyrotoxicosis in chronic lym-

phocytic thyroidits.In the present study the data appear to

provide additional evidence of the possiblerelationship between acute adrenal insuffici-ency and transient thyroid dysfunction. Onthe other hand, it is also likely that isolatedACTH deficiency could be a part of anautoimmune syndrome.

References

Abramson, E. A. and R. A. Arky (1968).Coexistent diabetes mellitus and isolatedACTH deficiency: report of a case. Metabo-lism 17, 492-495.

Bigazzi PE, et al.(1968). Immunofluorescencestudies on Addison's disease. hit. Arch Ablergy34, 455-469.

Copinschi, G., M. L'Hermite, R. Leclercq, J.Golstein, K. Vanhaelst, E. Virasoro and C.Robyn (1975). Effect of glucocorticoids on

pituitary hormonal responses to hypoglycemia.Inhibition of prolactin release. J. Clin. Endo-crinol. Metab. 40, 442-449.

Gharib, H., H. M. Frey, E. R. Jr. Laws, R.V. Randall and B. W. Scheithauer (1983).Coexistent primary empty sella syndrome andhyperprolactinemia. Arch. Intern. Med. 143,1383-1386.

Haraguchi, K., K. Hiramatsu and T. Onaya

(1984). Transient thyrotoxicosis after uni-lateral adrenalectomy in two patients withCushing's Syndrome. Endocrinol. Japon. 31,577-582.

Kojima, I., I. Nejima and E. Ogata (1982).Isolated adrenocorticotropin deficiency associ-ated with polyglandular failure. J. Clin.Endocrinol. Metab. 54, 182-186.

Lantigua, R. A., W. F. Strech, K. H. Lock-wood and L. Jacobs (1980). Glucocorticoidsuppression of pancreatic and pituitary hor-mones: Pancreatic polypeptide, growth hor-mone, and prolactin. J. Clin. Endocrinol.Metab. 50, 298-303.

Maruyama, H., M. Kato, O. Mizuno, K. Kata-oka and S. Matsuki (1982). Transient thyro-toxicosis occurred after cessation of steroidtherapy in a patient with autoimmune thy-roiditis and rheumatoid arthritis. Endocrinol.Japon. 29, 583-588.

Miller, M. J. and T. V. Horst (1982). IsolatedACTH deficiency and primary hypothyroidism.Acta. Endocrinol. 99, 573-576.

Pelkonen, R., A. Kuusisto, J. Salmi, P. Eistola,C. Raitta, S. L. Karonen and Aro Antti (1978).Pituitary function after pituitary apoplexy.Am. J. Med. 65, 773-778.

Richtsmeier, A. J., R. A. Henry, J. M. B. Jr.Bloodworth and E. N. Ehrlich (1980). Lym-

phoid hypophysitis with selective adrenocor-ticotropic hormone deficiency. Arch. Intern.

464 KANEMARU et al.Endocrinol. Japon.August 1989

Med. 140, 1243-1245.Shibutani, Y.(1988). Case report: Prolactin

dynamics in a patient with isolated ACTHdeficiency accompanied by hyperprolactinemia.Am. J. Med. 295, 140-143.

Sowers, J. R., H. E. Carlson, N. Brautbar andJ. M. Hershman (1977). Effect of dexametha-sone on prolactin and TSH responses to TRHand metoclopamide in man. J. Clin. Endo-crinol. Metab. 44, 237-241.

Sugiura, M., A. Hashimoto, M. Shizawa, M.

Tsukada, T. Saito, H. Hayami, S. Maruyamaand T. Ishido (1987). Detection of antibodiesto anterior pituitary cell surface membranewith insulin dependent diabetes mellitus andadrenocorticotropic hormone deficiency. Dia-betes. Res. 4, 63-66.

Yamamoto, T., T. Ogihara, K. Miyai, Y.Kumahara and Y. Hirata (1976). Coexistent

primary hypothyroidism and isolated ACTHdeficiency. Acta. Endocrinol. 82, 467-474.