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HYPOTHALAMIC HYPOPITUITARISM PRESENTING WITH RHEUMATOLOGIC SYMPTOMS.

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632
CASE REPORT
HYPOTHALAMIC HYPOPITUITARISM PRESENTING
WITH RHEUMATOLOGIC SYMPTOMS
MUHAMMAD YUNUS, ALFONSE T. MASI, and JOHN P. ALLEN
Rheumatologic manifestations of certain endocrine disorders, such as primary hypothyroidism, are
well known (1-4) and may be the presenting features
(3). However, such manifestations are distinctly rare in
noniatrogenic hypoadrenalism (5) and have not been reported in hypopituitarism (6). Described here is a patient with hypothalamic hypopituitarism who presented
with rheumatologic symptoms.
CASE REPORT
A 37-year-old white man presented with a 6month history of diffuse myalgia and arthralgia. His initial symptoms of frontal headache, maxillary pain, and
cough had improved after 2 weeks duration. Though no
swelling was apparent, he then experienced aches and
pains in the knees, elbows, hands, and shoulders, along
with gelling phenomenon. After 3 weeks, he developed
diffuse myalgia, particularly in his arms, forearms,
shoulders, legs, buttocks, and, to a lesser extent, in his
back and thighs. No stiffness, drawing sensation, or contracture was noted. These symptoms were continuous
and had no relation to weather, but worsened following
use of the involved muscles. The patient did not respond to antiinflammatory doses of aspirin and Clinoril
(sulindac) given at this time.
From the Division of Rheumatology, Department of Medrcine, and Department of Neurosciences, Peoria School of Medicine,
Peoria. Illinois.
Muhammad Yunus. MD: Assistant Professor of Medicine:
Alfonse T. Masi, MD. DRPH: Head and Professor, Department of
Medicine: John P. Allen, MD: Associate Professor of Neurosciences.
Address reprint requests to Muhammad Yunus, MD. Peoria
School of Medicine. 123 SW Glendale Avenue. PO Box 1649. Peoria,
Illinois 61656.
Submitted for publication May 7, 1980: accepted in revised
form October 17. 1980.
Arthritis and Rheumatism, Vol. 24.
No. 4 (April 1981)
Seven weeks after his arthralgia and myalgia began, this previously strong and physically active man
developed weakness, marked fatigue, pallor, and sensitivity to cold weather, associated with anorexia and a
30-pound weight loss. He denied loss of libido which
was confirmed by his spouse. At the time of presentation, he had been off work for a month, but despite rest
had continued to feel weak and achy. He had been a
sheet metal worker (coppersmith), smoked 6-8 cigarettes a day, and drank a modest amount of alcohol. He
denied being an anxious person and generally slept
well. The remainder of the history was unremarkable
except for allergic rhinitis.
Physical examination revealed general pallor
without other skin or mucous membrane changes. The
patient weighed 191 pounds and was 5’1 I ” in height.
His pulse rate was regular at 72/minute and blood pressure was I l0/60 without postural change. Findings of
an examination of head, eyes (including funduscopic
examination), ears, nose, throat, and neck were normal
with no lymphadenopathy or thyromegaly. He had no
clinical signs of hypothyroidism or myxedema on general or neurologic examination, which included normal
relaxation of deep tendon reflexes. Results of articular
evaluation were completely normal, but all muscles
were moderately weak and tender, especially in his
arms, thighs, and legs. He could not stand up from a sitting position with arms folded. There was no evidence
of contracture in any joint or muscle. Findings of the remainder of the examination, i h u d i n g neurologic and
genital assessment, were normal.
Initial hematologic, chemical, and immunologic
screening studies, including erythrocyte sedimentation
rate (10 mm/hour), rheumatoid factor, antinuclear antibodies, electrolytes, muscle enzymes, and calcium were
633
YUNUS ET AL
all normal or negative, as were febrile agglutinins and
serum lead level ( I 8 pg/ml). Serum T,, ordered 5 weeks
after the onset of initial symptoms, was borderline low
at 4.5 pg/ I00 ml.
The possibility of adrenal insufficiency was suspected on the basis of anorexia, weakness, weight loss,
and mild low blood pressure. A I-hour intramuscular
cortrosyn adrenal stimulation test was abnormal with
baseline and 30- and 60-minute values all less than 2
pg/100 ml. The patient was subsequently admitted for
complete endocrine evaluation.
Stimulation test results are summarized in Table
I . Other test results were as follows: Serum T, 2.7 pg/
100 ml (normal 4.5-1 I S ) ; resin T, uptake 27% (normal
25-37); T,-index 1 .O (normal 1.2-4.3); thyroid stimulating hormone (TSH) 5.1 pIU/ml (normal <lo); serum
adrenocorticotropic hormone (ACTH) 45 pg/ml (normal 20- 100); serum follicle stimulating hormone (FSH)
9.8 mIU/ml (normal 5-25); serum luteinizing hormone
(LH) 1 1 mIU/ml (normal 0-20); and serum testosterone
942 ng/100 ml (normal 400-1 100). No antibodies to
thyroid and adrenal cortex were present. Plasma os-
molality was 291 mOsm/kg and urine osmolality was
548 mOsm/kg after a 6-hour water deprivation period.
Cerebrospinal fluid showed no white cells. The glucose
level was normal, protein was raised at 74 mg/100 ml
(normal 15-50) with increased gammaglobulin (IgG) at
6.5 mg/lOO ml (normal 1-3.1). and a culture for bacteria including Mycobacterium tuberculosis and fungi
was negative. Serum angiotensin converting enzyme
(ACE), reported to be increased in sarcoidosis (7), was
21 IU/liter (normal 12--36).A skin test was negative for
P P D but positive for candida, mumps, and trichophyton. Results of roentgenograms of the skull,
tomograms of the sella turcica, chest, and hands, and a
visual field examination were all negative. A CT scan of
the head and a cerebral angiogram were both normal.
The initial electromyelogram (EMG) showed
polyphasic potentials and a widespread denervation
pattern with prolonged discharges of diphasic spikes or
larger positive waves, compatible with myopathic pattern. Results of a muscle biopsy with histochemical
studies were normal. Serum creatinine phosphokinase
(CPK) was 500 IU/liter (normal 50-150); on repeat it
Table 1. Basal and post-stimulation values o f various hormones in assessment o f hypothalamic-pituirary function
...
._
~- -. . -.
~
Stimulation
tests and assays
~
-
Patient (normal)
1%
'/i
I
I'h
2
3
..
8
5
4
~
72 hour ACTH
stimulation
(80 IU per 24
hours)
Serum cortisol
Urinary cortisol
Urinary 17 K S
<2
<I0
7.8
(5-25 pg/100 ml)
(20-90 g / 2 4 hour)
(6-24 mg/24 hour)
<2
t 2
2. I
16
2.6
2.9
8.9
( 5 0 0 Pg
intravenous)
Serum TSH
Serum prolactin
5. I (<I0 pIU/ml)
14.6 (0-20 ng/ml)
Propranolol and
glucagon stimulation'
Serum GH
Serum cortisol
0.7 (4ng/ml)
t 2
(5-25 &I00
1.X
LtI-RH stimulation
(200 pg 1ntravenous)t
14
Serum LH
Serum FSH
II
13.7 13.3
35.3 32.9
0.5
<2
ml)
(4ng/ml)
(&20mlU/ml)
(5-25 mlU/ml)
2.5
28
12
1.9
0.5
<2
2.1
<2
2.3
i 2
0.5
27
I2
- ~Propranolol 30 mg orally followed in 30 mlnutes by glucagon I mg intramuscularly
t hour values are same as in 1' 2 hour
~
~
-_
24
32
14.4
37
7. I
17.1
. .
~
T R H stimulation
L-dopa stimulation
(500 Lg orally)
Serum G H
~-
...
Values at hour intervals specified after initiation of respective stimulation
Basal values
-
~
48
72
-
21.3 30.3
593 1,507
19.3 IX.0
HYPOTHALAMIC HYPOPITUITARISM
634
was 498 IU/liter. The blood for CPK was drawn prior
to muscle biopsy and before the patient had received
any intramuscular injections. The CPK isoenzymes
showed 98% MM and 2% MB fractions. Aldolase was
4.1 mU/ml (normal 1-6). At the end of a 72-hour
ACTH stimulation test, the patient improved symptomatically and objectively.
After completion of the above studies, the patient was initially treated with cortisone acetate alone,
in a low physiologic dose of 12.5 mg twice daily. On the
second day of cortisone treatment, he experienced
marked reduction in myalgia, arthralgia, and weakness.
By the fourth day, these symptoms had dissipated completely and his appetite markedly improved. His blood
pressure stabilized at 125/75 and serum CPK fell to 100
3 days after initiation of cortisone acetate. After 4 days
of cortisone therapy, he was asymptomatic and had regained almost full strength.
At that time, L-thyroxine 0.2 mg daily was
started and the patient was discharged home. He returned to work after 1 month, though he required 37.5
mg of cortisone acetate daily for full and normal vigor.
An EMG showed improvement after 4 months and was
completely normal after 8 months. The patient regained
30 Ibs in 4 months. On followup after 16 months, he remains fully well and active without any symptoms.
DISCUSSION
This patient’s initial serum T, was borderline
low, raising the suspicion of hypothyroidism early in his
illness. The second T,, done 5 months later, was significantly low, indicating further progression of hypothyroidism during this period. Free thyroxine level (which
is not generally available) was not done. However, free
thyroxine index (T,), which correlates well with free
thyroxine level, was low. The baseline unmeasurable
serum cortisol which increased gradually during the 72hour ACTH stimulation, along with normal ACTH, indicated relative hypothalamic-pituitary insufficiency of
adrenal stimulation. The unavailability of a specific corticotropin releasing factor (CRF) stimulation test does
not allow determination of the exact level of insufficiency, i.e., at the hypothalamus, pituitary, or both.
However, the low T4, normal TSH, normal TSH stimulation by TRH, and normal response of LH to LH-RH
(FSH may fail to rise by LH-RH stimulation in normal
humans) suggest hypothalamic hypopituitarism. This is
compatible with the inadequate growth hormone (GH)
and cortisol stimulations by propranolol and glucagon
and the inadequate stimulation of G H by L-dopa (8).
The maximal G H response was only to 2.5 ng/ml (normal >5.0 increment) and serum cortisol remained unmeasurable during propranolol and glucagon stimulation (see Table 1). Since serum prolactin is usually
increased in pituitary stalk section (9), normal prolactin
level in our patient suggests a hypothalamic lesion without stalk involvement. Absence of antibodies to thyroid
and adrenal cortex are also more consistent with nonprimary organ failure.
Despite extensive investigations, including a normal angiogram and CT scan, a definite etiology for hypothalamic hypopituitarism was not found in this patient.
From our literature search, it appears that musculoskeletal aches and pains in hypopituitarism have
not been previously described. One documented case of
Addison’s disease presenting with generalized muscle
aching and stiffness was reported recently ( 5 ) , although
this association was mentioned earlier by Rowntree and
Snell (10). A standard textbook on endocrinology (1 1)
does not mention musculoskeletal aches or stiffness in
hypoadrenalism or hypopituitarism. However, cortisone-reversible localized flexion contractures (12- 14)
and backache (10,15) have been described in Addison’s
disease. Musculoskeletal aches and pains are common
during steroid withdrawal, regardless of whether adrenal suppression can be documented (16).
It would appear that adrenal insufficiency was
mainly responsible for the musculoskeletal symptoms of
generalized aches, pains, and weakness in our patient.
His symptoms initially improved symptomatically and
objectively during the adrenal stimulation studies. In
addition, striking improvement was noted within 48
hours of initiating a low physiologic dose of cortisone
acetate (25 mg daily), and his symptoms disappeared
completely after another 2 days. Creatinine phosphokinase returned to normal after 3 days of cortisone acetate
alone, suggesting that the initial rise in CPK might have
been secondary to hypoadrenalism. The patient had not
received replacement thyroid hormone at that time. It is
unlikely that the low physiologic replacement of cortisone would have resulted in such dramatic improvement of his musculoskeletal symptoms and elevated
CPK levels if his condition was due mainly to hypothyroidism.
EMG changes and high CPK with 98% MM
fraction suggest a myopathy, though muscle biopsy was
normal. Repeat EMG showed improvement after 4
months and was normal after 8 months, supporting the
relationship between myopathy and hypopituitarism.
The patient had received a physiologic dose of L-thy-
YUNUS ET AL
roxine 4 days after initiation of cortisone therapy, and
the progressive improvement in EMG findings may
have been due to cortisone or L-thyroxine therapy or
both. Tissue from muscle biopsies in hypothyroid myopathy are usually normal (17); EMG studies are variable showing hyperirritability and increase in polyphasic potentials in 42% a reduction in amplitude in
36% and a reduction in mean action potential duration
in 31% (17).
Our patient did not have any objective features
of arthritis, nor did he have characteristic features of
primary fibrositis such as symptom modulation by
weather, presence of anxiety, or specific trigger points
(18). Weakness, anorexia, weight loss, cold sensitivity,
pallor, and mild hypotension suggested hypoadrenalism
and hypothyroidism clinically, and endocrine evaluation indicated hypothalamic hypopituitarism.
Patients with undiagnosed musculoskeletal
symptoms should be evaluated for an endocrine cause,
including hypopituitarism. Secondary hypothyroidism
should not be missed, since treatment with thyroid hormone alone may precipitate adrenal crisis in patients
with associated hypoadrenalism (19).
REFERENCES
1. Ord WM: On myxoedema, a term proposed to be applied
to an essential condition in the “cretinoid” affection, occasionally observed in middle-aged women. Med Chir
Tran Lond 6157-58, 1878
2. Bland JH, Frymoyer JW: Rheumatic syndromes of myxedema. N Engl J Med 282:1171-1174, 1970
3. Hochberg MC, Koppes GM, Edwards CQ, Barnes HV,
Arnett FC Jr: Hypothyroidism presenting as a polymyositis-like syndrome. Arthritis Rheum 19(6):13631366, 1976
4. Golding DN: Hypothyroidism presenting with musculoskeletal symptoms. Ann Rheum Dis 29: 10-14, 1970
5. Calabrese LH, White CS: Musculoskeletal manifestations
of Addison’s disease. Arthritis Rheum 22558. 1979
635
6. Bland JH, Frymoyer JW, Newberg AH, Revers R, Norman RJ: Rheumatic syndromes in endocrine disease.
Semin Arthritis Rheum 9( 1):23-65, 1979
7. Lieberman J: Elevation of serum angiotensin converting
enzyme (ACE) level in sarcoidosis. Am J Med 59:365372, 1975
8. Eddy RL, Gilliland PF, Ibarra JD Jr, McMurry J F Jr,
Thompson JQ: Human growth hormone release: comparison of provocative test procedures. Am J Med 56: 179,
1974
9. Christy NP: The hormones of the anterior pituitary, Cecil
Textbook of Medicine. Edited by PB Beeson, W McDermott, JB Wyngaarden. Philadelphia, WB Saunders Company, 1979, p 2092
10. Rowntree L, Snell AM: A Clinical Study of Addison’s
Disease. Philadelphia, WB Saunders, 1931, p 182
11. Williams RH, Editor: Textbook of Endocrinology. Philadelphia, WB Saunders Company, 1974
12. Wisenbaugh PE, Heller HM: Flexion contractures in
Addison’s disease. J Clin Endocrinol Metab 20:792-794,
1960
13. Thorn GW: The Diagnosis and Treatment of Adrenal Insufficiency. Second edition. Springfield, Illinois, Charles
C Thomas, 1951, p 150
14. Almog C, Menachem S: Flexion contractures in Addison’s disease. Confin Neurol 32:33-37, 1970
15. Sheridan P, Murray-Leslie CF, Golding JR: Addison’s
disease presenting with chronic low backache. Br Med J
1:77, 1976
16. Dixon RB, Christy NP: On the various forms of corticosteroid withdrawal syndrome. Am J Med 68:224-230, 1980
17. Ramsay L: Thyroid Disease and Muscle Dysfunction.
Chicago, Year Book Medical Publishers, 1974
18. Smythe HA: Non-articular rheumatism and the fibrositis
syndrome, Arthritis and Allied Conditions. Eighth edition. Edited by JL Hollander, DJ McCarty Jr. Philadelphia, Lea & Febiger, 1972, pp 874-884
19. Christy NP: Hypopituitarism, Cecil Textbook of Medicine. Edited by PB Beeson, W McDermott, JB Wyngaarden. Philadelphia, WB Saunders Company, 1979, pp
2 100-2 102
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