A Case of Cushing’s Disease Revealed Six Years after Postpartum Hypopituitarism

Kyuzi Kamoi, Makoto Toyama and Norihito Sudo

Departments of Internal Medicine (K.K.), Neurosurgery (M.T.), Obstetrics and Gynecology (N.S.), Nagaoka Red Cross Hospital, Nagaoka, 940-2085 Niigata, Japan

Address all correspondence and requests for prints to: Kyuzi Kamoi, M.D., Nagaoka Red Cross Hospital, Nagaoka, 940-2085 Niigata, Japan. E-mail: kkam-int{at}echigo.ne.jp


    Introduction
 Top
 Introduction
 Case Report and Results
 Discussion
 References
 
The most frequent cause of hypopituitarism in postpartum women is Sheehan’s syndrome (1, 2). The natural course of Sheehan’s syndrome is the appearance of gonadotropic failure, followed by deficiency of TSH and, finally, deficiency of ACTH due to ischemic pituitary necrosis (3). Therefore, there have been no reports of patients with Sheehan’s syndrome who have an inappropriate secretion of ACTH.

We describe in this paper the first case of a woman with Cushing’s disease as a result of a pituitary macroadenoma, who had hypopituitarism 6 yr earlier in her clinical course due to Sheehan’s syndrome.


    Case Report and Results
 Top
 Introduction
 Case Report and Results
 Discussion
 References
 
A 44-yr-old woman, 158 cm in height, was admitted to the Nagaoka Red Cross Hospital because of anorexia, general fatigue, and sleeping disturbance. This was the second admission for this patient. Her father, who had had noninsulin dependent diabetes mellitus, had died at the age of 54 yr from acute myocardial infarction. Her mother has hypertension. The patient has one sister, one brother, and one daughter, who are all healthy.

The patient had choledocholithiasis at the age of 25 yr, when her weight was 52 kg (Fig. 1Go). At the age of 34 yr, her weight increased to 62 kg, and hypertension (180/100 mm Hg) and hyperlipidemia were found at her medical check-up. The serum concentrations of sodium and potassium were 140 and 4.5 mmol/L, respectively (Fig. 1Go). She was given loop diuretics for essential hypertension and an antihyperlipidemic drug. However, the patient stopped taking the medications after 2 weeks by her own decision. At the age of 35 yr, she was again determined to have hypertension by medical check-up and was given loop diuretics and reserpine and the same antihyperlipidemic drug. She stopped taking these medications 1 yr later. Since that time, these disorders were not controlled by either diet therapy or drugs.



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Figure 1. Characteristics of main clinical and laboratory findings from 25–44 yr of age in the patient. The patient underwent pregnancy at the age of 38 yr and developed preeclampsia at the 23rd gestational week, hypopituitarism on the 9th day postpartum, and Cushing’s disease at the age of 44 yr. Blood pressure represents systolic and diastolic values.

 
At the age of 38 yr, she visited the family physician because of amenorrhea. She had hypertension, hyperlipidemia, and was pregnant, and was placed on the same antihypertensive drugs again. The patient first visited our hospital to receive management of hypertension and pregnancy at the seventh gestational week. She weighed 64 kg, and her blood pressure was 170/100 mm Hg (Fig. 1Go). She had no abnormalities in visual acuity or visual field. On routine laboratory testing, her total white cell count was normal; however, she had 22% lymphocytes and 0% eosinophil, and the serum concentration potassium was 3.5 mmol/L. She did not have hyperglycemia. At the 20th gestational week, edema developed in her foot, but was not accompanied by proteinuria, and she had normal serum concentrations of creatinine (27 µmol/L) and albumin (40 g/L).

During the prenatal course she had a systolic blood pressure in the range of 180–200 mm Hg and a diastolic blood pressure in the range of 100–120 mm Hg, which was not treated with drugs. At the 20th gestational week, the patient was placed on loop diuretics, Ca2+ antagonist, hydralazine, reserpine, and methyldopa for superimposed chronic hypertension with edema, but the treatment was not effective. Hyperlipidemia was also present during the pregnancy, but it was not treated with drugs.

She was admitted to our hospital for preeclampsia-superimposed chronic hypertension at the 23rd gestational week. At that time, her weight was 71 kg, and she had edema of her hands and legs (Fig. 1Go). However, she did not have muscular weakness, back pain, striae cutis, acne, or bruising. Her blood pressure was 200/110 mm Hg. Routine laboratory testing revealed that the serum concentrations of sodium, potassium, creatinine, and albumin were 140 mmol/L, 2.9 mmol/L, 27 µmol/L, and 39 g/L, respectively (Fig. 1Go), and that the total white cell count was normal, although she had a low percentage of lymphocytes (14%) and eosinophils (0%). Proteinuria, glycosuria, and ketonuria were not present. Her urinary volume was 3000–4000 mL/day while using increased diuretics.

At the 27th gestational week, the patient delivered a female child by cesarean section because her fetus developed fetal asphyxia. The immature newborn weighed 650 g, with an Apgar score of 8 at 1 min and 9 at 5 min. Estimated blood loss during the operation was 680 mL, and there was transient hypotension.

After the delivery, the patient complained of general malaise, anorexia, and general myasthenia. Nine days postpartum, the patient was still unable to move in her bed, complained of strong thirst, and had hypotonic polyuria (8,900 mL/day). At that time, endocrinological consultation was made. Her body weight decreased to 66 kg. Her blood pressure was 180/100 mm Hg. The serum concentration of potassium (3.3 mmol/L) was low (Fig. 1Go). Visual acuity and visual field were intact. A normal diurnal variation in plasma concentrations of cortisol and ACTH was observed. The hormonal responses to GHRH, TRH, and insulin administration were evaluated in the patient. The results of these tests revealed that the patient had deficiencies of gonadotropin, TSH, and vasopressin secretion (Tables 1Go and 2Go). However, GH, PRL, and ACTH secretions were intact (Tables 1Go and 2Go). The concentrations of aldosterone in plasma and urine were normal. The antithyroid test, antimicrosomal test, and antipituitary antibody test were negative. Accordingly, the patient was diagnosed with postpartum hypopituitarism.


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Table 1. Stimulation tests with LHRH, TRH, and GRH on two admissions

 

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Table 2. Insulin-induced hypoglycemia stimulation test on two admissions

 
Thirteen days postpartum, magnetic resonance imaging (MRI) scanning of the pituitary gland showed that there was a large mass with hemorrhage in the gland (Fig. 2AGo). One month later, MRI of the pituitary gland showed that there was a partial empty sella without the mass, but with an atrophic pituitary gland (Fig. 2BGo). MRI of the pituitary gland performed 1 and 2 yr later showed no change.



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Figure 2. A, Coronal MRI scan without (A1) and with (A2) gadolinium contrast, performed 13 days after the delivery, showed a large mass with spots of decreased signal intensity in the sella turcica and a small mass of 8 mm in diameter within the large mass, which suggests the presence of a pituitary tumor with hemorrhage. B, One month later, sagittal MRI scan with gadolinium contrast showed a partially empty sella without the mass, but with an atrophic pituitary gland.

 
The patient was placed on L-T4, estrogen, progesterone, and desamino-8-D-arginine vasopressin (DDAVP). Treatment with Ca2+ antagonist and {alpha}-blocker were effective for the hypertension. Hyperlipemia disappeared 1 month after delivery. She was discharged 60 days postpartum. One year after the delivery, her weight was 66 kg, and blood pressure and serum potassium concentration normalized (Fig. 1Go).

Subsequent follow-up was made up to the age of 42 yr, and at that time, she weighed 73 kg, and her face appeared round. The serum potassium concentration had decreased to 3.4 mmol/L, and the serum cholesterol concentration had increased to 6.8 mmol/L (Fig. 1Go). She often felt strong thirst and drank 3–4 L/day water with nocturia, although she was receiving DDAVP, and experienced amenorrhea, albeit being treated with estrogen and progesterone. Primary aldosteronism was suspected, but the plasma aldosterone concentration was normal. Further examination was not performed, because the patient did not visit our hospital again since she was feeling well.

On the second admission at the age of 44 yr, her weight was 86.9 kg, her pulse rate was regular at 66 beats/min, and her blood pressure was 180/100 mm Hg (Fig. 1Go). She had not taken any medications since the age of 42 yr. She had a moon face, buffalo hump, and centripetal obesity. Skin turgor was low. Laboratory data showed that she had hypokalemia (3.1 mmol/L), hyperlipemia (total cholesterol, 9.4 mmol/L), and hypotonic polyuria (4000 mL/day). An electrocardiogram revealed elongation of QT, inversion of ST, and left ventricular hypertrophy. An abdominal echogram exhibited gallstones and a fatty liver. There were no abnormalities in visual acuity or visual field.

Hormonal examination during the second admission showed that she had deficiencies of gonadotropin, TSH and vasopressin secretion as in the first examination as well as GH deficiency (Tables 1Go and 2Go). However, the plasma concentrations of cortisol and ACTH were high over 24 h (Table 3Go). The concentrations of both cortisol and ACTH increased after CRH administration (Table 4Go). The high plasma ACTH level was not suppressed by the overnight dexamethasone test (oral administration of 1 mg dexamethasone at 2300 h) or the 2-day high dose dexamethasone test (oral administration of 2 mg dexamethasone every 6 h for 2 days; Table 5Go) (4). The urinary concentration of free cortisol (585–698 nmol/day) was also high over 24 h. Administration of 2.5 mg bromocriptine lowered the plasma levels of cortisol and ACTH, whereas administration of a somatostatin analog had no effect on the plasma levels of cortisol and ACTH. These data indicated that ACTH secretion was inappropriately high.


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Table 3. Diurnal variation of the plasma concentrations of cortisol and ACTH over 24 h measured at the time of each admission

 

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Table 4. CRH stimulation test on second admission

 

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Table 5. Suppression test by dexamethasone on second admission

 
MRI scanning revealed that a large mass had extended over the sella turcica (Fig. 3AGo), suggesting that the patient had an ACTH-secreting pituitary tumor. The tumor was resected by transsphenoidal approach. The resected tumor exhibited basophilic staining and had immunoreactivity for anti-ACTH antibody. After the tumor was resected, the plasma concentrations of cortisol and ACTH decreased, but they were high over the next 24 hours and responded strongly to CRH administration. In addition, MRI scanning showed that unresected parts of the tumor remained in the para- and suprasellar regions. Radiotherapy was therefore applied. Eight months after tumor resection, pituitary MRI revealed an empty sella (Fig. 3BGo).



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Figure 3. A, Six years after the first MRI scan, coronal MRI scan with gadolinium contrast revealed a large mass that extended into the sphenoid sinus in the pituitary fossa, which suggests the presence of a large pituitary tumor. The tumor was resected. B, Eight months later, a sagittal MRI scan with gadolinium contrast showed an empty sella with a shrunken pituitary gland.

 
The patient was again given L-T4, estrogen, progesterone, and DDAVP treatment. The hypertension and hyperlipemia disappeared after 1 month of therapy.


    Discussion
 Top
 Introduction
 Case Report and Results
 Discussion
 References
 
The clinical course of this case raises many interesting questions. First, what was the cause of the patient’s obesity, hypertension, hyperlipemia, and low level of serum potassium found at the age of 35 yr? The primary disorder that caused the obesity, hypertension, and hyperlipemia is debatable. Cushing’s disease may be the primary cause rather than other disorders, as one of the clinical and laboratory manifestations of Cushing’s disease is obesity, hypertension, or hyperlipemia, and it is usually refractory to treatment with diet and drugs, as in this case (4). In addition, the low level of serum potassium seen in this patient is common in Cushing’s syndrome. However, she had no other typical manifestations of Cushing’s syndrome, such as moon face, muscular weakness, striae cutis, acne, or bruising, and she was treated with diuretics, which could produce hypokalemia.

Second, why was the Cushing’s disease not discovered during the pregnancy? Preeclampsia may have occurred due to the superimposed hypertension from Cushing’s disease. Clinically diagnosing Cushing’s disease during pregnancy is difficult, because it may be confused with the normal physiological alterations in cortisol and ACTH levels that occur during pregnancy (5). Some of the clinical manifestations and routine laboratory findings in this patient resembled those seen in patients with preeclampsia as well as those seen in patients with Cushing’s syndrome (6). In particular, attention should be paid to the low level of serum potassium (4), but diuretics were used for the superimposed hypertension with edema, which resulted in hypokalemia indistinguishable from that due to Cushing’s disease.

Third, what was the cause of postpartum hypopituitarism in this case? Generally, the most frequent cause of hypopituitarism in postpartum women is Sheehan’s syndrome (1, 2). Sheehan’s syndrome results from ischemic pituitary necrosis after an episode of major blood loss at the time of delivery (1, 2, 3). This patient had an approximately 700-mL blood loss with transient hypotension during the operation, which is less than the volume of blood loss that leads to ischemic necrosis of the pituitary gland (1, 2, 3). Therefore, the failure of gonadotropin, TSH, and vasopressin secretion after the delivery cannot be solely attributed to ischemic pituitary necrosis due to blood loss with hypotension. This patient may have had an additional pituitary disturbance, namely pituitary apoplexy resulting from hemorrhagic infarction of a pituitary ACTH-secreting tumor. Spontaneous pituitary apoplexy due to hemorrhage of a pituitary tumor frequently occurs, but it is rare among patients with Cushing’s disease (7, 8). To our knowledge, two such cases have been previously reported (9). Therefore, the normal secretion of ACTH at this time may have occurred by apoplexy of a pituitary ACTH-secreting tumor due to the delivery, which was accompanied by blood loss and hypotension. Inappropriate secretion of ACTH may transiently be cured by apoplexy of a pituitary ACTH-secreting tumor. The fact that Cushing’s disease was revealed 6 yr after the episode at the time of delivery may support this view. After the delivery, this patient may have had either ischemic pituitary necrosis or apoplexy of a pituitary ACTH-secreting tumor. On the other cause, we should have considered lymphocytic hypophysitis. Lymphocytic hypophysitis is an autoimmune disorder in which the pituitary gland enlarges to mimic a solid pituitary macroadenoma that can be revealed by MRI scanning and sometimes produces postpartum hypopituitarism (10). The hypopituitarism with enlargement of the pituitary gland regresses either spontaneously or after steroid therapy (10). Accordingly, it is considered that lymphocytic hypophysitis may be another cause of Sheehan’s syndrome. In this case, the clinical picture resembles those seen in patients with lymphocytic hypophysitis. However, the period of time for the enlarged pituitary in this patient to regress was shorter than observed in patients with lymphocytic hypophysitis described previously, and this patient has no evidence such as autoimmune diseases in other regions of the endocrine system, as seen in patients with lymphocytic hypophysitis (10). Therefore, it is unlikely that this patient might have lymphocytic hypophysitis, although a biopsy should be obtained to confirm the presence of lymphocytic hypophysitis (10).

Fourth, why were we not able to diagnose early Cushing’s disease while the patient was being followed for postpartum hypopituitarism? ACTH-secreting macroadenoma, as in this case, is refractory to conventional therapy (10). When Cushing’s disease was diagnosed at the age of 44 yr in the patient, the pituitary tumor had extended over the sella turcica, indicating that it was a macroadenoma. The key is two factors. One reason is that she had Sheehan’s syndrome with diabetes insipidus. Although she had the typical clinical manifestations of Cushing’s syndrome including obesity, facial plethora, menstrual disorder, hypertension, and polydipsia/polyuria, and typical laboratory findings, including hypokalemia and hyperlipemia, at the age of 42 yr (4), we were not able to link these clinical and laboratory features with Cushing’s disease because some of these features could be explained by the pathophysiology of Sheehan’s syndrome with diabetes insipidus and simple obesity with essential hypertension and hyperlipemia. Moreover, there have been no previous reports on patients who suffered from both Sheehan’s syndrome and Cushing’s disease (4). A second reason is the evidence that since the time that hypertension and hyperlipemia, and later Sheehan’s syndrome, were diagnosed, the patient did not continuously take the medications and did not have continuous follow-up. At the age of 34 yr, after the patient had discontinued treatment for the first time, she may have had Cushing’s disease for the first time, and at the age of 42 yr, after her third discontinuation of treatment, Cushing’s disease may have recurred again, as Cushing’s disease is an endocrinopathy that manifests the highest frequency of mental changes that produce such behavior (4).

Taken together, the evidence suggests that in this case, Cushing’s disease had developed before pregnancy. It was cured by apoplexy of a pituitary ACTH-secreting adenoma due to the delivery and again developed afterward, albeit with deficiencies of gonadotropin, TSH, GH, and vasopressin secretion resulting from ischemic pituitary necrosis.

Recently, Yano et al. (12) reported that transgenic mice expressing leukemia inhibitory factor (LIF) driven by the pituitary glycoprotein hormone {alpha}-subunit promoter exhibited Cushingnoid features with corticotroph hyperplasia, but with markedly reduced numbers of gonadotroph, lactotroph and somatotroph. The finding indicates that oral ectoderm diverts two differential stream of hormone-secreting cells towards corticotroph and other pituitary cells by inappropriate expression of LIF. This case suggests that they may be the same ontogenous pituitary cells in humans as there are in mice.

In conclusion, this case provides us with interesting information on the ontogeny of pituitary cells, by means of the natural history of postpartum hypopituitarism, which was present initially, followed by clinical progression to Cushing’s disease. Careful clinical, laboratory, and radiological follow-up is necessary in such patients.


    Acknowledgments
 
We are grateful to Dr. Hisao Maruyama, Maruyama Medical Clinic (Takada, Niigata, Japan), who examined this patient the first time, for his assistance.

Received April 23, 1998.

Revised January 8, 1999.

Revised April 28, 1999.

Accepted May 3, 1999.


    References
 Top
 Introduction
 Case Report and Results
 Discussion
 References
 

  1. Sheehan HL, Summers VK. 1949 The syndrome of hypopituitarism. Q J Med. 42:319–378.
  2. Sheehan HL, Stanfield JP. 1961 The pathogenesis of post partum necrosis of the anterior lobe of the pituitary gland. Acta Endocrinol (Copnh). 37:479–510.
  3. Haddock L, Vega LA, Aguilo F, Rodriguez O. 1972 Adrenocortical, thyroidal and human growth hormone reserve in Sheehan’s syndrome. Johns Hopkins Med J. 131:80–99.[Medline]
  4. Miller W, Tyrrell JB. 1995 The adrenal cortex: adrenocortical hyperfunction. In: Felig P, Baxter JD, Frohman LA, eds. Endocrinology and metabolism, 3rd ed. New York: McGraw-Hill; 659–678.
  5. Manzanares JM, Martinez de Osaba MJ, Halperin I, Castelo-Branco C, Millan O, Vilardell E. 1995 Diagnosis of Cushing’s disease in pregnancy. Med Clin. 105:744–747 (in Spanish).
  6. Sudo N, Kamoi K, Ishibashi M, Yamaji T. 1993 Plasma endothelin-1 and big endothelin-1 levels in women with pre-eclampsia. Acta Endocrinol (Copenh). 129:114–120.[Medline]
  7. Mohr G, Hardy J. 1982 Hemorrhage, necrosis, and apoplexy in pituitary adenomas. Surg Neurol. 18:181–189.[Medline]
  8. Ostrov SG, Quencer RM, Hoffman JC, Davis PC, Hasso AN, David NJ. 1989 Hemorrhage within pituitary adenomas: how often associated with pituitary apoplexy syndrome? Am J Radiol. 153:153–160.[Medline]
  9. Mercado-Asis LB, Oldfield EH, Cuter Jr GB. 1995 Pituitary tumor hemorrhage in Cushing disease. Ann Intern Med. 122:189–190.[Free Full Text]
  10. Thodou E, Asa SL, Kontogeorgos G, Kovacs K, Horvath E, Ezzat S. 1995 Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings. J Clin Endocrinol Metab. 80:2302–2311.
  11. Blevins Jr LS, Christy JH, Khajavi M, Tindall GT. 1998 Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab. 83:63–67.[Abstract/Free Full Text]
  12. Yano H, Readhead C, Nakashima M, Ren S-G, Melmed S.1998 Pituitary-directed leukemia inhibitory factor transgene causes Cushing’s syndrome: neuro-immunoendocrine modulation of pituitary development. Mol Endocrinol. 12:1708–1720.




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