Hypopituitarism Secondary to Head Trauma
Salvatore Benvenga,
Alfredo CampennÍ,
Rosaria M. Ruggeri and
Francesco Trimarchi
Cattedra e Divisione di Endocrinologia, University of Messina
School of Medicine, 98125 Messina, Italy
Address correspondence and requests for reprints to: Salvatore Benvenga, M.D., Cattedra e Divisione di Endocrinologia, Policlinico Universitario, Padiglione H, 4° piano, 98125 Messina, Italy.
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Introduction
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In a classic article published in this journal
more than 50 yr ago, Escamilla and Lisser (1) reported that head trauma
accounted for hypopituitarism in only 4 of 595 patients (0.7%). In the
following 19 yr, Altman and Pruzanski (2) collected 15 additional cases
of posthead trauma hypopituitarism (PHTH) from the international
literature. In the subsequent 25 yr, Edwards and Clark (3) collected 34
new cases, so that their review concerned a total of 53 cases. No
subsequent review on PHTH has appeared thereafter.
After our initial observation of the first genuine case of
posttraumatic isolated hypogonadotropic hypogonadism (4), namely the
posttraumatic selective damage of the gonadotrophs, we became alerted
about PHTH. Our experience with this patient (4) proved to be fruitful,
because it helped us to diagnose PHTHrather than "idiopathic"
hypopituitarismin subsequent patients (5). We learned, in fact, that
head trauma can be minor and had occurred several years earlier, so
that the patient may lose recollection of it. Thus, we learned to help
the patient (and his or her relatives) to recollect these traumas.
In addition to screening the literature from 1986 through 1998,
we also screened the years 19701985 to ensure that Edwards and Clark
(3) had not missed some cases, as indeed they did (6, 7, 8, 9, 10, 11, 12, 13). Thus, we
bring the total of PHTH cases to 367, namely 314 more than the 53 cases
reviewed by Edwards and Clark (3). The 314 cases (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26) include our
own 15 cases (Refs. 4, 5 and our unpublished data), but not
the 11 cases reported by Cytowic and Smith (27) in a letter to the
editor because of the selectivity of their series (all women who had
developed amenorrhea) and the lack of hormone measurements. We warn the
reader that not all the articles report all the relevant parameters
that we will review, so that the resulting prevalences have different
denominators.
The aim of the present review is to assess the epidemiological,
clinical, and endocrinological features of hypopituitarism following
head trauma.
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Generalities
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PHTH is predominantly a medical problem of the young man because
the male to female ratio is 5:1 (Fig. 1
, top), and in about 60% of the cases head trauma had
occurred at the age of 1129 yr (Fig. 1
, middle). The
single decade most a risk is the third. Thereafter, the frequency of
PHTH declines progressively. Even though the majority of patients
develop symptoms of hypopituitarism relatively early (Fig. 1
, bottom), PHTH may became clinically evident at any time
after the accident, and 15% of patients are diagnosed 5 or more years
after the trauma. Particularly impressive are two patients in whom
posttraumatic central hypothyroidism was diagnosed 36 and 46 yr after
head trauma (3, 22). Of 15 of our patients (4, 5) with PHTH, head
trauma had occurred more than 10 yr earlier in 8 (Table 1
).

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Figure 1. Prevalence of gender (top),
age (middle), and lag-time between trauma and diagnosis
(bottom) in posttraumatic hypopituitarism.
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Table 1. Summary of the main clinical, hormonal and pituitary
imaging data in 15 patients with posttraumatic hypopituitarism
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The type of trauma is diverse, but in about three fourths of the cases,
it is represented by road accidents (Fig. 2A
). In our series (Table 1
), road
accidents accounted for half of the cases. Although it is unlikely that
a road accident and the following hospitalization are forgotten by the
patient, this happened to a number of our patients. For instance, our
first PHTH patient (case 15 in Table 1
), who sought our evaluation for
erectile dysfunction, had had a motorcycle accident 8 yr before our
observation (4). He did not mention this accident in the first history
he gave us, even though he had been hospitalized at the Neurosurgery
Institute of our University Hospital (4). For this relatively poorly
educated 26-yr-old man, to ask for "accidents or surgical
interventions at the head" was not sufficient to let him recollect
the trauma he had suffered 8 yr before. This required, when we
reinterrogated him, to explicity ask for car or motorcycle or bicycle
or truck or bus accidents. Even after these explicit specifications, it
was his wife who answered the question. Similarly, it was during
reevaluation of the first history and in the presence of the relatives
that nine of our patients were reminded of the trauma. Because most of
our patientstwo of whom are physicians!had not been hospitalized
for the head traumas (Table 1
), this fact clearly contributed to their
forgetfulness.

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Figure 2. Type of accident and its complications in
patients with hypopituitarism secondary to head trauma.
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Head trauma may or may not be complicated by skull fractures with
essentially the same frequency (Fig. 2B
), whereas a more or less
profound loss of consciousness occurs almost always (Fig. 2C
). In most
of the cases, coma lasts for days or weeks (Fig. 2D
). Of our 15 cases,
none had skull fractures and only three (cases 1, 2, and 15 in Table 1
)
had loss of consciousness.
In brief, data in Figs. 1
and 2
illustrate most of the characteristics
of the paradigmatic patients with PHTH. Such a patient is a male in his
20s who, within 1 yr from a road accident, will seek medical attention
for symptoms compatible with hypopituitarism. The relatively high
prevalence of females in our series is because over 80% of the
patients who are referred to our Division of Endocrinology are
women.
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Functional Consequences
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Endocrinologists use to link head trauma to one endocrine
disturbance: diabetes insipidus. However, diabetes insipidus occurs
only in about one of every three patients with PHTH (Fig. 3A
); in our series it occurred in one of
every five patients (Table 1
). Thus, endocrinologists should not rely
on its absence to rule out PHTH. Of the cell types present in the
anterior pituitary, the gonadotrophs seem to be the most fragile
because deficiency of FSH and/or LH is reported in almost 100% of the
cases of PHTH. TSH or ACTH deficiency occurs in about half of the cases
(44.3% or 52.8%, respectively) (Fig. 3B
). In our series, TSH deficiency is
higher because the vast majority of the patients referred to our
Division are women who are evaluated for thyroid dysfunction. GH or PRL
deficiency occurs in 23.7% or 3.8% of the cases, respectively. The
integrated GH secretion is better reflected by the circulating levels
of insulin-like growth factor I (IGF-I) (28). Unfortunately, serum
IGF-I was measured in only 11 cases (20, 26), and in all it was normal.
Of these 11 cases, serum GH was within normal limits in 10 (20).
Interestingly, this study (20) found that in the deceased subgroup mean
IGF-I was statistically lower than in the survived group. In our
series, GH and IGF-I were subnormal in two patients (13%). Because
head trauma may disturb the hypothalamic control on PRL,
hyperprolactinemia has also been reported (47.7%) (Fig. 3B
). This
prevalence of hyperprolactinemia is in agreement with the prevalences
of the pituitary stalk/hypothalamus site of lesion based on autoptic
data [45 of 106 or 42.0% (see footnote d of Table 2
)] or imaging data [ 32.9% (Fig. 5
)
]. Quite obviously, the combinations of hormone dysfunctions are
diverse. At one extreme, we can have the deficiency of all hormones and
resulting generalized hypopituitarism. At the other extreme, we have
selective deficiencies. Rarely, the deficiency of a given hormone may
be transient. This transitoriness was observed in one of our patients
(4), as well as in other cases (25, 26).
Because of the peculiar vascularization of the pituitary, the
peripheral layer of anterior pituitary cells under the capsule receive
arterial blood from the capsule, not from the two systems of portal
veins. These cells and those in a small area near to the posterior lobe
are the only surviving cells in cases of pure anterior lobe necrosis
(29). The severed portal vessels can regenerate, grow down into the
surviving parts of the anterior lobe, and, thus, permit some resumption
of the anterior pituitary function when the site of lesion is in the
pituitary. Indeed, "mytotic figures amongst the surviving cells"
(29) and "unmistakably repopulated appearance of the anterior lobe"
(30) have been documented. This process of revascularization and
repopulation clearly requires time. Thus, it took 12 yr for a boy to
recover completely from the anterior pituitary insufficiency that
complicated head trauma (25). In one of our patients (4) the lag-time
before resumption of the gonadotropin secretion was 10 yr from head
trauma and 1 yr from normalization of the pituitary computed tomography
(CT) scan (Fig. 4
). The spontaneous
recovery from posterior and anterior pituitary insufficiency observed 6
months after head trauma by Iglesias et al. (26) was very
partial. In this 32-yr-old man, the cause of panhypopituitarism was a
posttraumatic retention cyst that compressed and displaced pituitary
(26).

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Figure 4. CT scan of one patient (case 15 in Table 1 )
with posttraumatic hypopituitarism. Top, Coronal slice
of the sella turcica after contrast injection. Note that: 1) pituitary
stalk is regular (white arrowheads); 2) the upper
profile of the pituitary gland is normally concave; and 3) the
pituitary parenchyma is diffusely hypodense (black dot).
An early/partial empty sella is apparent. C, Internal carotid; CS,
cavernous sinus. Bottom, Repetition of the CT scan 1 yr
later. Density of the pituitary is virtually normal, partial empty
sella is still present (from Ref. 4, with permission of the authors and
the Journal of Endocrinological Investigation).
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Clinical Picture
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This is composite, because ample is the spectrum of the
possible endocrine dysfunctions (see Functional
Consequences). In addition, hypopituitarism can be subclinical and
be revealed only by hormone measurements. The clinical onset can be
quite acute and dramatic, leading the patient to the intensive care
unit. Otherwise, the symptomathology, which appears first and which
constitutes the reason for seeking endocrine evaluation, is most
frequently amenorrhea/infertility in women and erectile dysfunction in
men. In a short letter to the editor, Cytowic and Smith (27) reported
that they "found a 13% incidence of amenorrhea in a group of 84
young women (age, 19 to 35) who had mild to moderate head injury but no
permanent neurologic impairment . . . These 84 women came from a larger
group of 205 consecutive patients with closed head trauma . . . .
Eleven women had lack of menses one to six months after trauma from a
motor vehicle accident. All patients had had regular menses before the
head injury . . . ." Asthenia, psychic torpor, cold intolerance
(because of central hypothyroidism), hypothension (because of central
hypocortisolism), and galactorrhea (because of hyperprolactinemia) may
be variably associated. Clearly, the symptomathology can pass
undetected in a comatose patient with or without skull fractures.
However, we believe that it is important to ascertain whether there is
pituitary insufficiency, because: 1) hypopituitarism can be an
immediate or early complication of head trauma; and 2) adrenal and/or
thyroid insufficiency will contribute to maintain unconsciousness, and
either one will aggravate the prognosis.
When imaging studies were performed, CT and/or magnetic resonance
imaging (MRI) failed to reveal any abnormality in 5 of 76 (6.6%)
cases, which is in agreement with the 1 of 13 (7.7%) frequency
observed in our cases (Table 1
). Such normality is higher (10 of 11) in
the series reported by Cytowic and Smith (27). When lesions were
detected, these were vascular insults of the pituitary in half the
cases (Fig. 5
).
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Pathology
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Autopsy studies (30- 33) are summarized in Table 2
. The six cases
reported by Daniel et al. (29) are omitted from this table
because the authors did not specify whether these cases of traumatic
necrosis of the pituitary anterior lobe were sporadic cases or,
instead, were part of a large series of unspecified size. Patients had
died "soon after" head trauma (32), after "immediate or remote"
head trauma (30), or after an unspecified period of time since trauma
(31, 33). The circumstances of trauma were diverse, and hormone
measurements before death were unavailable. A comparison among such
studies is difficult because of the different size of the series and
the concurrence of more than one lesion.
Disagreements between studies are evident (Table 2
). For instance, the
anatomical integrity of the pituitary varies from 14% (30) to 74%
(33); certain lesions, such as anterior pituitary fibrosis or
hemorrhage of pars intermedia, are mentioned only by some authors (32).
On the other hand, certain other lesions, such as the necrosis of the
pituitary stalk, are found with exactly the same frequency (6%)
(30, 31, 32). Other differences are evident when correlations with death
(data not given in Table 1
) were searched (30, 31). For instance,
peripituitary/capsule lesions were observed more frequently in patients
who died within 2 days after trauma (30) or any time since trauma (31).
Concerning necrosis of the anterior lobe, instead, both studies (30, 31) agree that it is more frequent in patients who died within 1 week
since trauma.
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Final Considerations
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Pituitary insufficiency can have life-threatening
consequences. Hypopituitarism impairs adaptation to stressful events
and represents a negative risk factor for the prognosis of the
traumatized patient. PHTH, the characteristics of which can be
summarized as in Table 3
, is certainly
less rare than commonly believed. Among the reasons why it can escape
diagnosis, two seem to be prominent. First, the trauma may have
occurred decades earlier and may also have been forgotten. This is more
likely to occur when trauma was domestic, not followed by
hospitalization and/or not complicated by skull fractures, loss of
consciousness, or diabetes insipidus. Second, there could be lack of
insistence by the endocrinologist to ask specifically for past head
traumas to both the patient and his or her relatives. Of 100
endocrinologists we have inquired (unpublished data), all would
associate PHTH to a complicated head trauma occurred within "days"
to a "couple of years" from trauma, but none would think of
interrogating the relatives. Approximately four of five
endocrinologists would not consider the possibility of PHTH, should a
patient with no history of posttraumatic diabetes insipidus seek
consultation for symptoms compatible with pituitary insufficiency
(amenorrhea, asthenia, and so on). Thus, chances are that PHTH is
underdiagnosed whereas idiopathic hypopituitarism is overdiagnosed.
The question then arises whether a patient who had suffered a head
trauma needs to be followed up over time. Because long-term
longitudinal studies on this issue have not been performed, we lack
well-grounded answers to offer. A practical approach could be the
"3/4 rule" because: 1) about 3/4 of PHTH patients are
males 40 yr of age or less (at the time of trauma); 2) about 3/4
of PHTH causes are road accidents; and 3) PHTH occurs within 1 yr in
three fourths of cases. A patient who meets these criteria is a good
candidate to target for the follow-up (i.e. he is the one in
whom PHTH will occur with the highest likelihood). Follow-up can also
have forensic implications. This is an issue that has never been
approached before. These practical situations may develop: 1) PHTH is
considered, then is excluded, but eventually it develops several years
later; and 2) PHTH is diagnosed and recognized as a damage to be paid,
but after a number of years there is a spontaneous recovery due to
pituitary revascularization and repopulation.
In conclusion, physicians should be more alerted about PHTH,
particularly in the patients most at risk.
Received August 7, 1999.
Revised December 14, 1999.
Accepted December 20, 1999.
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