A man aged 27 years, 6 months was referred to the endocrine clinic for
short stature and a bone age of 12 years, 6 months. The patients history
was significant for a severe head injury from a motor vehicle accident in his
native country of Cameroon when he was 13 years old. His recovery was
complicated by polyuria, but he did not receive any therapy. Over time, his
thirst and polyuria subsided, and he denied nocturia. After the accident, the
patient did not grow any taller or develop axillary or pubic hair. He never
received medical treatment for his lack of development and he was not taking
Stephanie L. Lee
He immigrated to the United States when he was 21 years old. He took
college courses but failed because of fatigue and poor concentration. He
complained of headaches that occurred for the last year without vision
abnormalities. His voice had not deepened, and he did not shave. He denied
anosmia and noted occasional morning erections. On exam, he appeared to be a
prepubertal man appearing younger than his stated age. His blood pressure
sitting was 92 mm Hg/64 mm Hg with a pulse of 80 and, after standing, fell to
74 mm Hg/56 mm Hg with a pulse of 84. His height was 52 inches with a
waist-to-floor height of 31 inches and a heightwaist ratio ≤0.5. His
exam was significant for periorbital edema; gynecomastia without galactorrhea;
absence of a thyroid cartilage prominence (Adams apple); normal thyroid;
no beard, pubic or axillary hair; microphallus; small testes (Tanner stage 1);
normal cranial nerves exam; normal visual fields on confrontation; and delayed
relaxation of the bicep reflexes.
Lab testing showed a low free thyroxine 0.5 pg/dL (reference, 0.87-1.8),
inappropriately normal thyroid-stimulating hormone 2.24 (reference, 0.35-5.5),
growth hormone ≤0.1 ng/mL and low insulin-like growth factor I ≤6 ng/mL
(reference, 114-492). His adrenocorticotropic hormone was 16 pg/mL (reference,
9-52) with a basal morning cortisol of 3 mcg/dL and a subnormal stimulation to
13 mcg/dL at 60 minutes after 250-mcg IV cosyntropin. His luteinizing hormone
0.1 mIU/mL and follicle-stimulating hormone ≤0.3 mIU/mL were low with a
testosterone ≤10 ng/dL (reference, 241-827) and prolactin 8 ng/mL
(reference, 2.1-17.7). His electrolytes were normal with a sodium 137 mmol/L,
bicarbonate 27.7 mmol/L, chloride 97 mmol/L, potassium 4.3 mmol/L, creatinine
0.5 mg/dL and random glucose 65 mg/dL. The results of radiology studies showed
the humeral epiphysis was not closed on chest X-ray and the spheno-occipital
synchondrosis was unfused on CT, suggesting a delay of bone maturity (see
figure 1). An MRI scan showed a small pituitary and the absence of both the
infundibulum (pituitary stalk) and posterior pituitary bright spot
in the sella (see figure 2).
Clinically, the patient was found to have a eunuchoid habitus with long
limbs due to delayed pubertal closure of epiphyses of the long bone by sex
hormones. This can be documented with either a measurement of the waist to
floor ≤one-half height or arm span ≥2 cm longer than height. His physical
exam suggested panhypopituitarism with deficiencies in thyroid hormone (delayed
relations of deep tendon reflexes), adrenal hormone (low and orthostatic BP),
GH (short stature) and hypogonadism (lack of secondary sex characteristics).
Biochemically, panhypopituitarism was confirmed. He was started on
levothyroxine 75 mcg and prednisone 2.5 mg daily, which was changed to
hydrocortisone 10 mg in the morning and 5 mg in the afternoon to avoid
glucocorticoid excess limitation on growth. A few weeks later, he was started
on GH. After three years of GH therapy, his height increased from 51.97 inches
to 57.01 inches, and then he was started on testosterone with deepening of his
voice, growth of pubic and axillary hair and increased libido. Testosterone
therapy was not started until after substantial growth with GH and thyroid
hormone therapy to avoid early fusion of the epiphyses and reduction of his
final height. After seven years of HT, he is continuing to grow (see figure 3),
with a current height of 58.60 inches, he reports feeling well with good energy
and libido. He denies severe headache, lightheadedness or hypothyroid symptoms.
Figure 1. Delay of
bone maturation with GH and sex steroid deficiencies of panhypopituitarism. A.
An open epiphysis (blue arrow) of the humerus was noted on a routine chest
X-ray. B. An unfused spheno-occipital synchondrosis (green arrow) was noted on
an axial image of a CT scan.
Photos courtesy of: Stephanie L. Lee,
2. T1-weighted MRI images of the pituitary and hypothalamus. A. Coronal image
plus gadolinium demonstrating the ectopic posterior pituitary gland (red
arrow). B. Sagittal image without gadolinium. C. Sagittal image with
gadolinium. The sella turcica is shallow, and pituitary gland is thin and small
and enhances with contrast (green arrows). The pituitary stalk cannot be
identified on coronal and sagittal images. The normal high signal from
posterior lobe of the pituitary gland is not identified within the sella but
superior and posterior to the posterior clinoid, just beneath the hypothalamus.
This finding is consistent with an ectopic posterior lobe of the pituitary
gland (red arrow).
Figure 3. Linear growth after
sequential HT with thyroid hormone and glucocorticoids (red arrow), GH (blue
arrow) and testosterone (pink arrow).
Diabetes insipidus (DI) is a disorder in which large volumes of dilute
hypotonic urine are excreted. Central DI is due to decreased vasopressin and
most commonly occurs because of destruction of the long vasopressin-secreting
neurons that originate in the paraventricular and supraoptic nuclei of the
hypothalamus and transverse down through the pituitary stalk to terminate in
the posterior pituitary. The most common causes of DI are trauma, pituitary
surgery, accelerationdeacceleration head injury and subarachnoid
hemorrhage. DI may result from metastatic tumor, large sella masses such as
craniopharyngiomas and Rathke-cleft cysts but rarely by slow-growing anterior
pituitary adenomas. DI may be caused by infiltrative diseases such as
lymphocytic infundibulo-neurohypophysitis, Langerhans histiocytosis X and
sarcoid. Other rare causes of DI reported in the literature are acute febrile
illness, meningoencephalitis, electrical injury and herbicide (glufosinate)
Although the DI after closed head injury of this man may be from direct
injury to the pituitary, stalk or hypothalamus, it may be due to the
accelerationdeacceleration tearing injury of the long vasopressin nerves
and the venous plexus comprising the stalk. During a sudden deacceleration, the
pituitary stalk is damaged when the brain shifts in the cerebral spinal fluid
cushion, but the pituitary is fixed below within the skull by the bony cage of
the sella and above by the dura. It is important to realize that both anterior
and posterior pituitary dysfunction often occur in closed traumatic brain
injury. In a study by Agha and colleagues, 21.6% developed DI immediately after
the trauma and 6.9% had permanent DI after a median 17 months follow-up. CT or
MRI in a large group of patients with posttraumatic hypopituitarism, including
DI, reported hemorrhage in the hypothalamus or posterior pituitary in 55% of
patients, and approximately 5% of patients had stalk resection or infarction of
the posterior pituitary.
Similar to the course of postoperative injury to the vasopressin
neurons, DI after head trauma follows a triphasic course. The first phase of DI
of temporary antidiuretic hormone deficiency lasts for five to seven days and
is initiated by a partial or complete pituitary stalk section with neuronal
dysfunction due to axon shock and neuron dysfunction. The second phase of
inappropriate antidiuresis lasts from two to 14 days and is caused by an
uncontrolled release of vasopressin from the degenerating nerve terminals in
the posterior pituitary. After the vasopressin stores are depleted, a third
phase of DI develops if >80% to 90% of the vasopressin-secreting neuronal
cell bodies in the hypothalamus have degenerated. The major determinant of
whether DI is permanent is related to the location of the neuronal damage such
that the closer the injury is to the cell bodies in the hypothalamus, the more
likely the neurons will degenerate.
Occasionally, as illustrated by this patient, over time some patients
resolve their symptoms of DI. This observation has not been systematically
studied and is based on anecdotal experience and case reports. Presumably this
patient had partial central DI, and over time some, ADH nerve terminals were
able to form at the base of the hypothalamus, resulting in the resolution of DI
symptoms and the development of an ectopic posterior pituitary. Although
ectopic posterior pituitary located at the base of the hypothalamus has been
reported in cases of congenital absence of the anterior pituitary, it is
unlikely in this case, as his growth was normal until his head injury.
Subramanian Kannan, MD, is a PGY3 Resident in Internal Medicine at
University of Connecticut Health Center, and Stephanie L. Lee, MD, PhD, is
Associate Chief of the Section of Endocrinology, Diabetes and Nutrition, and
Associate Professor of Medicine at Boston University Medical Center.
For more information:
- Agha A. J Clin Endocrinol Metab.
- Agha A. Eur J Endocrinol. 2005;152:371-377.
- Benvenga S. J Clin Endocrinol Metab.
- Schneider HJ. JAMA. 2007;298:1429-1438.