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Original Studies |
Departments of Molecular and Clinical Endocrinology and Oncology (A.C., D.F., P.M., B.M., G.L.), Neurosurgery (P.C., A.F., E.d.D.), and Pathology (M.L.d.B.D.C., A.M., A.C.), Federico II University, Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Via A. Manzoni 150, 80123 Naples, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Fifty-nine patients with acromegaly who were undergoing surgical treatment were studied randomly before surgery; 37 patients were untreated, and 22 were treated with OCT at doses ranging 150–600 µg/day for 3–6 months. At study entry, untreated and OCT-treated patients had similar circulating GH and insulin-like growth factor I (IGF-I), glucose, and cholesterol levels as well as prevalence of overt diabetes mellitus, hypertension, and ECG abnormalities. In untreated and OCT-treated patients, respectively, radiological imaging documented microadenoma in 0 and 1, intrasellar macroadenoma in 10 and 6, intra- and suprasellar macroadenoma in 18 and 11, invasive macroadenoma in 9 and 4 patients.
Before surgery, serum GH and IGF-I levels significantly decreased
in the 22 OCT-treated acromegalics, and in 5 of them, a significant
shrinkage was documented. ECG abnormalities disappeared in 7 of 11
(63.6%) OCT-treated patients. In 3 of the 7 patients with diabetes
mellitus, treatment with OCT together with low carbohydrate intake
normalized blood glucose levels, whereas in 2 patients, insulin could
be replaced by oral antidiabetics, and in 2 patients, the insulin dose
was reduced. Presurgical blood glucose, total cholesterol and
triglyceride levels, as well as systolic (145.2 ± 3.4
vs. 132.9 ± 2.5 mm Hg; P <
0.01) and diastolic (94.3 ± 1.7 vs. 84.3 ±
1.6 mm Hg; P < 0.001) blood pressure levels were
significantly higher in untreated than in OCT-treated patients. Two
weeks after surgery, circulating GH and IGF-I levels were normalized in
11 untreated (29.7%) and 12 OCT-treated (54.5%) patients
(P < 0.005, by 
2 test).
Macroscopically, no difference was found between untreated and
OCT-treated adenomas, whereas at pathology, a significant increase in
cellular atypia (31.6% vs. 19.2%;
P < 0.05) was found in OCT-treated adenomas. One
patient in the untreated group died from cardiorespiratory arrest
during the early postoperative period. Finally, the average duration of
hospitalization after operation was longer in untreated than in
OCT-treated patients (8.6 ± 0.7 vs. 5.6 ±
0.5 days).
We conclude that a 3- to 6-month treatment with OCT before surgery for GH-secreting adenoma improved clinical conditions and surgical outcome and reduced the duration of hospitalization after operation.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The question of whether preoperative OCT therapy can improve the final outcome of surgery in acromegaly is still open, as no definitive data have been reported (6, 7, 8, 9, 10). In fact, a beneficial effect was reported on surgical outcome due to the finding that OCT caused significant tumor shrinkage (6, 7, 8, 9) and that OCT-treated tumors were conspicuously soft and well delineated from the remaining normal pituitary (6, 7). By contrast, in a controlled study to examine the morphological features of GH-secreting pituitary adenomas after OCT treatment, no consistent changes were detected in those adenomas preoperatively treated with OCT compared to untreated ones (10). Although OCT treatment has been shown to significantly improve glucose tolerance (1, 2, 3, 4) and cardiac abnormalities (11), which may affect the safety of anesthesiological procedures and the recovery after surgery, this aspect has not been investigated to date in acromegalics.
The aim of this retrospective study was to report the effects of a 3- to 6-month presurgical treatment with OCT in acromegaly, focusing on presurgical cardiological and metabolic conditions as well as GH/insulin-like growth factor I (IGF-I) normalization, tumor removal, and recovery time after operation.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Among 105 acromegalic patients undergoing neurosurgical treatment, complete records of clinical, biochemical, hormonal, and radiological assessment as well as microscopic and macroscopic findings were available for statistical analysis in 59 patients (32 females and 27 males, aged 18–66 yr). The protocol was performed in accordance within the guidelines of the Declaration of Helsinki for human experimental studies. Informed consent, orally and in the presence of a third person, was obtained from all patients before they entered the study. Acromegaly was diagnosed on the basis of progressive acral enlargement, high serum GH levels not suppressible below 2 µg/L by glucose administration (determined by oral glucose tolerance test), and high plasma IGF-I levels. Diabetic patients were not subjected to oral glucose tolerance test. None of the 59 patients received radiotherapy before surgery. Computed tomography (CT) and/or magnetic resonance imaging (MRI) revealed microadenoma in 1, intrasellar macroadenoma in 16, intra- and suprasellar macroadenoma in 29, and invasive macroadenoma in 13 patients. Overt diabetes mellitus (fasting glucose levels >140 mg/dL) was diagnosed in 21 patients, and reduced glucose tolerance (blood glucose levels >200 mg/dL 1 h after glucose load) was diagnosed in 13 patients. Hypertension (diastolic blood pressure values >95 mm/Hg at rest) was diagnosed in 22 patients.
Study protocol
Randomly before surgery, 37 of 59 patients were not treated with
drugs acting on the GH-IGF-I axis, whereas the remaining 22 patients
were treated with OCT for 3–6 months. OCT was administered sc at a
dose of 150 µg/day in 2 patients; this dose was increased up to 300
µg/day in 18 patients and up to 600 µg/day in 2 patients to
suppress circulating GH and IGF-I levels. Clinical, hormonal, and
radiological features at study entry for the 2 groups of patients are
shown in Table 1
. At diagnosis, all of
the patients were subjected to a complete clinical evaluation,
including electrocardiogram (ECG); blood pressure measurement; routine
blood and urine analysis; thyroid, gonadal, and adrenal hormone
profile; and CT and/or MRI study of the sellar region. Before surgery,
follow-up included the assay of circulating GH and IGF-I monthly in
OCT-treated patients and quarterly in untreated subjects; the clinical
evaluation and routine blood and urine analysis were repeated quarterly
before surgery in all patients. In patients with diabetes and
hypertension clinical, biochemical and hormonal evaluation was carried
out every 30–60 days before surgery to monitor the effects of
different treatments on these items. After surgery, clinical,
biochemical, and hormonal assessments were performed twice after 1–2
weeks, then after 1–3 months, and quarterly for the first year. The
circulating GH, IGF-I, glucose, total cholesterol, and triglyceride
levels shown in the present study refer to the assay performed at study
entry, 1–7 days before surgery to indicate the presurgical assessment,
and 1–2 weeks after surgery to indicate the postsurgical assessment.
Circulating GH and IGF-I were assayed in the morning after an overnight
fast.
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CT scan was carried out, before and after iv infusion of contrast medium, by a third generation scanner with 3.5-s acquisition time, 1.5-mm thickness axial and coronal sections, and scout-views. MRI (1.0 Tesla, Magnetom, Siemens, Germany) was carried out with T1-weighted SE sequences and 3-mm slides in coronal and sagittal sections before and after contrast enhancement with gadolinium-DTPA. In OCT-treated patients, CT scan and/or MRI were repeated after 3–6 months to evaluate tumor shrinkage, whereas in untreated patients, the radiological study was repeated only if surgery was delayed more than 3 months. A tumor reduction of at least 30% of the maximal tumor diameter compared to the baseline size was considered significant (12). After surgery, CT and/or MRI were repeated within 3–6 months and then after 1 yr.
Surgical approach
All 59 patients were operated on by expert neurosurgeons (P.C., E.d.D) using a transsphenoidal trans-rino-septal approach. The goal of the surgery was the complete selective removal of the adenoma. During the operation, the surgeons paid particular attention to the relative ease or difficulty in removing the tumor (easy, moderately difficult, or difficult), the consistency of the tumor (soft, firm, or hard), the separation of normal from pathological tissue (easy, moderately difficult, or difficult), and invasion of the tumor to normal structures (none, local, or diffuse).
Morphological studies
All examinations were performed separately by two expert pathologists (M.L.d.B.D.C. and A.M.) who were blind with respect to previous treatment of patients. For light microscopy, small pieces of tumor tissue were fixed in 10% buffered formalin and embedded in paraffin. Sections were stained with hematoxylin-eosin to establish histological diagnosis. For immunocytochemistry, the peroxidase-antiperoxidase technique was used. Paraffin sections 4–6 µm in thickness were immunostained for GH, PRL, LH, FSH, TSH, and ACTH. The dilution of primary antibodies varied from 100–640; the duration of exposure to the primary antibodies was 30 min. Negative controls were performed by incubating the sections with the same dilution of normal rabbit serum as those used for the corresponding specific antiserum. For electron microscopy, small pieces of tumor tissue were fixed in 4% glutaraldehyde, osmicated, dehydrated, and embedded in Epon. Ultrathin sections stained with uranyl acetate and lead citrate were analyzed using a EM 109 Zeiss microscope (Zeiss, New York, NY).
Assays
Serum GH and plasma IGF-I levels were assayed by RIA and immunoradiometric assay using commercially available kits [Radim (Pomezia, Italy) and Eurogenetics (Turin, Italy), respectively]. The normal ranges were: GH, 1–5 µg/L in males and 1–10 µg/L in females; and IGF-I, 90–210 µg/L for adults. Blood glucose, cholesterol, and triglyceride levels were routinely assayed by standard methods in our laboratory. For the purposes of this study, GH levels were considered normalized when they were lower than 5 µg/L in both sexes.
Statistical analysis
Data are reported as the mean ± SEM. The
significance was set at 5%. The effect of OCT treatment on surgical
outcome was analyzed using the 2 test. After surgery,
the cure was defined as a decrease in serum GH levels below 5 µg/L
and normalization of plasma IGF-I. The difference between the two
groups (untreated and OCT-treated patients) was evaluated using
two-tailed ANOVA.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Baseline GH and IGF-I levels were similar in untreated and
OCT-treated patients, as shown in Table 1
. Treatment with OCT for 3–6
months caused significant decreases in serum GH (from 71.4 ± 15.8
to 5.5 ± 1 µg/L) and IGF-I (from 518 ± 60 to 223.5
± 18.8 µg/L) in the 22 treated acromegalics, whereas no significant
change in circulating GH and IGF-I levels was observed in untreated
acromegalics (Fig. 1). In detail, 13 of
22 patients normalized GH, and 12 of them normalized both GH and IGF-I
levels after treatment with OCT at the dose of 150–600 µg/day for
3–6 months. Between 1–2 weeks after surgery, GH normalization
occurred in 15 OCT-treated patients (68.2%) and 13 untreated patients
(35.1%), whereas both GH and IGF-I normalized in 12 OCT-treated
(54.5%) and 11 untreated (29.7%) patients. In addition, in 5 of the
remaining 10 patients in the OCT-treated group (50%) and in 10 of the
remaining 26 patients in the untreated group (38.4%), serum GH levels
were decreased below 10 µg/L after surgery. Surgical outcome in
OCT-treated patients was significantly improved (P <
0.005, by 2 test), although postoperative GH and IGF-I
levels, considered as a whole, were similar in OCT-treated and
untreated patients (Fig. 1). One year after surgery, circulating GH and
IGF-I levels remained in the normal range in the 23 cured patients.
After surgery, radiotherapy was necessary in 2 OCT-treated and 10
untreated patients among the 36 uncured patients.
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At diagnosis, ECG abnormalities, reported in detail in Table 1,
were documented respectively in 19 untreated patients (51.3%) and 11
OCT-treated patients (50%), whereas hypertension was found in 14
untreated patients (37.8%) and 8 OCT-treated patients (36.4%). OCT
treatment for 3–6 months normalized ECG records in 7 of 11 patients.
In particular, both sinusal arrhythmia and ventricular or
supraventricular tachycardia disappeared in the 6 patients who
presented this sign before treatment. In another patient, the
abnormalities of the repolarization phase disappeared. In the remaining
4 patients, ECG records documented abnormalities of the repolarization
phase, probably due to left ventricular hypertrophy, which were not
significantly modified by the 3- to 6-month treatment with OCT. In
addition, a significant decrease in both systolic and diastolic blood
pressure was found in 5 of 8 hypertensive patients during long term OCT
treatment without any change in the therapeutic schedule of
hypertension. When considered as a whole, blood pressure values were
significantly lower in OCT-treated patients than in untreated patients
both before and after surgery (Fig. 2).
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At diagnosis, overt diabetes mellitus was recorded in 14 of 37
untreated patients (37.8%) and 7 of 22 OCT-treated patients (31.8%).
Insulin treatment was required in 9 untreated patients and 4
OCT-treated patients, whereas oral glucose-lowering drugs were given to
5 untreated and 3 OCT-treated patients, respectively. After long term
OCT treatment at the dose of 150–600 µg/day, oral glucose-lowering
drugs were withdrawn in all 3 patients because blood glucose
normalization was obtained using low carbohydrate intake alone.
Moreover, after OCT treatment in 2 of 4 patients, insulin treatment was
replaced with oral glucose-lowering drugs, whereas the insulin dose was
reduced in the remaining 2 patients. When considered as a whole, in
OCT-treated patients, blood glucose levels were significantly lower
than those in untreated patients before surgery and remained low at the
first follow-up after surgery (Table 2).
High total cholesterol and triglyceride levels were found in 7 and 4
OCT-treated patients and in 15 and 14 untreated patients. OCT treatment
for 3–6 months together with a hypolipidic regimen normalized total
cholesterol and triglyceride levels in all but 1 patient. Circulating
total cholesterol and triglyceride levels normalized after the
hypolipidic regimen alone in 6 of 15 patients. When considered as a
whole, total cholesterol and triglyceride levels in OCT-treated
patients were significantly lower than those in untreated ones before
surgery and remained low at the first follow-up after surgery (Table 2). However, it should be pointed out that blood triglyceride levels
were significantly higher in untreated than OCT-pretreated patients at
diagnosis (Table 2).
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Before surgery, CT and/or MRI scans documented a significant
shrinkage in 5 of 22 OCT-treated patients and in none of the untreated
patients. Macroscopically, no difference was found between OCT-treated
and untreated adenomas, as soft tissue was found in 43.2% and 45.4%,
firm tissue in 37.8% and 36.4%, and hard tissue in 18.9% and 18.2%
of the cases, respectively. The tumors were easily removed in most
cases (83.2% vs. 81.8%), and invasion of the surrounding
tissues was noticeable in 27% and 22.7% of OCT-treated and untreated
groups, respectively. At pathology, a significant increase in cellular
atypia was found in OCT-treated adenomas compared to untreated ones
(31.6% vs. 19.2%; P < 0.05; Fig. 3). The most striking feature was a
marked and variable cell enlargement, pertaining to both the nucleus
and the cytoplasm in most cases. The enlarged nucleus was often
eccentric, irregular in outline, and markedly hyperchromatic (Fig. 4). In some cells the chromatin granules
were coarse, the chromatin texture was lost, and the nucleus appeared
glassy. A chromocenter and/or 1–2 nucleoli were often in evidence and
sometimes very large (Fig. 4). Occasionally, multinucleated cells with
some variability in the size of the component nuclei were noticed. No
significant difference in the other parameters was found.
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One man, 34 yr old, in the untreated group died from cardiorespiratory arrest 20 h after operation. The entire duration of hospitalization after surgery was significantly shorter in OCT-treated patients than in untreated ones (5.6 ± 0.5 vs. 8.6 ± 0.7 days; P < 0.002). The time of hospitalization ranged between 4–20 days in the untreated group and between 3–13 days in the OCT-treated group. The motivations of the long term hospitalization were more frequently ventricular and supraventricular tachycardia in 5 patients who required careful monitoring of cardiac function before discharge and respiratory impairment with sleep apnea in 6 patients. In 2 of 37 patients in the untreated group, the duration of hospitalization was prolonged due to respiratory infections that required high dose antibiotics. After surgery, in 2 of 37 untreated patients, a 3-day stay in the intensive care unit was required because of the occurrence of runs of ventricular extrasystoles.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Another point that should not be disregarded is that pretreatment with OCT significantly improved the final outcome of surgery in our patients. This result was in agreement with the findings of some previous studies (6, 7, 8, 9), although no controlled study has been reported to date on this issue. In fact, some studies pointed out that significant tumor shrinkage occurs during OCT treatment in approximately half of the patients, with an apparent remission rate higher in treated than in untreated patients (6, 7, 8, 9). In the present study, tumor shrinkage occurred in a lower percentage of patients (22.7%), as the threshold of a 30% reduction in the maximal tumor diameter can be considered rather restrictive. As the present study reported a retrospective analysis, the data on the improvement of surgical outcome should be considered with caution. In fact, after surgery, although the number of subjects who had normalization of circulating GH and IGF-I levels was higher in OCT-treated than untreated patients, the average circulating GH and IGF-I levels were similar in both groups of patients. It should also be noted that the number of patients achieving postsurgical GH values below 10 µg/L was higher in the OCT-pretreated than in the untreated group (50% vs. 38.4%). This result can also be considered of benefit, as it is generally accepted that the lower basal hormone levels are, the easier hormone normalization is achieved (12).
In line with another recent report (10), no striking morphological alterations were found in GH-secreting adenomas associated with OCT treatment, except for the presence of varying degrees of cellular atypia. As cellular atypia of OCT-treated adenomas resembled that observed in chemotherapy-treated malignancies (20), a possible antimitotic effect of OCT is arguable. In fact, the antimitotic effect of OCT, probably mediated by somatostatin receptor subtype 5 (4), is dissociated from the antisecretive effect (21). However, treatment with OCT for 3–6 months at a dose of 150–600 µg/day did not improve softness or easy removal of the somatotroph adenomas analyzed in the present study, in line with a previous observation (10).
In conclusion, a short term treatment with OCT before surgery improved clinical and metabolic conditions in acromegaly. This occurrence appeared to limit the anesthesiological risk linked to metabolic and cardiac impairment in these patients and reduced the period of hospitalization after operation. This result produces a better cost/benefit ratio; in fact, the present cost for OCT treatment at a dose of 300 µg/day for 3 months is $1950, which is not dramatically different from the cost of 3-day hospitalization in the Neurosurgical Unit ($1160). It should also be considered that in 25% of pretreated patients (considered as the difference between 54.5% and 29.7% of surgery success rate in the two groups of patients), hormone normalization required no further treatment after surgery.
Received March 31, 1997.
Revised June 4, 1997.
Accepted June 18, 1997.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), in the period
immediately before surgery (
), and 10–15 days after surgery
(
) in 37 untreated and 22 OCT-treated
acromegalics.
