A Case of Cushings 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
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Introduction
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The most frequent cause of hypopituitarism in
postpartum women is Sheehans syndrome (1, 2). The natural course of
Sheehans 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 Sheehans syndrome who have an inappropriate secretion
of ACTH.
We describe in this paper the first case of a woman with Cushings
disease as a result of a pituitary macroadenoma, who had
hypopituitarism 6 yr earlier in her clinical course due to Sheehans
syndrome.
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Case Report and Results
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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. 1
). 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. 1
). 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 2544 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 Cushings disease at the age of 44 yr. Blood pressure represents
systolic and diastolic values.
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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. 1
). 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 180200 mm Hg and a diastolic blood pressure in the range of
100120 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. 1
). 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. 1
), 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 30004000 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. 1
). 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 1
and 2
). However, GH, PRL, and ACTH secretions
were intact (Tables 1
and 2
). 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.
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. 2A
). 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. 2B
). 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.
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The patient was placed on L-T4, estrogen,
progesterone, and desamino-8-D-arginine vasopressin
(DDAVP). Treatment with Ca2+
antagonist and
-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. 1
).
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. 1
). She often felt
strong thirst and drank 34 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. 1
). 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 1
and 2
). However,
the plasma concentrations of cortisol and ACTH were high over 24 h
(Table 3
). The concentrations of both
cortisol and ACTH increased after CRH administration (Table 4
). 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 5
) (4). The urinary
concentration of free cortisol (585698 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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MRI scanning revealed that a large mass had extended over the
sella turcica (Fig. 3A
), 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. 3B
).

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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.
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The patient was again given L-T4, estrogen,
progesterone, and DDAVP treatment. The hypertension and
hyperlipemia disappeared after 1 month of therapy.
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Discussion
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The clinical course of this case raises many interesting
questions. First, what was the cause of the patients 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. Cushings disease may
be the primary cause rather than other disorders, as one of the
clinical and laboratory manifestations of Cushings 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
Cushings syndrome. However, she had no other typical manifestations
of Cushings 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 Cushings disease not discovered during the
pregnancy? Preeclampsia may have occurred due to the superimposed
hypertension from Cushings disease. Clinically diagnosing Cushings
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
Cushings 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 Cushings disease.
Third, what was the cause of postpartum hypopituitarism in this
case? Generally, the most frequent cause of hypopituitarism in
postpartum women is Sheehans syndrome (1, 2). Sheehans 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 Cushings 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 Cushings 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
Sheehans 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 Cushings disease
while the patient was being followed for postpartum hypopituitarism?
ACTH-secreting macroadenoma, as in this case, is refractory to
conventional therapy (10). When Cushings 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 Sheehans syndrome with
diabetes insipidus. Although she had the typical clinical
manifestations of Cushings 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 Cushings disease because some
of these features could be explained by the pathophysiology of
Sheehans 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 Sheehans syndrome
and Cushings disease (4). A second reason is the evidence that since
the time that hypertension and hyperlipemia, and later Sheehans
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 Cushings disease for the first time, and at the age of
42 yr, after her third discontinuation of treatment, Cushings disease
may have recurred again, as Cushings 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,
Cushings 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
-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 Cushings disease. Careful clinical,
laboratory, and radiological follow-up is necessary in such
patients.
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Acknowledgments
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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.
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