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The Journal of Clinical Endocrinology & Metabolism 87(12):5430 –5434
Copyright © 2002 by The Endocrine Society
doi: 10.1210/jc.2002-020672
CLINICAL CASE SEMINAR
A 43-Year-Old Male with Untreated Panhypopituitarism
due to Absence of the Pituitary Stalk: From Dwarf
to Giant
D. T. DEN OUDEN, M. KROON, P. H. HOOGLAND, P. H. L. M. GEELHOED-DUIJVESTIJN,
J. M. WIT
AND
Departments of Internal Medicine (D.T.d.O., P.H.L.M.G.-D.), Clinical Chemistry (M.K.), and Radiology (P.H.H.), MCH
Westeinde Hospital, 2501 CK The Hague, The Netherlands; and Department of Pediatrics, Leiden University Medical Center
(J.M.W.), 2300 RC Leiden, The Netherlands
A 43-yr-old male was referred because of an x-ray made after
a fall, which showed open epiphysis of the arm. The man had
always been short for his age; during childhood he once consulted a pediatrician because of short stature, but thereafter
he never sought medical attention. At age 18 yr he was not
allowed to join the army because of his height of 147 cm. He
continued to grow steadily and finally reached 193 cm. He had
no complaints and considered himself reasonably fit. Physical
examination showed a disproportional man with a body mass
index of 29.3 kg/m2 and Tanner stage P1G1. Laboratory investigations showed hormone levels consistent with multiple pituitary deficiency, with dynamic tests consistent with hypo-
C
ONGENITAL HYPOPITUITARISM IS a rare disorder
consisting of multiple deficiencies of hormones originating from the adenohypophysis (GH, TSH, ACTH, and
gonadotropins). It is also called multiple pituitary deficiency
(MPD). It may lead to clinical signs at birth (hypoglycemia,
prolonged jaundice, and micropenis) and severe growth retardation. Therefore, it is usually diagnosed in infancy or
childhood. In many cases magnetic resonance imaging (MRI)
shows an absence or hypoplasia of the pituitary stalk, a small
anterior pituitary remnant, and the presence of an ectopic
posterior pituitary at or below the tuber cinereum (1– 6).
Treatment consists of substitution doses of GH, T4, hydrocortisone, and (during adolescence) sex steroids. With timely
and adequate therapy, rapid catch-up growth and normalization of serum T4, cortisol, and eventually sex hormones
occur, and final height is often within the genetic target
range (7).
Due to the extreme symptoms and clinical signs, treatment
is usually provided in infancy or early childhood, so there is
little documentation about the natural history of untreated
MPD. To date, seven case reports have been published (8 –
14). There is more information about the final height of patients with MPD who were treated with T4, hydrocortisone,
and sex steroids, but not with GH. They showed a final height
of –3.1 sd score (15).
Abbreviations: BMI, Body mass index; MPD, multiple pituitary deficiency; MRI, magnetic resonance imaging.
thalamic or pituitary stalk disease. Magnetic resonance
scanning of the brain showed a small anterior pituitary remnant, no pituitary stalk, and an ectopic neurohypophysis.
This case of untreated panhypopituitarism shows a particular growth curve with an average growth velocity of 2 cm/yr,
resembling patients with estrogen receptor mutation or aromatase deficiency. A literature study of other adult patients
with untreated panhypopituitarism shows a variable growth
pattern. Some speculations about possible reasons for this
variability in clinical characteristics are presented. (J Clin
Endocrinol Metab 87: 5430 –5434, 2002)
Here, we describe the case of a 43-yr-old man with untreated congenital hypopituitarism due to absence of the
pituitary stalk, who accidentally came under our attention
during a visit to a hospital for a fracture.
Case Report
The male patient, who was born in 1956, was 193 cm tall when he
presented to the orthopedic surgeon with an upper arm fracture after a
fall. The humerus x-ray showed an open epiphysis. He was then referred
to the internist, who diagnosed hypothyroidism, hypogonadism, and
hypocorticism. Laboratory findings are shown in Table 1. Treatment
with T4 and low dose hydrocortisone was initiated, and the patient was
referred to our center for further analysis.
The patient’s medical history revealed that he was the child of healthy
and unrelated parents. His father is 172 cm, and his mother is 158 cm,
which results in a target height (midparental height corrected for sex and
secular change of ⫹4.5 cm/generation) of 175.5 cm. He was born fullterm, with unknown birth weight. He was examined by a pediatrician
at 9 yr of age because of short stature. Unfortunately, the exact data from
this visit are no longer available, but in the letter to the general practitioner a height of “10 centimeters short for his age” (presumably 10 cm
below the third percentile) was mentioned. He had normal intelligence
and normal body proportions. His bone age was described as being
slightly retarded, and the metabolic rate was slightly decreased, for
which the patient received thyroid hormone. Because of side-effects, the
patient discontinued the medication and did not return to the pediatrician. From then on he did not see a doctor concerning his short stature
or any other complaints. At age 18 yr, he was not allowed to join the army
because of his height of 147 cm. He reported that he had always been
much shorter than other boys of his age until approximately 25 yr of age.
Thereafter, he had gradually become taller than most of his contempo-
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den Ouden et al. • Clinical Case Seminar
J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434 5431
TABLE 1. Hormonal measurements at presentation and after
treatment
May
1999a
Cortisol (nmol/
liter)
ACTH (ng/liter)
Aldosterone
(pmol/liter)
Renin (ng/liter)
Androsteredione
(nmol/liter)
Testosterone
(nmol/liter)
SHBG (nmol/
liter)
DHEA-S (␮mol/
liter)
LH (U/liter)
FSH (U/liter)
Prolactin (mU/
liter)
Estradiol (nmol/
liter)
Progesterone
(nmol/liter)
GH (mU/liter)
IGF-I (nmol/
liter)
IGF BP-3 (mg/
liter)
TSH (mU/liter)
FT4 (pmol/liter)
70
Oct.
1999b
306
Reference
96
150–700
8.6
133
0–50
170– 610
2
2.4
5– 65
1.7–10.0
⬍0.1
⬍0.7
18
12
⬍0.1
0.4
290
Oct.
2000c
9.8
16
10–70
2.3
⬍0.8
2.2–15.7
⬍0.7
0.2
140
⬍0.7
0.1
1.8– 8.0
1.5– 6.0
100–300
FIG. 1. Patient’s growth curve compared with contemporary references.
0.07– 0.15
prompted the consulting internist to substitute T4 and hydrocortisone,
and the results after more extensive testing during treatment with 50 ␮g
T4 and 10 mg hydrocortisone twice daily.
Serum LH, FSH, GH, ACTH, cortisol, testosterone, and SHBG were
measured by immunoassay using Immulite (Diagnostic Products, Los
Angeles, CA). Aldosterone and androstenedione were measured by RIA
(Diagnostic Products), TSH and free T4 were determined by immunoassay (Abbott Laboratories, Chicago, IL), renin was measured by RIA
(Bio-Rad Laboratories, Inc., Hercules, CA), and 25-hydroxyvitamin D
was determined by RIA (DiaSorin, Inc., Stillwater, MN).
Serum gonadotropin levels, testosterone, free T4, IGF-I, and vitamin
D were all low, whereas the serum PRL level was normal. Serum TSH
was slightly elevated. The results are consistent with MPD (panhypopituitarism). Dynamic tests (Table 2) showed no reaction of serum FSH
and LH to LHRH, and the TSH response to TRH was consistent with
tertiary hypothyroidism, as observed in patients with absent pituitary
stalk. The CRH test was performed after withdrawal of hydrocortisone
for 1 d, and there were very small responses of ACTH and cortisol. The
GHRH test showed a minimal response of serum GH with a peak of 0.7
mU/liter (0.3 mg/liter).
⬍0.07
0.08
⬍0.6
0.0–2.0
⬍0.1
4.5
0.0–13.0
13.0–39.0
1.90
7.35
6.1
8.0–35.0
1.6
8.3
2.08– 4.31
0.15
9.4
0.40– 4.0
10.0–21.0
DHEA-S, Dehydroepiandrosterone sulfate; IGFBP-3, IGF-binding
protein 3; FT4, free T4.
a
First presentation elsewhere.
b
T4 and hydrocortisone suppletion; testosterone starting dose.
c
T4, hydrocortisone, and testosterone suppletion.
raries. His estimated growth curve compared with the 1980 Dutch references (16) is shown in Fig. 1.
He stated that he had no physical discomfort, no gynecomastia, no
signs of orthostatic hypotension, and normal urine frequency, and he
indicated no symptoms of hypothyroidism. He never had any facial,
axillary, or pubic hair. He reported some erections, but no ejaculations.
He considered himself reasonably fit and stated that he never used any
medication, had stopped smoking 10 yr previously, and drank a maximum of one glass of alcohol per week. He disliked sunlight because he
was easily sunburned. He had finished high school (A level) and worked
in an administrative job in an office.
At physical examination he looked young for his age (see Fig. 2). His
height was 193 cm (1.64 sd score for the Dutch 1980 nationwide references) (16), 17.5 cm above target height. His sitting height was 91 cm
(P25) (17), his leg length was 102 cm (3 cm above the 97th percentile) (17),
his arm span was 200 cm, his weight was 109 kg, his blood pressure was
140/80 mm Hg, and his heart rate was 80 beats/min. His body mass
index (BMI) was 29.3 kg/m2. His voice was high-pitched. He had Tanner
stage P1G1. There was no gynecomastia. Thoracic kyphoscoliosis and
flat feet were present. No abnormalities of heart, lungs, or abdomen were
found.
Laboratory investigations
Erythrocyte sedimentation rate, hematological parameters, blood
glucose, and serum sodium, potassium, calcium, phosphate, magnesium, and creatinine were normal. Serum alkaline phosphatase was
slightly elevated (138 U/liter; reference range, ⬍120), as were alanine
aminotransferase (78 U/liter; reference range, 15– 45), aspartate aminotransferase (73 U/liter; reference range, 11– 40), and ␥-glutamyltransferase (277 U/liter; reference range, 8 –50).
Table 1 shows the hormonal levels at presentation previously, which
Radiology
The thoracic x-ray showed severe kyphosis. The x-ray of the left hand
and wrist showed a bone age of 16 yr according to Greulich and Pyle (18)
(Fig. 3). Bone densitometry of the lumbar spine showed a z-score of
– 0.59; the femur head showed a z-score of – 0.16. MRI of the sella turcica
showed a small anterior pituitary remnant on the sella floor, no pituitary
stalk, and an ectopic neurohypophysis (Fig. 4).
Echocardiography showed normal left ventricle function. At an
exercise-electrocardiogram test (after substitution of T4, hydrocortisone,
and testosterone), a maximum of predicted 225 watts was reached at a
maximum heart rate of 158 beats/min and a maximum blood pressure
of 176/60 mm Hg (normal).
Discussion
Agenesis of the pituitary stalk is a well described syndrome in pediatric literature, usually associated with MHD
or, more rarely and probably in cases of partial stalk transsection, with isolated GH deficiency (1– 4). However, this
case is remarkable for various reasons. In the first place it is
the particular growth curve, showing severe growth retardation in childhood and adolescence, a very low height for
age at 18 yr (147 cm), and continuing growth from 18 – 43 yr
of age, with an average growth velocity of 2 cm/yr up to a
height considerably taller than the target height calculated
from midparental height. Such tall stature associated with
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J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434
den Ouden et al. • Clinical Case Seminar
FIG. 2. Patient at presentation: 43 yr old.
TABLE 2. Dynamic hormonal tests
Test performed
CRH, 100 ␮ga
GHRH, 200 ␮g
LHRH, 100 ␮g
TRH, 200 ␮gb
Glucose, 75 g
a
b
ACTH (ng/liter)
Cortisol (nmol/liter)
GH (mU/liter)
FSH (U/liter)
LH (U/liter)
TSH (mU/liter)
Prolactin (mU/liter)
Glucose (mmol/liter)
Insulin (mU/liter)
T⫽0
T ⫽ 15
⬍0.5
388
⬍0.1
0.1
⬍0.7
1.8
140
5.9
27.1
9.6
286
0.3
T ⫽ 20
T ⫽ 30
T ⫽ 60
T ⫽ 90 min
⬍5.0
273
0.5
⬍5.0
370
0.7
0.4
⬍0.7
6.7
278
7.7
⬍5.0
217
0.5
0.1
⬍0.7
5.6
337
7.0
58.5
5.0
No hydrocortisone 1 d before test.
No T4 1 d before test.
eunuchoid habitus and open epiphyses is strongly reminiscent of the findings in a previously reported patient with
estrogen receptor mutation (19) and patients with aromatase
deficiency (20, 21), except that those patients had normal
growth during childhood. Indeed, our patient had immeasurable serum estradiol levels, which may explain the absence of final fusion of the epiphyses. However, our case
shows that such continuing growth can even occur in a
patient with GH deficiency and low serum T4 levels. This
indicates that in the absence of estrogens, normal GH and T4
secretion are not necessary conditions for continuing growth.
A second remarkable observation is that in an industrialized country a 43-yr-old man with a deficiency of GH and
androgens and a partial deficiency of the pituitary-thyroid
and pituitary-adrenal axis has not been in contact with the
medical profession since the age of 10 yr. Usually growth
retardation is detected at routine school examinations in
childhood or adolescence, or anxiety of the child and the
parents about short stature or pubertal delay lead to referral
to a pediatrician. In addition, it is remarkable that he has been
able to live a regular life without subjective complaints.
There is little information on the natural history of MPD;
to date, six adult untreated panhypopituitarism patients
have been described, for whom the characteristics are summarized in Table 3. There is a variable presentation, which
is clear from this table; the hormonal abnormalities are comparable, but the physical presentations seem to differ among
patients. The patients are sorted in this table according to
height. Based on this small group of adult panhypopituitarism patients, it is difficult to make a statement about the
existence of subgroups that differ in growth pattern, but it
seems that that there is a taller subgroup and a shorter one.
The trend is that taller patients also seem to have higher BMIs
than shorter patients (normal to high BMIs vs. BMIs well
below 20). Although high BMIs with especially high body fat
mass, as in our patient, are known in MPD patients (22), this
does not seem to be the case in the other relatively tall
patients.
den Ouden et al. • Clinical Case Seminar
J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434 5433
FIG. 4. MRI of the sella turcica, showing a small anterior pituitary
remnant (arrow) on the sella floor, no pituitary stalk, and an ectopic
neurohypophysis.
FIG. 3. X-Ray of the left hand/wrist: bone age 16 yr.
TABLE 3. Patient characteristics of six adult patients in literature with untreated panhypopituitarism compared with our patient
Age (yr), gender
Height (cm)
Weight (kg)
BMI (kg/m2)
Bone age (yr)
MRI
Cortisol (ng/ml)
ACTH (ng/liter)
LH (U/liter)
FSH (U/liter)
Prolactin (ng/ml)
GH (ng/ml)
IGF-I (ng/ml)
TSH (mU/liter)
CRH test (␮g given)
ACTH (ng/liter) peak
GHRH test (␮g given)
GH (mU/liter)
Insulin test (IU/kg)
GH (mU/liter) peak
LHRH test (␮g given)
LH (U/liter) peak
FSH (U/liter) peak
TRH test (␮g given)
TSH (mU/liter) peak
prolactin (ng/ml) peak
Our patient
Kageyama (12)
Wada (14)
Badawy (10)
Navarro (9)
Arrigo (11)
Pentimone (13)
43, M
193
109
29.3
16
Small ant. pit.,
no pit. stalk,
ectopic post.
lobe
2
Low N
2
2
High N
2
2
1
100
sign. 1
200
NS
ND
37, M
185
84
24.5
15
Transected pit.
stalk, ectopic
post. lobe
23, M
175
79.2
26.0
14
Transected pit.
stalk, ectopic
post. lobe
21, F
163
63.3
23.8
14
Ectopic post.
pit.
29, M
153
43.3
18.5
13
Absent post.
lobe and
pit. stalk
25, M
149
38
17.2
12.5
Pit. stalk
interruption
2
Low N
2
2
High N
2
2
1
100
sign. 1
100
NS
0.05
NS
100
NS
NS
500
sign. 1 60⬘
sign. 1
2
Low N
2
2
1
2
2
High N
100
sign. 1
100
NS
0.05
NS
100
NS
NS
500
sign. 1 60⬘
sign. 1
2
ND
N
2
1
2
2
2
2
2
1
2
2
1
100
sign. 1
65
sign. 1
0.15
NS
100
NS
NS
200
sign. 1 45⬘
ND
2
ND
2
2
ND
ND
ND
N
ND
48, M
148
40
18.3
17
No pit. stalk,
small ant.
pit., ectopic
post. lobe
2
2
2
2
ND
2
ND
1
100
NS
ND
100
NS
NS
200
sign. 1 60⬘
sign. 1
1
ND
ND
ND
200
Unclear
sign. 1
500
sign. 1 30⬘
sign. 1
ND
0.1
NS
63
NS
NS
200
sign. 1 120⬘
ND
ND
100
NS
NS
200
sign. 1 120⬘
sign. 1
ant., Anterior; pit., pituitary; post., posterior; N, normal; sign., significant; NS, not significant; ND, not done.
We can only speculate about the reason for these differences between the clinical characteristics of these small
groups of adult untreated panhypopituitarism patients. For
our patient and the two others with similar growth patterns,
one can postulate that because of the total absence of estra-
diol, the epiphyses did not close, and the patient kept growing, possibly because of factors other than GH or IGF-I. A
possible candidate for such a growth factor could be insulin,
which in our rather obese patient may be secreted more than
in the other cases. Insulin can act as a growth stimulus,
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J Clin Endocrinol Metab, December 2002, 87(12):5430 –5434
probably partially through activating the IGF-I receptor (23),
and it has been suggested that elevated insulin secretion
causes the continuing growth without GH in children with
craniopharyngioma (24). However, we cannot prove this
hypothesis, because insulin secretion was not measured before treatment. A second possible growth stimulus in patients with low GH secretion is PRL in high levels, which has
been implicated in the pathophysiology of growth without
GH in craniopharyngioma (24). However, in our patient serum PRL was not elevated. Another option is the existence
of an unknown growth factor or abnormal serum concentrations of IGF-binding proteins, which could be responsible
for the slow but steady growth in patients who are GH
deficient. Alternatively, the observation by Wiedemann and
Schwartz (25, 26) that estrogens have a slightly antagonistic
effect on the bioactivity of GH could explain why in the
absence of estrogens the low GH secretion present has a
greater effect than expected. Finally, differences in insulin
and/or sex steroid sensitivity could be postulated. Further
research will be necessary to reach a better understanding of
this subject.
With respect to growth of patients with MPD, there are
some data for patients only treated with T4, hydrocortisone,
and (at a relatively late stage) sex steroids, but not with GH.
They showed a mean height sd score of –3.1 (15), which was
not much lower than the final heights of patients treated with
GH in relatively low dosages and at low injection frequency,
but was higher than the final heights of untreated patients
with GH deficiency. The observation that these patients did
not continue to grow can be explained by the treatment with
sex steroids.
The patient is now being treated with T4, hydrocortisone,
and testosterone. Although he reported no physical problems before treatment, now he says that he has never felt as
good, and that his sex life has improved. We expect that
testosterone treatment will increase serum estradiol sufficiently to close the epiphyses and stop further growth. We
believe that GH treatment would further improve his physical status and quality of life (27). This may also improve his
cardiac performance, although there are no complaints or
objective evidence of heart problems to date.
In conclusion, this case shows the natural history of untreated panhypopituitarism due to congenital agenesis of the
neural pituitary stalk and demonstrates that continuing
growth is possible even without normal GH and T4 secretion.
Acknowledgments
Received April 30, 2002. Accepted September 7, 2002.
Address all correspondence and requests for reprints to: Dr. D. T. den
Ouden, Department of Internal Medicine, MCH Westeinde Hospital,
P.O. Box 432, 2501 CK The Hague, The Netherlands. E-mail:
[email protected].
den Ouden et al. • Clinical Case Seminar
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4.
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