7, Issue 1, Winter 2001
Articles in this issue:
Advance: Intraoperative MRI
used for Pituitary Tumors at MGH
by Brooke Swearingen, M.D.
A new intraoperative MRI has recently
been installed in the MGH neurosurgical operating suite. Unlike
standard MRI facilities, this is a portable machine which is
designed to be used in an operating room. It is small enough
to be stored under the operating table, and can be wheeled out
when needed. Dr. Robert Martuza, Chief of Neurosurgery at MGH,
calls it "The MRI equivalent of a portable x-ray"
and explains its importance as follows. "Physicians now
can view images during the actual operation, rather than having
to look at images made preoperatively and postoperatively. The
MRI offers real-time visualization during all stages of brain
surgery, so that neurosurgeons can plan the path of the surgery
at every point."
The MR scanner will allow images
to be obtained during and after neurosurgical procedures, both
to guide the surgeon during the operation, and to provide information
on the extent of residual tumor in those cases where visual
cues are inadequate. It will be especially useful in pituitary
surgery, since transsphenoidal procedures provide a relatively
limited exposure through the operative microscope, and it can
be difficult for the surgeon to determine the extent and location
of any residual tumor. It is now possible to obtain MR images
during an operation and use this information to achieve the
maximal tumor resection, while at the same time, using the images
to detect and avoid possible complications. To date, the scanner
has been used in over thirty transsphenoidal pituitary procedures.
When combined with the transnasal approach and endoscopy as
needed, the scanner will facilitate maximal tumor resection
while minimizing complications.
DURING AND AFTER SURGERY ON A PITUITARY ADENOMA
1. Intra-op MRI images pre- and post-resection
of a nonfunctioning adenoma. The left two panels show
pre-resection sagittal images obtained on the intra-op
MRI without contrast; the right two panels show post-resection
images - no visible tumor remains. The optic chiasm,
not visible on the pre-op scans because of compression
by the adenoma, is now visible on the post-op scans
(arrow), and has been completely decompressed.
This image shows a recurrent nonfunctioning macroadenoma
as imaged by a 1.5T diagnostic quality machine.
3b. After resection, an intra-operative image
is obtained on the 0.12T portable machine. The tumor
has been resected; the fat packing within the sella
Intra-op MRI images showing pre- and post-resection
views of a Rathke's cleft cyst in a patient whose
initial presentation was for severe headaches. The
left two panels show the cyst as a high signal mass
within the sella; the right two panels show the cyst
has been successfully drained. The patient's headaches
For comparison, a post-operative 1.5T image was obtained.
The fat is suppressed (dark signal). No residual tumor
was seen, confirming the intraoperative MRI finding
of a complete resection of the lesion.
Topics in Growth Hormone Deficiency
by Beverly M.K. Biller,
Two recent Journal of Clinical
Endocrinology and Metabolism articles address topics of interest
related to adult growth hormone deficiency. The first report,
entitled "Additional Beneficial Effects of Alendronate
in Growth Hormone (GH)-Deficient Adults with Osteoporosis Receiving
Long-Term Recombinant Human GH Therapy: A Randomized Controlled
Trial", was conducted in the Netherlands by N. R. Biermasz
et al. (1). These investigators designed a randomized, controlled
trial in osteoporotic GH- deficient patients to determine whether
adding a bisphosphonate to stable growth hormone replacement
would improve bone mass further.
Eighteen patients were selected from a cohort of GH-deficient
adults because of osteoporosis, defined as T score < -2 at
the femoral neck and the lumbar spine. These subjects had already
been receiving four years of GH replacement therapy. As one
would anticipate, from the studies of long-term growth hormone
replacement in GH-deficient adults, there had been a continuous
increase in lumbar spine bone mineral density (BMD) prior to
entry in the study, over the preceding four years of growth
hormone replacement therapy, averaging approximately 1% per
year. All patients were replete in vitamin D and calcium, had
no disorders expected to affect BMD, and were on stable sex
hormone replacement therapy for at least two years before entry
into the study. All subjects had normal serum PTH concentrations,
and none had been previously treated with bisphosphonates. The
subjects were randomized to receive a daily dose of 10mg of
alendronate or not, stratifying according to whether the GH
deficiency was of adult or childhood onset. All patients maintained
their GH replacement therapy at stable doses throughout the
one-year study period. The primary endpoints in the study included:
changes in biochemical markers of bone turnover, changes in
bone mineral density measurements, and the incidence of new
The study showed a significant
difference in biochemical markers of bone turnover between the
two treatment groups. There were no significant changes in parameters
of bone resorption (n-telopeptide) or bone formation (bone specific
alkaline phosphatase and osteocalcin) during the study in the
patients receiving growth hormone alone. In the patients receiving
alendronate in addition to growth hormone, the urinary n-telopeptide/creatinine
ratio decreased by 70.2+4% (p=0.002 for difference between groups).
There was also a significant difference (p=0.001) between the
decrease in serum bone specific alkaline phosphatase in the
alendronate plus growth hormone-treated patients compared with
that in the control patients receiving only growth hormone over
the year of the study.
Measurement of bone mineral density
showed that the patients receiving alendronate plus growth hormone
had a 4.4% increase in lumbar spine BMD which was significantly
(p=0.006) greater than the minimal change (0.7 percent) in the
patients continuing to receive growth hormone as shown in the
Figure. No new fractures developed in either group during the
12 month study period.
This study is interesting because
it demonstrates that beyond the previously reported improvement
in bone mass which can be achieved by replacing growth hormone
in adult GH- deficient patients (2), the addition of alendronate
to osteoporotic patients on stable GH therapy results in a further
increase in bone mass. The authors appropriately point out that
this study does not address the question as to whether bisphosphonate
treatment alone would be beneficial in growth hormone deficient
patients who were not taking GH replacement. This study was
conducted in the Netherlands, where endocrinologists routinely
supplement all growth hormone deficient patients with replacement.
The authors indicate in the discussion that they would be unable
to recruit a control population consisting of GH-deficient patients
who were not receiving GH replacement. This observation reflects
the high level of acceptance of growth hormone replacement in
Europe compared with the United States. If confirmed in larger
studies, these findings suggest that growth hormone deficient
patients with severe osteopenia would likely benefit from the
addition of alendronate to their growth hormone regimen.
| Individual percent change
in lumbar spine BMD during the 12-month study period. The
BMD increase was significantly greater at 6m in the alendronate
plus GH group compared with the control group continuing
on GH alone (*, P = 0.006) and at 12 months (**, P = 0.006).
(Biermasz et al, J Clin Endocrinol Metab, 2001; 86: 3083,
Reproduced with permission from the Endocrine Society)
The second article, entitled "Hypothalamo-Pituitary
Surveillance Imaging in Hypopituitary Patients Receiving Long-Term
Growth Hormone Replacement Therapy", by G. Frajese et al.,
from Saint Bartholomew's Hospital in London, addresses an important
safety issue in GH replacement therapy (3). Some endocrinologists
are concerned about the theoretical possibility that a sellar
mass might enlarge with growth hormone replacement. It is important
to recognize that there is an underlying recurrence rate of
pituitary adenomas in patients who are not treated with GH of
approximately 1% per year, depending on the series cited, and
on the nature of the original tumor and the treatment which
was administered. Therefore, it is to be expected that some
patients treated with GH will have recurrent tumors. In order
to link GH therapy as a causative agent in pituitary adenoma
recurrence, a higher rate than expected must be demonstrated.
This recent study is a prospective
evaluation of serial head scans performed in 100 consecutive
patients initiated on growth hormone replacement for adult onset
GH deficiency. The 60 females and 40 males who participated
ranged in age from 18 to 69 years, and were confirmed to have
GH deficiency on the basis of having a peak growth hormone response
< 3 ng/ml following stimulation testing (insulin tolerance
test in 81% of patients and glycogen stimulation test in 19%
of patients). The most common diagnoses were clinically nonfunctioning
pituitary adenomas, Cushing's disease, prolactinomas, and craniopharyngiomas.
Ninety-one percent of patients had received radiation therapy
in addition to surgery. Patients were treated between one and
32 years (median, 9 years) after the diagnosis of sellar abnormality.
The dose of GH replacement was titrated to maintain serum IGF-I
levels between the median and upper end of the age-related reference
Head scans (94% by MRI, 6% by
CT due to claustrophobia or size) were performed at baseline,
six months, 12 months, and annually thereafter in all subjects.
Nearly all subjects (92%) were followed for at least two years
and approximately one quarter of subjects had four years of
follow-up. The study demonstrates that in 99% of patients, there
was no increase in the amount of tissue within the pituitary
fossa. Only one patient demonstrated growth of sellar tissue
following initiation of growth hormone. This 40 year old man
had been treated with surgery and radiation for a nonfunctioning
pituitary adenoma three years prior to the initiation of GH.
He had a partially empty sella on the baseline scan, and had
expansion of sellar tissue to fill the pituitary fossa during
the first six months of growth hormone therapy. The GH replacement
was continued and no further change in sellar contents was observed.
These data are important because
they show no increased risk of tumor recurrence beyond what
is expected in patients with known pituitary disease. The authors
were careful to point out in the discussion that most of their
patients had received radiation therapy, at a rate higher than
currently used in most pituitary centers, which may have affected
the results. The authors also caution that because some of the
patients had microprolactinomas or small corticotroph adenomas,
the risk of recurrence in their population may have been lower
than the expected rate. Certainly, the duration of the study
(maximum follow-up four years) does not permit conclusions to
be reached regarding the use of GH over a longer period of time.
However, it has been established that children who were treated
for GH deficiency as a result of CNS tumors (including malignancies)
are at not increased risk for tumor recurrence as a result of
GH replacement (4, 5). It will be important to continue to gather
data regarding the risk of tumor enlargement in patients taking
growth hormone replacement therapy. Nevertheless, to date, no
published information suggests that GH replacement confers any
increased risk of tumor recurrence beyond what is expected from
the natural history of treated pituitary adenomas.
1. Biermasz NR et al. Additional
Beneficial Effects of Alendronate in Growth Hormone (GH)-Deficient
Adults with Osteoporosis Receiving Long-Term Recombinant Human
GH Therapy: A Randomized Controlled Trial. J Clin Endocrinol
Metab. 2001; 86:3079-85.
2. Biller BMK et al. Withdrawal of Long-Term Physiologic Growth
Hormone (GH) Administration: Differential Effects on Bone Density
and Body Composition in Men with Adult-Onset GH Deficiency.
J Clin Endocrinol Metab. 2000; 85:970-6.
3. Frajese G et al. Hypothalamo-Pituitary Surveillance Imaging
in Hypopituitary Patients Receiving Long-Term Growth Hormone
Replacement Therapy. J Clin Endocrinol Metab. 2001; 86:5172-5.
4. Moshang T Jr et al. Brain Tumor Recurrence in Children Treated
with Growth Hormone: The National Cooperative Growth Study Experience.
J Pediatr. 1996; 128:S4-7.
5. Packer RJ et al. Growth Hormone Replacement Therapy in Children
with Medulloblastoma: Use and Effect on Tumor Control. J Clin
Oncol. 2001; 19:480-7.
Physiology and Treatment in HIV Disease
by Steven Grinspoon, M.D.
Recent data suggest that GH secretion
is abnormal in HIV-infected patients. Increased GH concentrations
during overnight frequent sampling are seen among patients with
low weight and AIDS wasting (1). Conversely, reduced GH concentrations
are seen in association with increased visceral adiposity among
HIV-infected patients with the recently described fat redistribution
syndrome in the setting of highly active antiretroviral therapy
(2). It remains unclear whether HIV-infected patients with severe
visceral adiposity are GH deficient, but recombinant human GH
(rhGH) is now under investigation as a lipolytic agent in such
patients. The spectrum of abnormalities in GH secretion in HIV
disease and the potential therapeutic uses and limitations of
rhGH in HIV disease will be reviewed in this article.
GH secretion is under the dual
influences of somatostatin (inhibitory) and GHRH (stimulatory)
and is nutritionally regulated. Acquired resistance to the action
of GH occurs in acute and chronic undernutrition. Circulating
GH stimulates secretion of Insulin-Like Growth Factor-I (IGF-I)
via the GH receptor in the liver. In undernutrition, acquired
resistance to the action of GH occurs by receptor and post-receptor
mechanisms, resulting in reduced serum concentrations of IGF-I
and increased GH. In prior studies, increased GH in association
with reduced weight and lean body mass has been shown among
men with the AIDS wasting syndrome (1, Figure 1).
1. (Reproduced with permission from The Endocrine
Society - Grinspoon, et.al.: The Journal of Clinical Endocrinology
& Metabolism 1996;81:4051-8).
The wasting syndrome, defined as
weight less than 90% IBW and/or weight loss > 10% of preillness
baseline, is an AIDS defining complication of HIV disease and
is a common manifestation of advanced HIV disease. Wasting occurs
less often in the era of highly active antiretroviral therapy,
but reduced muscle and lean mass are seen in up to 20% of patients
treated with potent antiretroviral therapy.
Growth hormone has been shown,
at high doses (6 mg/day), to improve nitrogen balance and increase
lean body mass in HIV-infected patients with the wasting syndrome
(3). In a randomized, placebo controlled study, rhGH resulted
in an improvement of approximately 3.0 kg in lean body mass
as well as functional status (4). At the doses given, side effects
including fluid retention and arthralgias were not uncommon.
In contrast, standard replacement dosing for GH deficiency in
adults with hypothalamic-pituitary disorders is much lower and
initiated at doses as low as 0.002 mg/kg/day (equivalent to
0.14 mg/day in a 70 kg man). Given the physiologic resistance
to GH in the AIDS wasting syndrome, it remains unknown if therapy
with lower doses would be effective and better tolerated. The
use of supraphysiologic dosing in AIDS wasting also contrasts
to the potential uses of more physiologic dosing of GH in the
HIV lipodystrophy syndrome (see below).
At the current time, patients
experiencing wasting should be evaluated for malnutrition and
malabsorption as well as hypogonadism. Treatment with testosterone
in hypogonadal men with AIDS wasting has been shown to reduce
GH secretion, as a function of improved lean body mass (5).
Such experimental data suggests that testosterone, by improving
lean body mass, reverses, in part, the acquired resistance to
GH seen in the wasting syndrome. If no clear etiology exists
for wasting in HIV-infected patients, treatment with rhGH may
be considered in appropriate patients without known glucose
intolerance or specific contraindications to rhGH.
In contrast, to the wasting syndrome,
patients treated with highly active antiretroviral combination
therapy often demonstrate abnormal accumulations of fat, particularly
in the trunk and neck areas, in association with loss of subcutaneous
fat in the extremities and face (6). Early estimates suggest
that one half to three quarters of patients receiving highly
active antiretroviral therapy experience changes in fat redistribution,
known as the HIV lipodystrophy syndrome. The mechanisms of the
HIV lipodystrophy syndrome are not known. In non HIV-infected
patients, generalized obesity is associated with reduced GH
secretion, which may be a function of increased somatostatin
tone (7). Recent data suggest reduced GH concentration in HIV-infected
patients with fat redistribution (2, Figure 2).
2. (Reproduced with permission from The Endocrine
Society - Rietschel, et al: The Journal of Clinical Endocrinology
& Metabolism 2001; 86:504-10).
However, in contrast to the generalized
obesity in non HIV-infected patients, GH concentrations were
inversely related to excess abdominal visceral adiposity, but
not BMI itself. These data suggest that reduced GH concentrations
may be a function of the unique changes in body composition
HIV-infected patients. Such patients are unlikely to be GH deficient
in the classical sense, but may have a functional deficiency
in GH related to metabolic changes and increased visceral adiposity.
Growth hormone is lipolytic, and
has recently been considered for treatment of the changes in
fat redistribution associated with the lipodystrophy syndrome.
Preliminary studies using supraphysiologic doses of growth hormone
have resulted in a substantial reduction in visceral fat (8,
9). However, side effects, including worsening of glucose intolerance
and symptoms of GH excess, have been associated with a dose
of 6 mg/day. Further studies are now underway to determine if
lower, more physiologic doses of GH may be useful to reduce
excess visceral adiposity (10). It is possible that at sufficiently
low doses of GH, lipolytic effects resulting in improved insulin
sensitivity may outweigh direct negative effects of GH on insulin
sensitivity. Recombinant human GH is not FDA approved for, and
cannot be recommended for treatment of the HIV lipodystrophy
syndrome until further data become available.
HIV disease is associated with
a wide spectrum of abnormalities in GH secretion, including
increased GH secretion in the wasting syndrome and reduced GH
secretion in the lipodystrophy syndrome. Short-term recombinant
human GH has been used successfully at supraphysiologic doses
to increase lean body mass in patients with AIDS wasting. Studies
are currently underway to determine the effects of lower doses
of GH to reduce visceral adiposity in the HIV lipodystrophy
1. Grinspoon S, Corcoran C, Lee
K, et al.: Loss of lean body and muscle mass correlates with
androgen levels in hypogonadal men with acquired immunodeficiency
syndrome and wasting. J Clin Endocrinol Metab 1996; 81(11):
2. Rietschel P, Hadigan C, Corcoran C, Stanley T, Gertner J,
Grinspoon S: Assessment of growth hormone dynamics in the HIV
lipodystrophy syndrome. J Clin Endocrinol Metab 2001; 86:504-10.
3. Mulligan K, Grunfeld C, Hellerstein MK, Neese RA, Schambelan
M: Anabolic effects of recombinant human growth hormone in patients
with wasting associated with human immunodeficiency virus infection.
J Clin Endocrinol Metab 1993; 77(4): 956-62.
4. Schambelan M, Mulligan K, Grunfeld C, et al.: Recombinant
human growth hormone in patients with HIV-associated wasting.
A randomized, placebo-controlled trial. Serostim Study Group
[see comments]. Ann Intern Med 1996; 125(11): 873-82.
5. Grinspoon S, Corcoran C, Stanley T, Katznelson L, Klibanski
A: Effects of androgen administration on the growth hormone-insulin-like
growth factor I axis in men with acquired immunodeficiency syndrome
wasting. J Clin Endocrinol Metab 1998; 83(12): 4251-6.
6. Carr A, Samaras K, Burton S, et al.: A syndrome of peripheral
lipodystrophy, hyperlipidaemia and insulin resistance in patients
receiving HIV protease inhibitors. AIDS 1998; 12(7): F51-8.
7. Veldhuis JD, Iranmanesh A, Ho KK, Waters MJ, Johnson ML,
Lizarralde G: Dual defects in pulsatile growth hormone secretion
and clearance subserve the hyposomatotropism of obesity in man.
J Clin Endocrinol Metab 1991; 72(1): 51-9.
8. Engelson E, Kotler DP: Serono symposium on the HIV-associated
lipodystrophy syndrome, Phoenix, Arizona, 2000.
9. Wanke C, Gerrior J, Kantaros J, Coakley E, Albrecht M: Recombinant
human growth hormone improves the fat redistribution syndrome
(lipodystrophy) in patients with HIV. AIDS 1999; 13(15): 2099-103.
10. Lo JC, Mulligan C, Noor M, Schwartz J-M, Grunfeld C, Schambelan
M: The effects of recombinant human growth hormone on glucose
metabolism and body composition in HIV-positive subjects with
fat accumulation syndromes. 2nd International Workshop on Adverse
Drug Reactions and Lipodystrophy in HIV 2000; Toronto, Canada
(Supplement 5): 9.
11. Grinspoon S, Gelato M. The rational use of growth hormone
in HIV-infected patients. J Clin Endocrinol Metab (editorial).
Nicholas T. Zervas, M.D. Lectureship
Massachusetts General Hospital
May 21, 2002 at 12 Noon
Senior VP of Academic Affairs
Director of Burns and Allen Institute
Cedars Sinai Medical Center - UCLA School of Medicine
information call Ivy at 617-726-3870
Your patients may qualify for research
studies in the Neuroendocrine Clinical Center. We are currently
accepting the following categories of patients for screening
to determine study eligibility. Depending on the study, subjects
may receive free testing, medication and/or stipends.
men over age 65
- Evaluating the benefits
of testosterone and mild exercise on strength
diagnosed Acromegaly patients
- Evaluating preoperative
|HIV positive women
with weight loss or fat redistribution
- Evaluating testosterone
- Evaluation of bone loss
|Dr. Steven Grinspoon
|HIV positive men
and women with fat redistribution
- Novel dietary strategies
- Novel treatments to redistribute
- Determination of growth
|Dr. Steven Grinspoon
Dr. Colleen Hadigan
Dr. Gary Meininger
|Women with anorexia
||Dr. Anne Klibanski
women with prolactinomas
- Evaluating an alternative
to estrogen therapy
|Dr. Karen K. Miller
|Women with hypopituitarism,
- Testosterone replacement
|Dr. Karen K. Miller
- Evaluating the effects
of growth hormone on bone and muscle strength
|Dr. Wesley Fairfield
patients with inflammatory bowel disease
- Determination of growth
hormone administration on glucocorticoid myopathy
|Dr. Wesley Fairfield
with hypopituitarism (panhypopituitary or partial hypopituitarism)
- GH deficiency/replacement
Dr. Wesley Fairfield
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