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Acromegaly with Apparently Normal GH Secretion: Implications for Diagnosis and Follow-Up

Department of Internal Medicine (E.V.D., C.A.J., A.L.B.), Division of Endocrinology and Metabolism, Department of Neurosurgery (W.F.C., A.L.B.), and Pituitary and Neuroendocrine Center (C.A.J., W.F.C., A.L.B.), University of Michigan, and Veterans Affairs Medical Center (C.A.J., R.D.-F., A.L.B.), Ann Arbor, Michigan 48109

Address all correspondence and requests for reprints to: Ariel L. Barkan, M.D., 3920 Taubman Center, Ann Arbor, Michigan 48109-0354. E-mail: . abarkan{at}umich.edu

Abstract

The biochemical diagnosis of acromegaly is conventionally based on elevated plasma GH levels that fail to suppress after an oral glucose load. We studied 16 newly diagnosed patients with acromegaly with normal mean plasma GH but elevated age and gender-adjusted plasma IGF-I concentrations (476 ± 29 µg/liter, mean ± SE). Plasma GH was sampled every 10 min for 24 h, and an oral glucose tolerance test was performed. The control group included 46 healthy subjects. All patients had 24-h mean GH values that overlapped with those of the healthy controls. Mean plasma GH was less than 2.5 µg/liter in 12 patients. Patients had higher 24-h nadir GH values than healthy controls (P < 0.001). During the oral glucose tolerance test, nadir plasma GH was less than 1 µg/liter in eight patients. Plasma IGF-I normalized in 11 of 14 patients after transsphenoidal surgery. Four patients with normal IGF-I after transsphenoidal surgery were restudied. Mean and nadir GH decreased in all of them. In our experience in many patients with acromegaly, the diagnosis could be missed if only the existing GH-based criteria are used. Revised GH criteria in combination with plasma IGF-I should be used for the diagnosis and follow-up of acromegaly.

ACROMEGALY IS USUALLY caused by GH hypersecretion from a pituitary adenoma and is associated with increased morbidity and mortality rates. Traditionally, the diagnosis of acromegaly is made clinically and confirmed by elevated plasma GH levels that fail to suppress after an oral glucose challenge.

Over the years, the criteria for diagnosis and for biochemical cure of acromegaly have changed as more sensitive GH assays have become available. In the early 1980s a decrease of GH levels to less than 10 µg/liter was regarded as a successful outcome because such GH levels were thought to have a negligible metabolic effect (1). In addition, a decrease of GH to less than 2 µg/liter after oral glucose was considered normal (2, 3, 4). Currently, postglucose GH values less than 1 µg/liter or 24-h mean GH less than 2.5 µg/liter are recommended as criteria of normalcy (5), and spontaneous mean GH concentrations less than 2.5 µg/liter, the safe GH level, were suggested to result in normalization of mortality rates (3, 6, 7).

Most of the actions of GH are mediated through the circulating and locally produced IGF-I. Plasma IGF-I concentrations correlate better than plasma GH levels with the clinical manifestations of acromegaly (8), and successful treatment is associated with normalization of IGF-I concentrations (8, 9). As many as 50% of treated patients with plasma GH nadir less than 1 µg/liter after a glucose load have elevated serum IGF-I levels (10). Normalization of plasma IGF-I by the GH antagonist pegvisomant abolishes the clinical syndrome of acromegaly even in the presence of pathologically high GH concentrations (11). Nevertheless, GH-based criteria are still the most widely used parameters for the diagnosis and follow-up of acromegaly.

We present 16 newly diagnosed patients with clinically active acromegaly and abnormally elevated plasma IGF-I levels, who had 24-h mean plasma GH levels within the normal range for healthy individuals. Based on our experience, such patients may represent as many as 25% of all patients with acromegaly.

Patients and Methods

Patients

Between January 1996 and December 2000, we studied 16 patients, 6 women (mean age 61 yr, range 49–73 yr) and 10 men (mean age 50 yr, range 30–72 yr), who presented with clinical symptoms and signs of acromegaly, elevated age, and gender-adjusted plasma IGF-I levels but normal random (<5 µg/liter) and/or glucose-suppressed (<2 µg/liter) plasma GH levels. Most of them were referred to us by regional endocrinologists or neurosurgeons because of discrepant clinical and biochemical data or came to us for a second opinion having been told elsewhere that the diagnosis of acromegaly was excluded based on normal GH levels. None of the patients was previously treated for acromegaly. During the same period, an additional 47 patients with acromegaly and obviously elevated plasma GH levels underwent transsphenoidal surgery (TSS) at the University of Michigan.

Control groups

Normative plasma GH data were obtained from four groups of healthy individuals: 17 younger men with a mean age (±SD) of 25 ± 5 yr and mean body mass index (BMI) of 23.5 ± 1.2 kg/m²; 10 older men with a mean age 69 ± 7 yr and mean BMI 22.8 ± 3 kg/m²; 8 younger women with mean age of 25 ± 4 yr and mean BMI of 22.9 ± 2.9 kg/m²; and 11 older women with a mean age of 69 ± 4 yr and mean BMI of 24.5 ± 1.9 kg/m².

Protocol

The protocol was approved by the Institutional Review Board of the University of Michigan. Written informed consent was obtained from all patients and healthy subjects before any protocol procedures.

None of the subjects had renal disease, liver disease, or anemia. Each patient was admitted to the General Clinical Research Center of the University of Michigan. Three meals and a bedtime snack were served daily. During the study all subjects continued taking all their prescription medications including hormone replacement therapy where applicable. Plasma GH was measured every 10 min for 24 h (0700–0700 h). Subsequently, fasting morning plasma IGF-I was measured, and 100 g oral glucose was given at 0700 h with GH measured every 10 min until 0900 h. All patients had pituitary magnetic resonance imaging (MRI) scans. Fourteen patients subsequently underwent TSS.

Four patients were restudied under the same protocol 24–54 wk after TSS that resulted in normalization of plasma IGF-I. Healthy volunteers underwent blood sampling every 10 min for plasma GH for 24 h under similar conditions.

Assays

Plasma GH was measured by a chemiluminometric assay with a sensitivity of 0.01 µg/liter (Nichols Institute Diagnostics, San Juan Capistrano, CA). Plasma IGF-I was measured by a two-site immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX). The upper normal limit is 270 µg/liter for adult women and 318 µg/liter for adult men.

Data analysis

Mean 24-h plasma GH was calculated as the average of all plasma GH values over the 24-h sampling period. Trough 24-h plasma GH was calculated as the mean of the lowest 5% of the GH values over the 24-h sampling period. The maximum and nadir plasma GH values are defined as the highest and lowest GH value, respectively. The 24-h plasma GH profiles were also analyzed by Cluster Program version 6.00 (12), with cluster size 2 x 2 and t statistic of 3 and 2 for detecting significant increases and decreases in plasma GH, respectively. The minimum absolute peak value was set at 0.03 µg/liter to minimize the effect of assay variability (13). Pulse frequency is the number of GH pulses per 24-h as detected by Cluster. The nadir plasma GH during an oral glucose tolerance test (OGTT) is the lowest GH value during the 2-h period following the administration of oral glucose.

Statistical analysis was performed with Excel 97 (Microsoft Corp., Redmond, WA) and SAS 6.12 (SAS Institute, Inc., Cary, NC). Comparisons between GH secretion parameters in the patients and the control groups were done by ANOVA adjusting for age, gender, and BMI. The relationship between postglucose plasma GH nadir and other plasma GH parameters was examined by linear regression analysis. The comparisons of GH parameters before and after TSS were done by paired t test. P values less than 0.05 were considered as statistically significant.

Results

Patient characteristics

All patients had acromegalic features and/or acral enlargement and at least two of the following signs and symptoms: perspiration (63%), arthropathy (50%), headaches (31%), and carpal tunnel syndrome (31%). Snoring was the most frequent symptom reported by family members in 88% of patients. Two patients (13%) had diabetes mellitus and three patients (19%) had been previously diagnosed with sleep apnea syndrome. The duration of clinical acromegaly ranged between 5 and 30 yr.

Pituitary tumors were demonstrated by MRI scan in 15 of 16 patients. Ten patients had a microadenoma (maximum diameter 3–10 mm), and five patients had a pituitary macroadenoma (maximum diameter 15–30 mm). None had radiological evidence of tumor necrosis or hemorrhage. One patient with apparently normal pituitary MRI scan and another patient with a pituitary macroadenoma refused treatment.

Plasma IGF-I

All patients had elevated plasma IGF-I levels (Fig. 1). In the six female patients, plasma IGF-I was 457 ± 58 µg/liter (mean ± SE, range 345–726 µg/liter, normal 270 µg/liter). In the 10 male patients, mean plasma IGF-I was 487 ± 33 µg/liter (range 345–619 µg/liter, normal 318 µg/liter).

View larger version (23K): [in this window] [in a new window]   Figure 1. Plasma 24-h mean GH values in patients and controls overlap (A). Patients had significantly higher trough GH levels than controls (B). Plasma GH nadir values during OGTT in the 16 patients with acromegaly (C). Plasma IGF-I values of the 6 women and 10 men with acromegaly (D). The dashed lines represent the upper normal IGF-I limits for female and male adults. , Men; •, women.

All individual GH values in the patients were within the range observed in healthy controls (Fig. 1). There was complete overlap between the 24-h mean plasma GH values in the patients and the healthy subjects. All patients had 24-h mean GH less than 3.2 µg/liter (range 0.64–3.1 µg/liter) and 12 of 16 patients had 24-h mean GH less than 2.5 µg/liter. The maximum plasma GH values in the patients were also similar to those of the healthy controls (P = 0.85 after adjusting for gender, age, and BMI). In contrast, both the nadir and 24-h trough plasma GH values were significantly higher in the patients than in controls (P < 0.001 for both comparisons). However, in one female patient, even the nadir and trough GH values overlapped with those of healthy individuals.

The GH pulse frequency in the patients was slightly higher than in healthy controls (10.6 ± 2.6 vs. 9.3 ± 1.9 pulses/24 h, P = 0.048). However, there was complete overlap between the pulse frequency range in the patients and the healthy controls.

GH response to OGTT

In 8 of 16 patients, plasma GH was suppressed to less than 1 µg/liter following oral glucose load (Fig. 1). When the upper normal limit of 0.14 µg/liter, as determined by Freda et al. (10) and corrected for the assay standard to 0.21 µg/liter, was used, one female patient had plasma GH nadir below that value.

There was a strong correlation between the postglucose plasma GH nadir and the 24-h trough plasma GH (R² = 0.77, P < 0.0001) and nadir (R² = 0.84, P < 0.0001) plasma GH levels (Fig. 2).

View larger version (17K): [in this window] [in a new window]   Figure 2. Correlation between trough plasma GH during OGTT and trough plasma GH in the 16 patients.

Fourteen patients underwent TSS. In 13 patients a pituitary tumor was identified. The female patient with the lowest nadir (0.13 µg/liter), trough (0.15 µg/liter), and postglucose nadir (0.16 µg/liter) GH levels had a 3-mm pituitary lesion on MRI scan but no identifiable tumor during TSS. She underwent resection of one third of the pituitary gland based on the MRI data and normalized plasma IGF-I levels postoperatively. Overall, TSS resulted in normalization of plasma IGF-I in 11 of 14 patients and clinical improvement in 10 of 14 patients. One patient had a cardiorespiratory arrest several days after TSS and died. His postoperative IGF-I was not measured.

Pathology

A GH-producing pituitary adenoma was histologically and immunochemically identified in 13 of 14 patients. In the patient who underwent partial hypophysectomy with postoperative normalization of IGF-I, a small fragment of adenoma with positive stain for GH and prolactin was found microscopically.

GH secretion postoperatively (Figs. 3 and 4)

Four patients were restudied after successful TSS when all had normal age- and gender-adjusted plasma IGF-I levels. They all had experienced improvement of their symptoms of acromegaly. The 24-h mean plasma GH decreased in all four patients, by 23–97% (58 ± 18%, P = 0.071). The 24-h trough, nadir, and postglucose nadir GH decreased in all patients by 14–99% (P < 0.08 for all comparisons). The postglucose plasma GH nadir was above 0.3 µg/liter in one female patient who also had 24-h trough GH and nadir GH values above the maximum for the same gender and age control group. She subsequently developed abnormally elevated plasma IGF-I level without experiencing any worsening of her symptoms.

View larger version (20K): [in this window] [in a new window]   Figure 3. Decrease in 24-h mean plasma GH (A), trough plasma GH (B), plasma GH nadir during OGTT (C), and plasma IGF-I (D) in four patients with acromegaly studied after successful TSS.

View larger version (42K): [in this window] [in a new window]   Figure 4. Profiles of 24-h plasma GH of two patients with acromegaly before and after successful TSS. There is a marked decrease of the trough GH values.

Among a total of 63 patients with newly diagnosed and clinically active acromegaly, we identified 16 patients with 24-h mean plasma GH levels within the range observed in healthy controls. In 12 patients the diagnosis of acromegaly would have been missed if the criterion of 24-h mean plasma GH less than 2.5 µg/liter was used (5). In eight patients the postglucose plasma GH less than 1 µg/liter also excluded the diagnosis of acromegaly, according to the most recently agreed-upon diagnostic criteria (5), and in one patient the postglucose GH fell into a strictly defined normal range (10). Eight patients had both 24-h mean plasma GH less than 2.5 µg/liter and postglucose GH nadir less than 1 µg/liter. At the same time, all patients had abnormally elevated gender and age-adjusted plasma IGF-I levels. Therefore, the traditional GH-based diagnostic criteria cannot exclude the presence of a somatotroph adenoma. In these patients, plasma IGF-I was the most sensitive and reliable test for the diagnosis of acromegaly.

Cases of acromegaly with normal or minimally elevated GH levels but abnormally high circulating IGF-I levels have been reported before (8, 14, 15, 16). Brockmeier et al. (17) found eight patients (3.7%) with basal GH concentrations less than 5 µg/liter but with abnormal GH response to oral glucose (>2 µg/liter) among 216 patients with acromegaly. It has been suggested that enhanced tissue sensitivity to the normal GH milieu may explain the presence of the clinical syndrome of acromegaly in such patients (15). In our patients, removal of a GH-producing tumor was followed by normalization of IGF-I and clinical improvement and was always accompanied by a decline in GH levels. Thus, it was the true elevation of GH output (albeit within the population-defined normal range) that caused acromegaly in these patients.

Most previous studies (6, 18, 19) concluded that achieving a mean GH of 2.5 µg/liter reduces mortality risk to normal. In a recent study (20), the persistence of elevated IGF-I was associated with higher mortality risk regardless of GH levels. These studies, however, did not address the issue of morbidity in acromegaly. Whereas it is well known that successfully treated patients may still have clinical signs and symptoms of acromegaly, persistence of symptoms could be attributed to irreversibility of these manifestations rather than to continuous low-grade GH hypersecretion. Our data, in newly diagnosed patients before and after successful therapy, indicate that even minimal biochemical activity of acromegaly can be associated with a full-blown, severe clinical syndrome. The majority of our patients had improvement of headaches, arthralgias, acral enlargement, sweating, and sleep apnea after normalization of IGF-I by TSS. Therefore, it is important to identify and appropriately treat patients with features of acromegaly and elevated IGF-I levels even if their plasma GH concentrations are apparently normal.

Elevated trough and nadir GH concentrations were the most consistent characteristics of the GH profiles both in our series of newly diagnosed patients with acromegaly (Fig. 5) and treated patients (21). Continuous exposure of the liver and other tissues to even minimally elevated tonic GH levels is sufficient to increase IGF-I production into a supranormal range (22). It has been previously shown that in patients with active acromegaly plasma GH levels are consistently elevated with pronounced tonic component (23). Frequent blood sampling, as used in this study, is not practical in a clinical setting. However, there is an excellent correlation between the postglucose nadir GH and the spontaneous trough and nadir of GH profiles. Therefore, postglucose GH nadir is a good estimate of the trough GH concentrations over a 24-h period and could be a valuable diagnostic test if revised strict criteria are used. In addition, OGTT might be useful in detecting persistence of abnormal GH secretory pattern and increased risk of recurrence following TSS, as suggested by the clinical course of one of our patients. However, in another patient with a very small pituitary tumor, even the spontaneous and glucose-suppressed trough GH levels were within the normal range. The diagnosis of acromegaly in this patient was confirmed surgically by the presence of a cluster of GH-producing cells at the area of the pituitary gland that corresponded to MRI scan findings and by the postoperative normalization of IGF-I that was associated with dramatic clinical improvement. In this patient, IGF-I was clearly the most sensitive test for the diagnosis of active acromegaly.

View larger version (34K): [in this window] [in a new window]   Figure 5. Representative 24-h plasma GH profiles of three patients (left), compared with plasma GH profiles of healthy individuals of the same gender with similar mean plasma GH levels (right). In all three patients, GH secretion is tonic rather than pulsatile.

The patients with acromegaly and normal GH represented approximately 25% of all newly diagnosed patients with acromegaly seen in our institution over the past 5 yr. Many of these patients were referred to our institution because of the difficulty in making the diagnosis of acromegaly based on the available biochemical data. Therefore, the percentage of patients with normal mean GH values in the general population of patients with acromegaly must be lower. However, our data show that a proportion of patients with acromegaly might be undiagnosed when traditional GH-based criteria are used. In the past, many of these patients would have been labeled as having acromegaloidism, pachydermoperiostosis, burnt-out acromegaly, or nonfunctioning pituitary tumors. Our data show that the plasma GH criteria for the diagnosis and follow-up of acromegaly need to be redefined. The emphasis should be on the criteria for the interpretation of OGTT because the postglucose GH nadir is an excellent proxy for the trough and nadir GH levels that are consistently elevated in acromegaly. Meanwhile, serum IGF-I measurements could uncover cases of acromegaly that would otherwise be missed and consequently not treated. Making the diagnosis of acromegaly in these patients is important because normalization of plasma IGF-I, even in the presence of apparently normal GH levels, brings about improvement in the morbidity and, hopefully, the mortality of acromegaly.

Acknowledgments

Footnotes

This work was supported by Grant R0-1-DK38449 and the VA Research Service Merit Review Award (to A.L.B.) and Grant M01-RR00042 (General Clinical Research Center).

Abbreviations: BMI, Body mass index; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; TSS, transsphenoidal surgery.

Received August 14, 2001.

Accepted April 1, 2002.

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