Bulletin Volume 6, Issue 1,
Articles in this issue:
MORTALITY AFTER TRANSSPHENOIDAL SURGERY FOR CUSHINGS DISEASE
by Brooke Swearingen, M.D.
The clinical course of untreated
Cushings syndrome is marked by a significant increase
in morbidity and mortality. In the original report of this syndrome
written by Harvey Cushing in the 1930s, the duration from presentation
of illness to death was 4.7 years. In 1952 the 5 year survival
rate for patients was approximately 50%. The introduction of
early surgical procedures to cure hypercortisolism and the advent
of modern glucocorticoid replacement regimens improved the 5
year survival rate after adrenalectomy to 86%. With the advent
of modern neurosurgical techniques using transsphenoidal resection,
cure rates of hypercortisolism have changed dramatically. Current
cure rates for patients with microadenomas, are approximately
90% when performed by experienced pituitary neurosurgeons. An
important unanswered question has been the impact of current
diagnostic and therapeutic approaches on the long-term mortality
rate of patients with Cushings disease. A retrospective
case series of 161 patients treated for Cushings disease
at Massachusetts General Hospital between 1978 and 1996 was
therefore done to determine long-term mortality rates in patients
treated for Cushings disease with modern neurosurgical
techniques. In this study, records were reviewed for all patients
who underwent transsphenoidal surgery for documented Cushings
disease and all surviving patients were contacted, with deaths
confirmed by hospital, physician or family records.
The diagnosis of Cushings
disease was based on clinical and biochemical evidence. A normal
or elevated plasma ACTH level and the results of abnormal suppression
testing were all consistent with the diagnosis of Cushings
disease, and cure was defined as a fasting serum cortisol level
of less than 138nm/L and a urine free cortisol of less than
55nm/day. Recurrence was determined in surviving patients by
endocrine reevaluation and questionnaire reports. A Kaplan-Meyer
product-limit estimation with 95% confidence intervals was used
to analyze survival. The 161 patients (32 men and 129 women)
had a total of 193 transsphenoidal procedures for Cushings
disease. The mean age at the time of surgery was 38 years with
a range of 8-76 years. Eighty-nine percent of the patients had
microadenomas as defined by maximum tumor diameter of less than
1 cm, and 90% of these patients were cured. Of patients with
macroadenomas, 65% were surgically cured. The overall cure rate
for all patients was 85% and 28 of the patients required multiple
procedures. Among the 136 cured patients with long-term follow-up,
7% of patients showed evidence of recurrence with a post-operative
interval of 1 to 11 years (median 4 years). Therefore the long-term
cure rate for patients with microadenomas was 96% at 5 years
and 93% at 10 years, compared to 91% and 55% for macroadenomas.
There were no perioperative deaths resulting from the transsphenoidal
procedure at our Center. The most common complication was persistent
sinus congestion in 9% of patients. Among major complications,
there was a 2.6% evidence of cerebrospinal fluid rhinorrhea
requiring repair and 1.5% incidence of meningitis. Permanent
diabetes insipidus occurred in 6% of cases. In patients cured
after one procedure, ACTH, TSH and gonadotropin insufficiency
was found in 31, 23 and 14% of patients respectively.
Survival data was obtained in 99%
of surgically treated patients with a median follow-up of 8
years. Six patients, 62 to 81 years of age, died at intervals
of 4 to 9 years after surgery and the causes of death were cardiovascular
in two patients, stroke in two patients, lymphoma in one patient
and trauma in one patient. Of importance, the overall survival
in the patient group was similar to that in an age- and sex-matched
sample from the normal United States population (Figure 1).
The overall 5 year survival rate was 99% and the 10 year survival
rate was 93%.
INSERT FIGURE 1 (BS)
INSERT FIGURE 2 (BS)
The advent of modern diagnostic
techniques for Cushings disease, improved neurosurgical
procedures and refinement in post-operative management and hormone
replacement therapy has had a dramatic impact on short-term
outcomes and long-term survivals for patients with Cushings
disease. In contrast to initial reports showing a marked increase
in mortality rates among patients with this disease, current
data now indicate that transsphenoidal surgical techniques performed
in centers with an expertise in pituitary surgery provide cure
in the vast majority of patients. Patients who are cured appear
to now have survival rates no different from that of the United
States population. Of note, other studies that have examined
the long-term outcome in Cushings disease show a decreased
survival despite therapy in a series where a significant minority
of patients had ongoing cortisol excess. These data demonstrate
that normalization of the hypercortisolemic state can have a
significant impact on long-term mortality to the extent that
it is indistinguishable from a normal population. In addition,
the overall cure rates for patients with microadenomas, representing
the vast majority of patients, is approximately 90% and among
patients with microadenomas the long-term 10 year cure rate
remains high at 93% (Figure 2).
For patients with macroadenomas,
the overall cure rate is significantly less at 65% and the 10
year cure rate is 55%. Therefore, even in patients who have
short-term surgical cures, vigilance is critical in detecting
early recurrence and initiating aggressive therapy to normalize
serum cortisol levels.
1. Cushing H. The basophil adenomas
of the pituitary body and their clinical manifestations. Bulletin
of the Johns Hopkins Hospital. 1932; 50:137-95.
2. Meier CA, Biller BM. Clinical
and biochemical evaluation of Cushings syndrome. Endocrinol
Metab Clin North Am. 1997; 26:741-62.
3. Orth DN, Liddle GW. Results
of treatment in 108 patients with Cushings syndrome.
N Engl J Med. 1971; 285:243-7.
4. ORiordain DS, Farley
DR, Young WF Jr, Grant CS, van Heerden JA. Long-term outcome
of bilateral adrenalectomy in patients with Cushings
syndrome. Surgery. 1994; 116:1088-93.
5. Mampalam TJ, Tyrrell JB, Wilson
CB. Transsphenoidal microsurgery for Cushings disease.
A report of 216 cases. Ann Intern Med. 1988; 109:487-93.
6. Katznelson L, Bogan JS, Trob
JR, Schoenfeld DA, Hedley-Whyte ET, Hsu DW, et al. Biochemical
assessment of Cushings disease in patients with corticotroph
macroadenomas. J Clin Endocrinol Metab. 1998; 83:1619-23.
7. Blevins LS Jr, Christy JH,
Khajavi M, Tindall GT. Outcomes of therapy for Cushings
disease due to adrenocorticotropin-secreting pituitary macroadenomas.
J Clin Endocrinol Metab. 1998; 83:63-7.
8. Swearingen B, Biller BMK,
Barker F, Katznelson L, Grinspoon S, Klibanski A, Zervas N.
Long-term mortality after transsphenoidal surgery for Cushing
disease. Ann Intern Med. 1999; 130(10): 821-4.
COMPLICATIONS OF RADIATION THERAPY FOR NON-PITUITARY TUMORS
by Howard H. Pai, MD, FRCPC, and Anne Klibanski, M.D.
The treatment of benign and malignant
neoplasms in the head and neck region and the brain represent
a special challenge to oncologists due to the close proximity
of these tumors to neurovascular structures. Surgical access
is limited and complete tumor resection is often not possible
due to the risk of damage to neurovascular structures with aggressive
surgery. Extensive surgery can also result in significant disfigurement
or loss of function. Some examples include malignant neoplasms
of the nasopharynx, nasal cavity and paranasal sinuses, benign
and malignant tumors of the brain such as meningiomas, gliomas,
and neuroectodermal tumors. Neoplasms located in the base of
skull region is another example of where surgical resection
is limited by the presence of critical structures such as the
pituitary gland, hypothalamus, brainstem, cranial nerves and
blood vessels. External beam radiation therapy has the advantage
of being non-invasive and has an established role in the management
of these tumors. The delivery of radiation therapy to this region
must be very carefully planned, as these structures are also
susceptible to damage by radiation. One clinically relevant
aspect of radiation effects on normal tissue in this region
is the neuroendocrine effect of radiation to the pituitary gland
and hypothalamus, which is the focus of this article.
It is well-established that therapeutic
doses of radiation can cause damage to the pituitary gland and
hypothalamus. For example, patients with secretory pituitary
adenomas who are treated with external beam radiation therapy,
typically with fractionated doses of at least 45 Gy, have a
gradual decline in excess hormone production by the adenoma.
However, because the rest of the normal pituitary gland receives
the full dose of radiation, a decline in the other hormones
secreted by the pituitary gland is frequently observed. One
could debate whether the presence of the adenoma itself compromises
pituitary gland function thus contributing to hypopituitarism
after external beam radiation therapy. However, patients treated
with external beam radiation therapy for non-pituitary gland
neoplasms also exhibit hypopituitarism following external beam
radiation therapy. Evidence supporting hypothalamus and pituitary
gland damage following external beam radiation therapy for non-pituitary
gland tumors comes from several sources. Children who receive
cranial or craniospinal irradiation for leukemia or primary
tumors of the brain often develop hypopituitarism. Hypopituitarism
is manifested by anterior pituitary gland hormone deficiencies.
Clinically apparent growth hormone insufficiency is particularly
prevalent in children. Other anterior pituitary gland hormones
can also be affected with deficiencies in TSH, LH, FSH, and
ACTH. Patients can also develop hyperprolactinemia after external
beam radiation therapy. The mechanism involves decreased availability
of dopamine from the hypothalamus to the pituitary gland through
radiation damage to the hypothalamus or portal system. The inhibitory
effect of dopamine on prolactin secretion is diminished, resulting
in a rise in prolactin. More than one hormone can be affected.
A less common neuroendocrine effect is precocious puberty observed
in prepubertal patients. For reasons not well understood, vasopressin
insufficiency (an indicator of posterior pituitary gland function)
after external beam radiation therapy is rarely seen.
Radiation induced pituitary gland-hypothalamic
dysfunction also occurs in adults with high incidence. The same
type of anterior hormone deficiencies can occur as with children.
The incidence of each hormone defect varies from study to study.
Growth hormone deficiency can range from 60 to 100%, hyperprolactinemia
from 15% to 85%, hypothyroidism from 15 to 65%, hypoadrenalism
from 14 to 55%, and hypogonadism from 30 to 60%. Clinically
overt diabetes insipidus is a very uncommon event in adults,
similar to children.
Hypopituitarism after external
beam radiation therapy is a late effect typically occurring
2-3 years after radiation therapy but as early as 6 months.
Patients continue to be at risk many years after completion
of external beam radiation therapy with cases documented 10
to 15 years after treatment. Thus, the importance of lifelong
monitoring after external beam radiation therapy cannot be over-emphasized.
The patho-physiological mechanism of damage is not well elucidated
but may reflect damage to the microvasculature of the pituitary
gland or portal system or direct damage to the hormone producing
cells of the pituitary gland. The hypothalamus is also susceptible
to radiation injury resulting in hypopituitarism.
Monitoring of hypothalamic-pituitary
gland function following external beam radiation therapy begins
with a complete baseline evaluation prior to completion of external
beam radiation therapy to detect any pre-existing endocrine
deficits. Baseline neuroendocrine evaluation should assess central
and end organ endocrine function including thyroid, adrenal,
gonadal, prolactin, vasopressin, and growth hormone secretion
when appropriate, using history and physical and blood tests.
Provocative blood tests can be used to determine a central or
primary origin but certain stimulatory tests such as insulin
stress test are relatively contraindicated in patients with
brain or parasellar tumors due to the risk of hypoglycemia induced
seizures especially if prior neurosurgical procedures have been
performed. Patients should be routinely monitored for endocrine
changes at 6 months after completion of external beam radiation
therapy and then at 1 year and yearly thereafter. Our protocol
for neuroendocrine follow-up after external beam radiation therapy
to the pituitary gland-hypothalamic region consists of a history
and physical, blood levels for prolactin, T4, fT4, 8 am cortisol
and/or ACTH stimulation test, FSH, LH, free and total testosterone
in males and estradiol in non-menstruating pre-menopausal females.
Subclinical adrenal insufficiency is important to diagnosis
and treat to avoid precipitating acute adrenal insufficiency
during periods of stress such as a surgical procedure. Tests
for vasopressin or growth hormone insufficiency are only ordered
for adults with symptoms or signs suspicious for diabetes insipidus
or in whom GH therapy is contemplated, respectively. Hormone
replacement should be instituted when an endocrinopathy is found.
Controversy exists as to whether GH replacement should be offered
for adult patients with neoplasms. Although there are no data
supporting tumor proliferation during exogenous GH administration,
it has been our policy to avoid growth hormone replacement for
adults after radiation therapy for malignant or aggressive neoplasms.
Not all patients who receive radiation
to the pituitary gland-hypothalamic region develop pituitary
or hypothalamic insufficiency. Several factors may influence
the risk of developing hypopituitarism. These include age, gender,
daily dose of radiation and total dose of radiation delivered
to the pituitary gland and hypothalamus. With respect to gender,
women become hyperprolactinemic after radiation more often than
men. Patients who are older (e.g. > 40-50 years) tend to
have a higher incidence of endocrinopathies after radiation,
noted in 3 separate studies. One possible explanation for this
may be decreased pituitary reserve with aging. Limited data
have suggested that fraction size or the daily dose of radiation
delivered may influence the risk of endocrinopathy with larger
fraction sizes causing a higher incidence of hypopituitarism
. This observation is consistent with the general axiom that
larger fraction size is associated with increased late toxicity
for neurovascular tissue. The total dose of radiation absorbed
by the pituitary gland and hypothalamus is undoubtedly a risk
factor for causing hypothalamic-pituitary gland damage resulting
in hypopituitarism. In the early 1980s, the first indication
of a dose response was suggested in a report from Australia,
albeit from a small series of patients and with only estimations
of dose to the pituitary gland and hypothalamus and using fraction
sizes not considered standard in the US. In the late 80s,
a large series of patients (n=268) who received cranial irradiation
for various neoplasms were analyzed for dose response effect
. It was noted that at very low therapeutic doses of radiation
of 12 Gy, the incidence of endocrinopathy was negligible. At
doses > 20 Gy, the incidence became clinically relevant and
a dose response was seen between 20 Gy and 35 Gy or above. This
study was performed in United Kingdom where higher dose per
fraction (e.g. 2.5 to 3.75 Gy per fraction) was used compared
to US standards. A smaller series of patients (n=32) treated
at the University of Rochester in NY were analyzed and found
to have a dose response such that patients receiving doses greater
than 50 Gy had a higher incidence of hypothyroidism and hypoadrenalism
. A dose response from 18 Gy to > 24 Gy to > 35 Gy
for GH insufficiency exists for children treated with cranial
irradiation for acute leukemia or brain tumors. At Massachusetts
General Hospital and the Harvard Cyclotron Laboratory, we have
treated over 500 patients with moderate to high dose radiation
using proton beam radiation therapy to the parasellar region
for non-pituitary gland and non-hypothalamus tumors of the base
of skull region, most typically chondrosarcomas and chordomas
of the clival region. A significant number of these patients
have been followed for neuroendocrine outcome prospectively
and recent analysis of 107 such adult patients have shown that
doses above 50 centigray equivalent (CGE) to the pituitary gland
or hypothalamus significantly increases the risk of hypopituitarism
. Patients receiving 70 CGE to any portion of the pituitary
gland were also at increased risk. A high incidence of hyperprolactinemia
was also observed using proton therapy with a 10-year actuarial
incidence of over 85%. What was unique to this study was the
ability to determine the dose to the pituitary gland and hypothalamus
more precisely using 3 dimensional computerized treatment planning
algorithms not available in the past at other institutions.
|Table 1. Neoplasms which
frequently require radiation therapy to the pituitary /
- Primitive neuroectodermal
tumor of the CNS (e.g.
- Pineal gland tumors
- CNS Germ cell tumors
- Gliomas, ependymomas of
the brainstem or thalamus region
- Pituitary adenomas
- Parasellar meningiomas
- Chordomas, chondrosarcomas,
giant cell tumors of the clivus or
- Cancer of the nasopharynx,
nasal cavity or paranasal sinuses
Radiation therapy has a proven
role in the treatment of neoplasms arising from the brain and
head and neck region where sensitive neurovascular structures
preclude aggressive surgical resection. Radiation can also cause
damage to these neurovascular structures such as the pituitary
gland and hypothalamus resulting in hypopituitarism. Both children
and adults can be affected and the incidence of hypopituitarism
is very high. Patients often require hormone replacement therapy
and life long monitoring is strongly recommended. Patients with
neoplasms listed in Table I are recommended to have longitudinal
endocrine follow-up after radiation therapy. However, any patient
receiving radiation therapy where the pituitary gland and hypothalamic
region is at risk for irradiation should be screened as well.
Radiation induced hypopituitarism is generally limited to dysfunction
of the anterior pituitary gland. The types of endocrinopathies,
timing and risk factors have been described. The radiation dose
is an important factor with several studies indicating a dose
response for hypopituitarism. In the last decade, advancements
in computer technology, diagnostic imaging and radiation treatment
techniques have enabled radiation oncologists to deliver radiation
more precisely to the intended target. This approach limits
the dose to surrounding normal tissue thereby improving the
therapeutic ratio. Efforts should continue in this direction
to reduce the incidence of radiation induced hypopituitarism.
Littley, M D, Shalet,
S M, Beardwell, C G, Robinson, E L, Sutton, M L., Radiation-induced
hypopituitarism is dose-dependent. Clinical Endocrinology, 1989.
31: p. 464-373.
Constine, Louis S,
Woolf, Paul D, Cann, Donald, Mick, Gail, McCormick, Kenneth, Raubertas,
Richard F, Rubin, Philip. Hypothalamic-Pituitary dysfunction after
radiation for brain tumors. N Engl J Med, 1993. 328: p. 87-94.
Pai, Howard H, Katznelson, Laurence,
Klibanski, Anne, Finkelstein, Dianne M, Adams, Judith A, Fullerton,
Barbara C, Thornton, Allan, Leibsch, Norbert J., Munzenrider,
John E. Hypothalamic/Pituitary Gland Dysfunction following High
Dose Conformal Mixed Proton-Photon Beam Radiotherapy to the
Base of Skull Region: Demonstration of a Dose Effect Relationship
using Dose Volume Histogram Analysis. in 41th ASTRO (American
Society for Therapeutic Radiology and Oncology) conference.
1999. San Antonio, TX.
HORMONE REPLACEMENT IN ADULTS: CARDIOVASCULAR CONSIDERATIONS
by Gemma Sesmilo, MD
The approval of growth hormone
(GH) for the treatment of adults with GH deficiency has raised
a great deal of interest regarding the long-term benefits of
this therapy. A number of clinical studies have demonstrated
that GH replacement has beneficial effects on body composition
and bone mineral density. A topic of new and important interest
is how growth hormone affects the cardiovascular risk profile.
Life expectancy and cardiovascular
disease in GH deficient patients
Rosen & Bengtsson in 1990 reported
that hypopituitary patients receiving conventional replacement
had a decreased life expectancy. They examined the records of
333 patients diagnosed with hypopituitarism between 1956 and
1987 from their endocrine clinic in Goetheburg and found a higher
mortality rate in these patients than in the Swedish population.
This increased mortality was attributed to cardiovascular disease.
Cross-sectional studies have demonstrated
a higher prevalence of atherosclerotic plaques, endothelial
dysfunction and increased carotid intimal-medial thickness in
hypopituitary patients as compared to controls, even at early
stages of the disease. These indicators of atherosclerosis have
been shown to correlate with the incidence of coronary events
in epidemiological studies. These findings are consistent with
the concept of increased cardiovascular risk in hypopituitary
patients, however, the role of GH and the effect of GH replacement
on this risk is less well known.
Clinical characteristics of
the GH deficiency syndrome
The growth hormone deficiency syndrome
is characterized by obesity with increased body fat. The excess
fat is centrally distributed mostly in the visceral compartment,
which is a known cardiovascular risk factor. Other features
such as insulin resistance, impaired plasma fibrinolytic activity
and dyslipoproteinemia have been described in growth hormone
deficient patients in cross-sectional studies and all are thought
to contribute to increased cardiovascular risk.
GH effects on body fat distribution
Growth hormone replacement therapy
decreases total body fat, including visceral fat and increases
lean body mass, resulting in no net change in body weight. Several
groups but not all, have demonstrated reduction in central fat
with GH treatment. Important differences among studies exist
and these are likely due to different doses of GH used as well
as duration of therapy. GH is a lipolytic hormone with known
dose dependent effects. The first reports regarding GH replacement
in adults used high doses, resulting in IGF-I values out of
the reference range, with high incidence of adverse events mainly
due to fluid retention. More physiological approaches are discordant
in the reduction of central fat as assessed by the waist to
GH effects on lipid levels
There are conflicting reports regarding
the effect of GH replacement on the lipid profile. One of the
most important limitations is the lack of long-term controlled
trials, which makes it difficult to ascertain the effects due
to GH versus the placebo effect. A randomized placebo-controlled
study conducted in our Unit assessed the effect of physiological
doses of GH on 32 GH deficient patients treated over 18 months.
No long-term changes in the lipid profile were found. Some other
studies with a short-term placebo-controlled phase, followed
by an open follow-up, have shown reductions in LDL cholesterol
and/or increases in HDL cholesterol but others have not. There
is agreement in the increase of lipoprotein (a) [Lp(a)] levels
with GH replacement, but it is still not clear how Lp (a) contributes
to cardiovascular risk.
GH effects on glucose metabolism
GH is known to have anti-insulinic
properties, whereas IGF-I is an insulinotropic agent. GH replacement
has been reported to impair insulin action in many studies,
but studies of insulin sensitivity using clamp techniques have
shown reversibility of these findings with maintained GH treatment.
Other approaches to the study of glucose metabolism in treated
GH deficient patients have not been able to show a complete
recovery of the initial decline in insulin sensitivity caused
by GH. While it is known that GH treatment initially causes
insulin resistance, it is thought that the changes in body composition
with decreases in body fat and increases in lean body mass can
contribute to the reversal of this effect. It is recommended
that glucose levels be monitored in patients who initiate GH
treatment. Typically if a patient develops diabetes, the drug
is discontinued. Diet and exercise should be reinforced in patients
Proposed mechanisms of GH effect
Based on the reported effects of
GH on different cardiovascular risk factors, it is difficult
to know how GH administration will affect the process of atherosclerosis.
There are two prospective open-labeled studies that have assessed
carotid intimal-medial thickness as an indicator of atherosclerosis
in GH treated patients. Both of them showed a decrease in this
parameter, as early as 6 months after treatment (Figure 1).
INSERT FIGURE 1 (GS)
There are some proposed mechanisms
whereby GH can contribute to the reduction in cardiovascular
risk. Boger et al. reported in a randomized placebo-controlled
study, a decreased nitric oxide production in GH deficient patients
as compared to controls which was restored with GH administration.
They proposed that this effect could be mediated by a direct
action of IGF-I on nitric oxide synthesis by endothelial cells.
Recently, Serri et al proposed another mechanism of GH action
on the process of atherosclerosis. In an open-label study, they
found that GH deficient patients have increased monocyte production
and elevated peripheral levels of cytokines such as interleukin-6
and TNF-alpha. Given the important role that inflammation plays
in the process of atherosclerosis, they postulated that GH effects
may be mediated by the inflammatory pathway with potential beneficial
GH deficient patients have evidence
of early atherosclerosis and increased cardiovascular mortality.
Ultrasonographic studies have reported a decrease in carotid
intimal-medial thickness after GH administration, suggesting
a beneficial effect of GH on atherosclerosis. GH decreases total
and central body fat, increases Lp (a), but effects on other
lipoproteins are more controversial. GH initially causes insulin
resistance which may be restored with prolonged treatment. Proposed
mechanisms of GH action on atherosclerosis include reduction
of nitric oxide production and inflammatory activity modulation.
Cardiovascular risk may prove to be an important factor in determining
the benefit to risk ratio of GH replacement. However, further
studies using clinical cardiovascular end-points are needed
to confirm the beneficial effect of GH replacement in the process
Rosen T, Bengtsson
BA. Premature mortality due to cardiovascular disease in hypopituitarism.
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Finkelstein JS, et al. Effects of physiologic growth hormone therapy
on bone density and body composition in patients with adult-onset
growth hormone deficiency. A randomized, placebo-controlled trial.
Ann Intern Med. 1996; 125(11):883-90.
Evans LM, Davies JS,
Goodfellow J, Rees JA, Scanlon MF. Endothelial dysfunction in
hypopituitary adults with growth hormone deficiency. Clin Endocrinol
(Oxf). 1999; 50(4):457-64.
Fowelin J, Attvall
S, Lager I, Bengtsson BA. Effects of treatment with recombinant
human growth hormone on insulin sensitivity and glucose metabolism
in adults with growth hormone deficiency. Metabolism. 1993; 42(11):1443-7.
Pfeifer M, Verhovec
R, Zizek B, Prezelj J, Poredos P, Clayton RN. Growth hormone (GH)
treatment reverses early atherosclerotic changes in GH-deficient
adults. J Clin Endocrinol Metab. 1999; 84(2):453-7.
Serri O, St-Jacques
P, Sartippour M, Renier G. Alterations of monocyte function in
patients with growth hormone (GH) deficiency: effect of substitutive
GH therapy. J Clin Endocrinol Metab. 1999; 84(1):58-63.