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Original Studies |
Departments of Neurological Surgery (A.A., K.R.L., L.T.H., C.B.A., C.B.W.) and Medicine (J.B.T.), School of Medicine University of California, San Francisco, San Francisco, California 94143-0112
Address all correspondence and requests for reprints to: Aviva Abosch, Department of Neurological Surgery, University of California, San Francisco, 779 Moffitt Hospital, 505 Parnassus Avenue, San Francisco, California 94143-0112.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A variety of surgical approaches and medical therapies have been used to treat acromegaly, since the disease was first described by Pierre Marie in 1886 (6). The necessity of treatment to provide symptomatic relief, halt the progression of deformities, and decompress the sella turcica has long been recognized. More recently, various investigators have attempted to address the increased mortality rate associated with acromegaly (1, 7, 8, 9), and to correlate mortality with posttreatment GH levels (8). The pulsatile nature of daily GH secretion has led to interest in insulin-like growth factor I (IGF-I) as an index of therapeutic outcome (9), but data correlating IGF-I with mortality is, as yet, lacking.
The clinical behavior of GH-secreting pituitary tumors varies widely, but this variability has not yet provided clues that enable clinicians to predict which patients are likely to have a recurrence despite optimal therapy (5).
Although the remission rate in most surgical series has been considered high (10, 11), over the past decade, the definition of a cure has become increasingly stringent. The rationale for this comes from data suggesting that mortality rates remain higher than those of the normal population until the GH level drops below 2.5 ng/mL (8).
We report here the initial results and long-term outcome of a large series of acromegalic patients who underwent transsphenoidal resection of their GH-secreting pituitary tumors, and compare these results with those of other surgical series. We used univariate and multivariate analyses to determine which patient and/or tumor characteristics are predictive of initial disease remission, persistence, or ultimate recurrence following surgical resection of GH-secreting pituitary tumors. We also compared the long-term mortality rates observed in our series with those expected based on standard mortality tables, as well as with those recently reported in the literature (4, 7, 8).
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Subjects and Methods |
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We conducted a retrospective review of the hospital and office records of 254 consecutive patients with acromegaly who underwent transsphenoidal microsurgery for a GH-secreting adenoma at the University of California, San Francisco. Operations were performed exclusively by one surgeon (C.B.W.). The records of all patients meeting our study criteria (see below) who were operated on between January 1974 and September 1992 were reviewed. Information on perioperative GH levels was obtained from medical records.
Inclusion and exclusion criteria
Patients were included in this study if at least 2 yr had elapsed since the time of surgery to ensure a minimum of 2 yr of follow-up. The diagnosis of a GH-secreting adenoma was confirmed by the patient’s history, a physical examination to document excessive acral growth and characteristic coarsening of facial features, radiographic imaging (pneumoencephalography, computerized tomography, and, since 1985, magnetic resonance imaging), and histopathology. Surgical specimens since 1987 were routinely processed by immunohistochemistry using antibodies to GH.
Patients were excluded from the study if they were younger than 18 yr of age at the time of surgery, had undergone previous surgery for acromegaly, or if the diagnosis could not be verified by a preoperative GH level of >10 ng/mL or postoperative pathological confirmation consistent with a GH-secreting adenoma. Patients were also excluded if a postoperative GH level was not available. Older age and general medical status were not contraindications for transsphenoidal surgery so long as the patient was deemed able to tolerate general anesthesia. In fact, no patients diagnosed with acromegaly were rejected for surgery.
Clinical evaluation
Immediately before surgery, all patients were interviewed to obtain the details of their illness, and underwent a complete physical and neurological examination. Endocrinological evaluation of patients included pre- and postoperative determinations of basal (fasting) serum GH levels.
Neuroradiological evaluation
The method of preoperative radiographic diagnosis of pituitary tumors evolved over the 18-yr study period. Initial radiographic evaluation consisted of pneumoencephalography, which was superseded first by computerized tomography, and finally by magnetic resonance imaging in sagittal and coronal planes, with and without gadolinium enhancement.
Surgical procedure
All operations were performed by one surgeon (C.B.W.). With the aid of an intraoperative image intensifier, a sublabial transsphenoidal approach to the sella was used, as has been described previously (12). Once general endotracheal anesthesia was induced, lumbar subarachnoid drainage (LSAD) catheters were placed in most patients. Placement of LSADs allowed for the injection of saline into the subarachnoid space, to encourage descent of the tumor into the operative field. The exact strategy for each surgical resection was determined by the surgeon at the time of operation, and was based on tumor size, consistency, shape, and location. In each case, the goal was the selective removal of all tumor tissue, while sparing normal gland. Hydrocortisone was administered at the time of surgery, and the dose was tapered over 5 days postoperatively.
All patients underwent a postoperative examination before being discharged from the hospital, and had a follow-up examination or telephone interview 6 weeks after surgery. Patients who developed complications related to the surgery were evaluated at the onset of symptoms, with follow-up evaluations as mandated by the specific problem.
Classification of tumors
Tumors were classified based on neuroradiographic and
intraoperative findings of the degree of sellar destruction (grade) and
suprasellar extension (stage), according to the grading system
developed by Hardy (12) and modified by Wilson (13) (Table 1
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Interim clinical follow-up and GH data were obtained through the retrospective review of University of California, San Francisco hospital and departmental records. We also attempted to contact all patients living in the United States to obtain current clinical information by telephone interview and by laboratory testing. If a current address was not available, we attempted to locate the patient through relatives and referring physicians. Information was obtained regarding the clinical status of all patients contacted, including the presence or absence of acromegalic symptoms (e.g. headache, progression of deformities, visual field impairment, impotence, amenorrhea, osteoarthritis, and excessive sweating), current medical therapy, and any intervening therapies, such as another operation or radiation treatment. At the time of contact, patients were asked to arrange for a GH level determination at a central laboratory. If this was not possible, patients were asked to provide any available recent GH levels. Long-term follow-up consisted of GH levels being obtained or evidence of recurrence after the initial 30-day postoperative period. All patients were asked if they had taken hormone replacement medications, and if they had experienced symptoms of anterior pituitary dysfunction at any point following surgery.
Data collection
Data were recorded on a standard questionnaire form and entered into a computer database. Each questionnaire was reviewed for completeness and accuracy by one of two nurses (L.T.H. or C.B.A.) and one physician (J.B.T.).
Postoperative GH levels and pituitary function
Basal GH levels were measured before surgery and during the first 30 days after surgery. Follow-up GH assays were performed at a central lab whenever possible to minimize interlab variability (14). This entailed collection of serum specimens at local laboratories, which were then shipped on dry ice to a central lab for analysis.
Because there is no consensus about the optimal method for assessing cure in acromegalic patients, a subset of patients in the latter years of this study underwent oral glucose tolerance testing (OGTT), IGF-I, and basal GH level analysis at a central laboratory at the time of their long-term follow-up. We compared the follow-up basal GH levels with those obtained by OGTT, and compared each of these values with IGF-I levels. OGTT-derived GH levels <2 ng/mL were considered normal (15). Normal values for IGF-I are dependent on age and sex, and are not included here.
Postoperative sodium levels were also checked once on all patients, and until serum sodium levels reached normal in those patients with transient postoperative hyponatremia.
Definitions
Postoperative remission was defined as a GH level that was 
5
ng/mL within the first 30 days following surgery, and with no
subsequent GH levels that were greater than 5 ng/mL during this same
interval. Patients for whom no immediate postoperative GH levels were
available, but who on follow-up had normal GH levels, no clinical
symptoms of acromegaly, and no subsequent therapy, were also considered
to be in remission. Those patients who had a single GH level greater
than 5 ng/mL but who, on follow-up, had normal levels without
intervening therapy and no clinical symptoms, where also considered to
be in remission. Patients not meeting these criteria were considered to
have persistent disease. A recurrence was defined as an initial
remission followed by a rise in GH levels, recurrent symptoms, or
further therapy (Fig. 1).
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Statistical analysis
Logistic regression was used to analyze predictors of persistence. A backward, stepwise regression procedure was used for multivariate analyses. Results were considered statistically significant if the two-tailed P value was <0.05. For the purpose of statistical modeling, the logarithm of the maximum preoperative GH level was used to prevent overweighting of the few extremely high values.
Expected mortality rates by age and sex, divided into 5-yr age groups, were obtained from the U.S. Bureau of Census (16) and compared with those observed in this study. The expected mortality rates for patients in this study were determined based on person years of follow-up for each sex and age group. The difference between observed and expected rates was tested using the exact probabilities of the Poisson distribution (17).
Kaplan-Meier analysis was used to generate survival curves for the patients in remission, and for those with persistent disease (18), based on the initial postoperative outcome. Expected survival curves were generated based on standard life-table methods using 5-yr intervals.
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Results |
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The median age of our patients was 40 yr (range, 18–76 yr). There
were 149 (59%) male and 105 (41%) female patients. The median
duration of symptoms before surgery was 18 months (range, 1–480
months); radiation therapy had been administered to 14 patients before
surgery, but had ultimately failed to control their disease.
Bromocriptine or somatostatin analogs had been given to 37 patients
before surgery (Table 2).
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). Only
one patient had intradural, intracranial disease extension (Stage D),
42 (17%) had intracavernous disease extension (Stage E), and 22 (9%)
had diffuse destruction of the sellar floor (Grade IV). Morbidity and mortality from surgical procedure
A summary of postoperative complications is provided in Table 3. The major postoperative complication
rate was 8%, including 15 (6%) cases of hyponatremia, 5 (2%) cases
of CSF leak, 6 (2%) cases of meningitis (all of which resolved
promptly with intravenous antibiotics), and 4 (2%) cases of
hypopituitarism. There was a 28% rate of minor complications. There
were no known cases of clinically significant hemorrhage in the
postoperative period or deaths linked to surgery.
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Of the 254 patients with acromegaly who underwent transsphenoidal microsurgical resection of pituitary adenomas during the study period, 76% were found to be in remission postoperatively, and 24% had persistent disease.
Predictors of outcome
Univariate analysis revealed that younger age, larger tumor size,
higher stage and grade, and preoperative GH level were each
predictive (P = 0.01) of disease persistence.
Considering size alone, 75% of microadenomas (diameter <1 cm) and
71% of macroadenomas went into remission following surgery. In the
multivariate analysis, tumor size and patient age were no longer
predictive of persistence, but higher stage, higher grade, and higher
preoperative GH level all remained so (P < 0.01).
Thus, 73% of Grade IV tumors and 48% of Stage E tumors persisted,
whereas only 24% of Grade I and 30% of Stage 0 tumors persisted
(Table 4). For those patients in
remission postoperatively, 59% had a preoperative GH level of <30
ng/mL, whereas 36% had a preoperative GH level of 
30 ng/mL
(Table 5). Not surprisingly, 60% of
patients with Grade IV (diffuse destruction of the sellar floor or
distant spread) tumors had preoperative GH levels greater than 30
ng/mL. For patients with persistent disease after surgery, 30% had a
preoperative GH level of <30 ng/mL, whereas 69% had a preoperative GH
level of 30 ng/mL.
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Follow-up on patients with persistent disease
Of the 61 patients with persistent disease after surgery, 22
received radiation as their only additional therapy (Fig. 2). Of these, 19 were in remission by GH
criteria at follow-up, and 3 were in clinical remission but no GH
levels were obtained. Three patients with persistent disease underwent
a second transsphenoidal operation. In these cases, the surgeon judged
the second procedure likely either to result in remission, or to induce
temporary remission before radiation treatment. Thus, 1 patient
underwent a second transsphenoidal operation, after which GH levels
returned to normal. Two other patients underwent repeat transsphenoidal
operations followed by radiation therapy, after which GH levels
returned to normal. Of the patients who received postoperative medical
therapy, 2 were placed on bromocriptine, with 1 patient in remission
and 1 patient not in remission at follow-up. Five patients were treated
with postoperative octreotide, with 4 patients in remission and 1
patient not in remission at follow-up. Of the 9 patients who did not
receive further therapy after surgery, all had persistent disease by GH
levels at follow-up. Of the patients with persistent disease, a total
of 11 patients were lost to follow-up and 9 patients had died by the
time of follow-up.
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Of the 193 patients in initial remission, 13 underwent prophylactic postoperative irradiation for known residual tumor that was either inaccessible or adherent to surrounding structures. These 13 patients were excluded from further long-term remission analysis so as not to confound the analysis of results based solely on initial surgical outcome. These 13 patients were, however, included with the other remissions for the purposes of mortality analysis. Follow-up GH levels were unavailable on 51 of the 193 patients. This left 120 patients who remained in remission by GH criteria at long-term follow-up. Of note, 101 of these 120 patients had follow-up GH levels <2.5 ng/mL.
Nine of the 193 patients sustained disease recurrences. Five of these 9
patients then underwent further therapy, with 1 in clinical remission
(no GH level available) and 1 not in remission after irradiation and
treatment with somatostatin and parlodel. One patient went into
remission after irradiation and parlodel treatment alone, and 2
patients remain on somatostatin therapy, with GH levels <5 ng/mL (Fig. 1).
The median time until recurrence was 3.3 yr. A median of 95 months of follow-up was obtained for patients who had not received prophylactic radiation after surgery, and who remained in remission for the duration of follow-up (range = 1.5–251 months). Tumor size, stage, grade, and preoperative GH levels could not, however, be linked in a statistically meaningful way to disease recurrence, because the number of recurrences was too small (9/128).
OGTT and IGF-I levels
Of the patients with central laboratory values at follow-up who
were in clinical remission and had basal GH levels <2.5 ng/mL (n
= 97), 13% nonetheless had elevated IGF-I levels. Conversely, 5
patients with normal IGF-I levels at follow-up had elevated basal GH
levels. Of the patients who were in clinical remission and had OGTT
levels 2 ng/mL (n = 96), 10% had elevated IGF-I levels. These
patients did not receive additional treatment for their abnormal IGF-I
levels.
Mortality rates
Of the 193 patients in initial remission following surgery, 18
were out of the country, and 11 were lost to follow-up, leaving 164
(94%) for whom follow-up data were obtained. Twenty of these patients
had died, yielding a cumulative observed mortality rate for these
patients (Fig. 3A, solid line)
that did not differ significantly from the expected rate.
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). When these results were analyzed according to sex
(Table 6), the observed mortality rate
relative to the expected rate in men was 4.0 vs. 1.8,
indicating a trend towards increased mortality for male patients with
persistent disease. However, in female patients with persistent
disease, the increase in the observed rate relative to the expected
rate (5.0 vs. 1.1) was statistically significant (Table 6).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The definition of a biochemical cure of acromegaly has been
the subject of much controversy (9). Given that disease recurs in some
patients, albeit a small percentage of them, a successful outcome after
treatment is perhaps better described as remission. Throughout the
1970s and 1980s, a posttherapeutic GH level <5 ng/mL was felt to be
consistent with disease cure (11, 19, 20). According to this
definition, 76% of our patients would be considered to have an initial
biochemical remission. This rate compares favorably with those of other
series of acromegalic patients undergoing surgical treatment for their
disease (see Table 7), which range from
53% (12) to 81% (21). The major complication rate of 8% in our study
is nearly the same as the cumulative complication rate of 7% reported
by Ross and Wilson (11) in their review of the literature.
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Disease persistence
Previous attempts to correlate patient or tumor characteristics with clinical outcome have suggested that higher preoperative basal GH levels and larger tumor size are predictive of disease persistence after surgery (22). Other investigators have noted a correlation between younger patient age and higher pretherapy GH levels (24). Of the various patient and tumor characteristics investigated in our study, larger tumor size, higher stage and grade, and higher preoperative GH levels were all predictive of disease persistence, whereas sex, prior therapy, and symptom duration were not.
Bates and colleagues (8) found a highly significant correlation (P < 0.01) between pretreatment GH and posttreatment levels, suggesting that those patients with lower posttreatment GH levels tended to be those who had lower pretreatment levels. We have found a similar correlation, which implies that patients with a postoperative GH level <5 ng/mL may represent a subgroup of acromegalic patients with milder disease or with less invasive tumors.
Disease recurrence
The reported rates of disease recurrence after successful transsphenoidal surgery for acromegaly are low, ranging from 0–7% (11, 22, 25). However, many of the large surgical series have not reported long-term follow-up on GH levels; therefore, the rate of recurrence after surgery may be underestimated. The small number of recurrences in our study (9/128; 7%) precluded drawing conclusions about the predictive value of the patient and tumor characteristics studied. A better understanding of which patients are likely to suffer disease recurrence is needed so as to anticipate the therapeutic needs of this subset.
Overexpression of the GHRH gene has recently been linked to neoplastic progression and clinical aggressiveness of GH-secreting adenomas (5). It is conceivable that advances in our understanding of the molecular genetics of pituitary adenomas will enable us to determine which groups of patients will not be cured by surgery, either initially or in the long term, and to develop new treatment modalities.
Mortality rates among patients with disease persistence and remission
Acromegaly is associated with changes in lipoprotein metabolism, high fibrinogen levels (26), and an increase in mortality rates caused by cardiovascular events, stroke, and malignancies. Interventions that lower GH levels enough to alleviate or eliminate symptoms and reverse cosmetic deformities do not necessarily lower this increased mortality rate (4, 7).
Bates and colleagues (8) demonstrated in their retrospective analysis of 79 patients that mortality rates of acromegalic patients decreased to those of age- and sex-matched controls if posttherapy GH levels <2.5 ng/mL could be achieved. In their study, GH levels measured five times during waking hours were averaged, and the lowest average GH value obtained at any point during the follow-up period was used as the GH result. GH values >2.5 ng/mL but <5 ng/mL, however, did not result in mortality rates reaching those of the controls. In contrast to our study, most of the patients in the Bates study were treated with external beam radiotherapy with or without bromocriptine (n = 50). A smaller number of patients (n = 11) underwent surgical hypophysectomy for their disease, but all of these required additional treatment in the form of irradiation (n = 4) or bromocriptine (n = 7). Another difference is that we used a single, basal GH level, obtained during a discrete, 30-day postoperative period, as our GH result.
Given the differences in methods of GH assessment, treatment
modalities, and outcome between the Bates study and our own, it was
unclear whether the same stratification of mortality rate by
posttherapy GH levels would hold true. However, comparison of
mortality data in our study between the group of patients with GH <2.5
ng/mL (n = 105) and the group with GH 2.5 ng/mL but 5 ng/mL
(n = 51), did not indicate any survival benefit for the former
group.
Our study is the first surgical study to assess long-term mortality
rates among postoperative acromegalic patients. The mortality rate for
those patients in remission (GH 5 ng/mL) after surgery did not differ
significantly from the expected rate over time. Although GH assays
during the early years of this study did not permit quantification of
levels below 5 ng/mL, 119 of the patients in immediate postoperative
remission and 101 patients in long-term remission by study criteria had
GH levels that were <2.5 ng/mL.
GH levels and IGF-I
The optimal method for evaluating GH secretion is controversial (16, 20, 27, 28). Various investigators have advocated the use of fasting GH levels, mean GH values of a series collected over 24 h, GH nadir during the first 2 h following OGTT, or IGF-I levels to assess the outcome of treatment in acromegaly (9). Although we used single basal GH levels in our analysis, a mean GH value calculated from multiple samplings throughout a 24-h period is arguably more representative of disease status. Alternatively, IGF-I levels might be considered a truer reflection of disease status, because IGF-I synthesis is controlled by GH, but its serum concentration fluctuates far less (9, 29). As others have found (22), however, we too noted patients in whom IGF-I levels were well within the normal range, yet GH levels remained elevated. Clearly, a better understanding is needed of the functional relationship between the IGFs and GH secretion in acromegaly. Jenkins and colleagues (30) found a high correlation between basal GH levels and both IGF-I and the OGTT-derived GH nadir in their treated patients, which supports the validity of basal GH levels in assessing treatment outcome.
When we compared GH results obtained by OGTT with those obtained as basal levels, 97% of our patients who had basal GH levels <2.5 ng/mL also had OGTT-derived GH levels <2 ng/mL. This finding indicates that outcome assessment based on fasting, basal GH levels correlates well with GH levels determined by OGTT. In our study, neither GH determination by OGTT nor IGF-1 levels enhanced the information provided by basal GH testing.
Recommendations for clinical practice
In addition to deaths from vascular causes, patients with active
acromegaly are at higher risk of developing extrapituitary neoplasms
such as colorectal cancer (31) and melanocytic tumors of the eye
choroid (32). Our finding that mortality rates among acromegalic
patients in clinical remission following transsphenoidal surgery
decreased to those of the normal population argues for prompt therapy
aimed at lowering GH levels to below 5 ng/mL (or 10 mU/L). The high
percentage (69%) of patients with disease persistence who had
preoperative GH levels 30 ng/mL indicates that clinicians should be
ready to use additional modes of therapy for these patients, as
indicated by clinical outcome and laboratory follow-up.
In our study, a small subset of patients had normal GH levels at follow-up and clinical remission, but nonetheless had elevated IGF-I levels. We do not currently recommend further treatment for these patients. As the clinical significance of an elevated IGF-I level when the GH level is normal is unknown, neither the risk nor expense of further medical, radiation, or surgical treatment seems warranted.
Despite advances in radiotherapy and medical therapy for acromegaly, transsphenoidal microsurgery remains the most effective initial treatment for GH-secreting pituitary tumors (33, 34). In addition to providing immediate relief from the symptoms of a sellar mass, surgery also provides the most immediate and complete restitution of normal GH levels (35). There are currently no known medical therapies that provide this degree of biochemical control for most patients (36, 37), although relief of clinical symptoms can be rather substantial with octreotide therapy (25). Thus, from the standpoint of safe and immediate relief of clinical symptoms and of normalization of mortality risks, transsphenoidal surgery remains the optimal treatment for acromegaly.
Received March 9, 1998.
Revised May 28, 1998.
Accepted June 3, 1998.
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D. R. Clemmons and C. Strasburger Monitoring the Response to Treatment in Acromegaly J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5289 - 5291. [Full Text] [PDF]
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N. R. Biermasz, F. W. Dekker, A. M. Pereira, S. W. van Thiel, P. J. Schutte, H. van Dulken, J. A. Romijn, and F. Roelfsema Determinants of Survival in Treated Acromegaly in a Single Center: Predictive Value of Serial Insulin-Like Growth Factor I Measurements J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2789 - 2796. [Abstract] [Full Text] [PDF]
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 C. Schmid, P. Wiesli, R. Bernays, K. Bloch, J. Zapf, C. Zwimpfer, C. Ghirlanda, and M. Brandle Decrease in sE-Selectin after Pituitary Surgery in Patients with Acromegaly Clin. Chem., March 1, 2004; 50(3): 650 - 652. [Full Text] [PDF]
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 A. Colao, D. Ferone, P. Marzullo, and G. Lombardi Systemic Complications of Acromegaly: Epidemiology, Pathogenesis, and Management Endocr. Rev., February 1, 2004; 25(1): 102 - 152. [Abstract] [Full Text] [PDF]
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P. U. Freda, A. T. Nuruzzaman, C. M. Reyes, R. E. Sundeen, and K. D. Post Significance of "Abnormal" Nadir Growth Hormone Levels after Oral Glucose in Postoperative Patients with Acromegaly in Remission with Normal Insulin-Like Growth Factor-I Levels J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 495 - 500. [Abstract] [Full Text] [PDF]
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I. M. Holdaway, R. C. Rajasoorya, and G. D. Gamble Factors Influencing Mortality in Acromegaly J. Clin. Endocrinol. Metab., February 1, 2004; 89(2): 667 - 674. [Abstract] [Full Text] [PDF]
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 N. R. Biermasz, A. M. Pereira, M. Frolich, J. A. Romijn, J. D. Veldhuis, and F. Roelfsema Octreotide represses secretory-burst mass and nonpulsatile secretion but does not restore event frequency or orderly GH secretion in acromegaly Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E25 - E30. [Abstract] [Full Text]
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F. G. Barker II, A. Klibanski, and B. Swearingen Transsphenoidal Surgery for Pituitary Tumors in the United States, 1996-2000: Mortality, Morbidity, and the Effects of Hospital and Surgeon Volume J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4709 - 4719. [Abstract] [Full Text] [PDF]
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D. R. Clemmons, K. Chihara, P. U. Freda, K. K. Y. Ho, A. Klibanski, S. Melmed, S. M. Shalet, C. J. Strasburger, P. J. Trainer, and M. O. Thorner Optimizing Control of Acromegaly: Integrating a Growth Hormone Receptor Antagonist into the Treatment Algorithm J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4759 - 4767. [Abstract] [Full Text] [PDF]
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Z.'e. Hochberg, K. Pacak, and G. P. Chrousos Endocrine Withdrawal Syndromes Endocr. Rev., August 1, 2003; 24(4): 523 - 538. [Abstract] [Full Text] [PDF]
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P. De, D. A. Rees, N. Davies, R. John, J. Neal, R. G. Mills, J. Vafidis, J. S. Davies, and M. F. Scanlon Transsphenoidal Surgery for Acromegaly in Wales: Results Based on Stringent Criteria of Remission J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3567 - 3572. [Abstract] [Full Text] [PDF]
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J. J. Kopchick, C. Parkinson, E. C. Stevens, and P. J. Trainer Growth Hormone Receptor Antagonists: Discovery, Development, and Use in Patients with Acromegaly Endocr. Rev., October 1, 2002; 23(5): 623 - 646. [Abstract] [Full Text] [PDF]
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S. Melmed, F. F. Casanueva, F. Cavagnini, P. Chanson, L. Frohman, A. Grossman, K. Ho, D. Kleinberg, S. Lamberts, E. Laws, et al. Guidelines for Acromegaly Management J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4054 - 4058. [Full Text] [PDF]
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A. C. F. Costa, A. Rossi, C. E. Martinelli Jr., H. R. Machado, and A. C. Moreira Assessment of Disease Activity in Treated Acromegalic Patients Using a Sensitive GH Assay: Should We Achieve Strict Normal GH Levels for a Biochemical Cure? J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3142 - 3147. [Abstract] [Full Text] [PDF]
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C. Parkinson, W. D. J. Ryder, and P. J. Trainer The Relationship between Serum GH and Serum IGF-I in Acromegaly Is Gender-Specific J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5240 - 5244. [Abstract] [Full Text] [PDF]
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J. Kreutzer, M. L. Vance, M. B. S. Lopes, and E. R. Laws Jr. Surgical Management of GH-Secreting Pituitary Adenomas: An Outcome Study Using Modern Remission Criteria J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4072 - 4077. [Abstract] [Full Text] [PDF]
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S. Melmed CLINICAL PERSPECTIVE: Acromegaly and Cancer: Not a Problem? J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2929 - 2934. [Full Text] [PDF]
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G. A. Kaltsas, A. M. Isidori, D. Florakis, P. J. Trainer, C. Camacho-Hubner, F. Afshar, I. Sabin, J. P. Jenkins, S. L. Chew, J. P. Monson, et al. Predictors of the Outcome of Surgical Treatment in Acromegaly and the Value of the Mean Growth Hormone Day Curve in Assessing Postoperative Disease Activity J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1645 - 1652. [Abstract] [Full Text]
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A. J. van der Lely, A. F. Muller, J. A. Janssen, R. J. Davis, K. A. Zib, J. A. Scarlett, and S. W. Lamberts Control of Tumor Size and Disease Activity during Cotreatment with Octreotide and the Growth Hormone Receptor Antagonist Pegvisomant in an Acromegalic Patient J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 478 - 481. [Abstract] [Full Text]
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N. R. Biermasz, H. van Dulken, and F. Roelfsema Ten-Year Follow-Up Results of Transsphenoidal Microsurgery in Acromegaly J. Clin. Endocrinol. Metab., December 1, 2000; 85(12): 4596 - 4602. [Abstract] [Full Text]
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G. Barrande, M. Pittino-Lungo, J. Coste, D. Ponvert, X. Bertagna, J. P. Luton, and J. Bertherat Hormonal and Metabolic Effects of Radiotherapy in Acromegaly: Long-Term Results in 128 Patients Followed in a Single Center J. Clin. Endocrinol. Metab., October 1, 2000; 85(10): 3779 - 3785. [Abstract] [Full Text]
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N. R. Biermasz, H. van Dulken, and F. Roelfsema Long-Term Follow-Up Results of Postoperative Radiotherapy in 36 Patients with Acromegaly J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2476 - 2482. [Abstract] [Full Text]
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A. Giustina, A. Barkan, F. F. Casanueva, F. Cavagnini, L. Frohman, K. Ho, J. Veldhuis, J. Wass, K. von Werder, and S. Melmed Criteria for Cure of Acromegaly: A Consensus Statement{dagger} J. Clin. Endocrinol. Metab., February 1, 2000; 85(2): 526 - 529. [Abstract] [Full Text]
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M. R. DRANGE, N. R. FRAM, V. HERMAN-BONERT, and S. MELMED Pituitary Tumor Registry: A Novel Clinical Resource J. Clin. Endocrinol. Metab., January 1, 2000; 85(1): 168 - 174. [Abstract] [Full Text]
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 N.J.L. Gittoes, M.C. Sheppard, A.P. Johnson, and P.M. Stewart Outcome of surgery for acromegaly--the experience of a dedicated pituitary surgeon QJM, December 1, 1999; 92(12): 741 - 745. [Abstract] [Full Text] [PDF]
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N. R. Biermasz, H. van Dulken, and F. Roelfsema Direct Postoperative and Follow-Up Results of Transsphenoidal Surgery in 19 Acromegalic Patients Pretreated with Octreotide Compared to Those in Untreated Matched Controls J. Clin. Endocrinol. Metab., October 1, 1999; 84(10): 3551 - 3555. [Abstract] [Full Text] [PDF]
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 R N Clayton, P M Stewart, S M Shalet, and J A H Wass Pituitary surgery for acromegaly BMJ, September 4, 1999; 319(7210): 588 - 589. [Full Text]
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S. Melmed Tight Control of Growth Hormone: An Attainable Outcome for Acromegaly Treatment J. Clin. Endocrinol. Metab., October 1, 1998; 83(10): 3409 - 3410. [Full Text]
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