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Department of Medicine, Columbia College of Physicians and Surgeons, New York, New York 10032
Address all correspondence and requests for reprints to: Pamela U. Freda, M.D., Department of Medicine, Columbia College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: puf1{at}columbia.edu.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Little is known about the physiology of ghrelin secretion in acromegaly. Some recent data have suggested that ghrelin levels are lowered in patients with active acromegaly (12), and some, but not all, evidence indicates that circulating concentrations of GH and/or IGF-I could influence ghrelin secretion (13, 14, 15, 16, 17, 18). Increasing evidence also suggests that insulin may be an important regulator of ghrelin secretion (9) and, thus, hyperinsulinemia, a common metabolic abnormality in acromegaly, could be an important determinant of ghrelin secretion in acromegaly. Recent studies have also shown that octreotide, which is known to suppress other gastrointestinal peptides, could suppress gastric ghrelin secretion in acromegaly (17).
Because changes of circulating ghrelin levels could be relevant to body composition changes in acromegaly, further investigation of ghrelin physiology and the potential dysregulation of ghrelin secretion in acromegaly was warranted. To examine circulating ghrelin levels in active acromegaly and the potential effects of therapy on these levels, we have studied fasting and glucose-suppressed serum ghrelin levels in patients with acromegaly, both before and after surgical or long-acting octreotide therapy.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We studied two groups of patients with active acromegaly
Group I (surgical therapy). Nine newly diagnosed patients with acromegaly were studied both preoperatively and after transsphenoidal surgery (mean time since surgery, 10 months; range, 2–24 months). In this group were five women and four men (mean age, 43 yr; range, 16–57 yr). All patients had pathological confirmation of a GH-secreting pituitary tumor. Two patients in this group had primary thyroid disease and were on stable doses of L-thyroxine replacement. Three other patients had type II diabetes mellitus before therapy and were being treated with glipizide, metformin, or rosiglitazone maleate. Diabetes resolved in two patients after therapy (no. 9 and 17). Mean body mass index (BMI) of the patients before therapy was 27.5 kg/m2.
Group II (long-acting octreotide). Ten patients with active acromegaly were studied before and during long-acting octreotide (Sandostatin LAR, Novartis Pharmaceuticals, East Hanover, NJ) therapy. In this group were six women and four men (mean age, 43 yr; range, 25–59 yr). Mean BMI of the patients before therapy was 28.9 kg/m2. Of the 10 patients, 7 had previously undergone transsphenoidal surgery with confirmation of a GH-secreting tumor between 3 and 84 months before beginning Sandostatin LAR (mean, 27 months). Of these patients, four received other medical therapy postoperatively, including cabergoline (patients 11, 12, 14, and 19) and pegvisomant (patients 12, 14, and 19). Two other patients had previously received cabergoline therapy only (patients 13 and 18). All medical therapies were discontinued at least 1 month before initiation of somatostatin analog therapy. One patient received no prior treatment for acromegaly (patient 15). Sandostatin LAR therapy was initiated with 7–10 d of sc Sandostatin, followed by monthly injections of 20 mg Sandostatin LAR. The dose was increased or decreased every 3 months, depending on IGF-I response. At the time of the testing reported here, six patients were being treated with 20 mg every 4 wk, two patients with 30 mg every 4 wk, one patient with 20 mg every 5 wk, and one patient with 10 mg every 6 wk. The mean duration of long-acting octreotide therapy was 11.2 months (range, 3–29 months).
All patients in both group I and group II had active acromegaly before either therapy, with nadir GH levels above our age-matched normal range, and IGF-I levels were above normal in all except patient 18. Patient 18 had GH hypersecretion secondary to McCune-Albright syndrome as documented by elevated mean GH on 24-h sampling, failure of GH suppression after oral glucose, and pituitary enlargement on magnetic resonance imaging. All patients were ambulatory, and no patients had active hepatic or renal disease. Baseline characteristics for each patient are shown in Table 1
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Study procedures
Oral glucose tolerance testing (OGTT) was performed both before and after therapy in seven surgically treated patients and eight octreotide-treated patients. The four additional patients (Table 1
, patients 8, 9, 10, and 19) had pretherapy fasting blood sampling and OGTT performed after therapy. The OGTT was performed after an overnight fast. While seated, patients had blood sampled at baseline (fasting) and then at 60, 90, and 120 min after drinking 100 g dextrose (Trutol 100, NERL Diagnostics Inc., East Providence, RI). Blood was allowed to clot at room temperature for 15 min and was then centrifuged; the serum was frozen at -80 C in multiple aliquots. Fasting blood samples were assayed for IGF-I, insulin, and glucose. Blood samples at all time points were assayed for GH and serum ghrelin levels. Serum ghrelin levels were also measured in fasting serum samples from healthy subjects. All samples for ghrelin from each subject were run in the same assay and in duplicate.
This protocol was approved by the Institutional Review Board of Columbia-Presbyterian Medical Center (New York, NY), and informed consent was obtained from all subjects.
Assays
Ghrelin. Ghrelin was measured by RIA (Phoenix Pharmaceuticals, Inc. Belmont, CA). This RIA uses I125-labeled bioactive ghrelin as a tracer and polyclonal antibody raised in rabbits against full-length, octanoylated human ghrelin that recognizes both the octanoyl and des-octanoyl forms of the hormone. Ghrelin levels reported in this study were assayed from serum samples. We assessed comparability of plasma and serum ghrelin levels in simultaneously collected samples run in one assay; serum and plasma ghrelin levels were not significantly different and correlated highly (r = 0.993; P < 0.0001). Serial dilutions of samples across the range of ghrelin levels reported in this study measured in parallel with the human ghrelin standard. The lower limit of detection for this assay in our laboratory was 20 pg/ml. In our laboratory, the intra-assay coefficient of variation (CV) was 8.54%, and the interassay CV was 11.3%.
GH: immunoradiometric assay (IRMA). GH was measured by a two-site IRMA obtained from Diagnostic Systems Laboratories, Inc. (Webster, TX). The standards for this IRMA contain 22K recombinant human GH and are calibrated to the World Health Organization (WHO) International Reference Preparation of human GH (code 88/624), the most recent calibrator from the WHO. There is no cross-reactivity with other human pituitary hormones including human prolactin or with other species of GH. The intraassay CV is 3.1%, and the interassay CV is 5.9%. The assay sensitivity in our laboratory is 0.05 µg/liter. The upper limit of normal for nadir GH level after oral glucose in our laboratory is 0.14 µg/liter (19, 20).
IGF-I. IGF-I was measured by RIA using a polyclonal rabbit antibody generated against human IGF-I obtained from Nichols Institute Diagnostics (San Juan Capistrano, CA). In this assay, soluble IGF-I is separated from its binding proteins by extraction with acid-ethanol and precipitated at -20 C. Recombinant human IGF-I is used for the standards and labeled with I125 for the tracer. The antiserum for IGF-I shows virtually no cross-reactivity with IGF-II or GH. The standard is calibrated against WHO First International Reference Reagent 1988, IGF-I 87/518. The intraassay CV is 4%, and the interassay CV is 11%. Assay sensitivity is 13.5 µg/liter. The normal ranges for this assay are: age, 16–24 yr, 182–780 µg/liter; 25–39 yr, 114–492 µg/liter; 40–54 yr, 90–360 µg/liter; and 55 yr or older, 71–290 µg/liter. IGF-I levels for all patients were compared with their age-appropriate normal ranges.
Insulin was measured by polyclonal RIA (Linco Research, Inc., St. Charles, MO) and serum glucose by the hexokinase method.
Statistical analysis
Mean fasting ghrelin levels before and after surgery or before and during long-acting octreotide therapy were compared in each group by paired t test. Fasting and nadir ghrelin levels after oral glucose were also compared by paired t test. The percentage fall in ghrelin levels during OGTT was compared before and after therapy by paired t test. Fasting serum insulin levels were log transformed, and pre- and posttherapy levels were compared by paired t test. Homeostasis model assessment (HOMA) scores [fasting serum insulin (µU/ml) x fasting plasma glucose (mmol/liter)/22.5; Ref. 21 ] were calculated for each patient. Linear regression analysis was used to assess the correlation between baseline GH, IGF-I, weight, BMI, insulin, HOMA score, and ghrelin levels. Mean values ± SE are reported.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Group I (surgical therapy).
Mean serum fasting ghrelin levels rose significantly after surgery (from 312 ± 56 pg/ml before surgery to 547 ± 94 pg/ml after surgery; P = 0.013; Fig. 1). Fasting serum ghrelin levels were higher in all patients after surgery. Ghrelin levels rose on average to 191% of presurgery levels (range, 112% to 349%; Table 1).
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). Fasting serum ghrelin levels were lower in all patients during Sandostatin LAR therapy. Fasting serum ghrelin levels on average fell with octreotide therapy to 47% of baseline values (range, 26% to 70% of baseline values). Healthy subjects. Mean fasting ghrelin level in the healthy subjects was 513 ± 40 pg/ml (range, 333–940 pg/ml).
Serum ghrelin levels after oral glucose
Group I (surgical therapy). Serum ghrelin levels fell significantly during oral glucose both before (fasting vs. nadir serum ghrelin, P < 0.01) and after surgery (fasting vs. nadir ghrelin, P < 0.03; by paired t test). Ghrelin levels suppressed during OGTT by a mean of 19.4% before surgery and by 17.5% after surgery. Ghrelin suppression during OGTT was not significantly different before vs. after surgery.
Group II (octreotide therapy).
Serum ghrelin levels fell significantly during oral glucose both before (fasting vs. nadir serum ghrelin, P < 0.01) and during octreotide therapy (fasting vs. nadir ghrelin, P < 0.01; by paired t test). Serum ghrelin levels suppressed during OGTT by a mean of 19.5% before octreotide and by 25.8% during octreotide therapy. Ghrelin suppression during OGTT was not more significant during octreotide therapy than before. The degree of ghrelin suppression after oral glucose did not correlate with GH or IGF-I levels. Mean serum ghrelin levels during OGTT testing are shown in Fig. 2.
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Group I (surgical therapy).
Mean presurgery fasting GH levels were 4.4 ± 1.5 µg/liter and fell to a mean of 0.31 ± 0.17 µg/liter after surgery. Nadir GH levels after oral glucose were between 0.05 and 0.24 µg/liter in these patients. Mean serum IGF-I level was 873 ± 144 ng/ml (range, 420-1908 ng/ml) before surgery and fell to 298 ± 63 ng/ml (range, 129–780 ng/ml) after surgery. IGF-I levels of all patients fell into age-appropriate normal ranges after surgery (Table 1).
Group II (octreotide therapy). Mean preoctreotide fasting GH levels were 5.8 ± 1.5 µg/liter and fell to a mean of 0.80 ± 0.32 µg/liter during octreotide therapy. Nadir GH levels after oral glucose were between 0.05 and 2.9 µg/liter in these patients. Mean serum IGF-I level was 655 ± 67 ng/ml (range, 307-1060 ng/ml) before octreotide therapy and fell to 311 ± 56 ng/ml (range, 117–730 ng/ml) during octreotide therapy. In two patients (no. 10 and 16), IGF-I levels remained above the age-adjusted normal range. Ghrelin levels fell on octreotide therapy in these two patients similarly to the patients with normalization of IGF-I.
Basal GH, nadir GH, and percentage fall in GH during either treatment did not correlate with ghrelin levels before or after therapy or the change in ghrelin levels with therapy in either group of patients.
Insulin levels and insulin resistance estimation by HOMA score
Group I (surgical therapy).
In those patients without diabetes mellitus, mean serum insulin level was 19.7 ± 5.4 µU/ml (range, 6.1–48 µU/ml) before surgery and fell to 9.7 ± 0.93 µU/ml (range, 7.8–15 µU/ml) after surgery (P = 0.05). Insulin levels fell in five patients and rose slightly in two patients after surgery (Table 1). Mean HOMA score before surgery was 6.7 ± 2.1 and fell to 2.3 ± 0.47 after surgery (P = 0.03).
Group II (octreotide therapy).
In those patients without diabetes mellitus, mean serum insulin level before octreotide was 13.9 ± 2.8 µU/ml (range, 4.3–29.9 µU/ml) before octreotide therapy and fell to 11.2 ± 2.8 µU/ml (range, 4.2–29.8 µU/ml) during octreotide therapy (P = 0.03). On octreotide therapy, insulin levels fell in seven patients and rose in one patient (Table 1). Mean HOMA score before octreotide was 3.9 ± 1.2 and during octreotide therapy was 2.5 ± 0.32 (P = 0.20).
Correlation of insulin levels and HOMA score with ghrelin levels.
Pretherapy serum ghrelin levels correlated negatively with serum insulin levels (r = -0.494; P = 0.03; Fig. 3). Insulin resistance as estimated by HOMA score was also negatively correlated with serum ghrelin levels (r = -0.573; P = 0.01).
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After surgery, all patients gained weight, on average 9 ± 1.8 lb (range, 1.5–19 lb). Postsurgery weights were significantly higher (P = 0.0013 by paired t test). With octreotide therapy, weight change was variable; five patients lost weight (range, 1.5–3 lb), four gained weight (range, 1.0–7.4 lb), and one patient’s weight did not change. Before therapy, serum ghrelin levels did not correlate with weight or BMI. However, after therapy in the surgically treated group, serum ghrelin correlated negatively with weight (r = -0.823; P = 0.012).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In humans, exogenously administered ghrelin is known to stimulate pituitary GH secretion, but the relationship between endogenous ghrelin secretion and pituitary GH secretion is not yet clear. In one study, a role for serum ghrelin in the fasting-induced rise in GH was suggested by the finding that fasting induced a distinct rhythm in ghrelin secretion that was followed by a similar pattern of change in GH levels (15). A possible role for ghrelin in endogenous and potentially tumoral GH secretion is also suggested by the expression of ghrelin receptor in normal pituitary and somatotroph pituitary tumors (22). Evidence does support some degree of feedback regulation by circulating GH or IGF-I concentrations on normal gastric ghrelin secretion. GH administration to GH-deficient patients has been shown to acutely lower ghrelin levels (16), but with chronic administration GH therapy did not modify serum ghrelin levels (18). In rodents, circulating ghrelin levels were reduced by the administration of GH and increased by hypophysectomy, suggesting possible negative feedback of GH on gastric ghrelin secretion (13, 14). Also, in rodents, gastric ghrelin expression was decreased by exogenous GH administration (14). In our current study and another recent report, ghrelin levels were lower in patients with active acromegaly than in healthy subjects (12). All of our patients had normalization of GH and IGF-I levels after surgery that was associated with a rise in ghrelin levels, suggesting that preoperative GH and/or IGF-I hypersecretion could have been a factor in preoperative ghrelin suppression. We did not see, however, a correlation between GH or IGF-I levels and serum ghrelin levels. It is possible, however, that variability among our patients in other determinants of circulating ghrelin levels, such as BMI, could have obscured such a relationship.
Preoperative hyperinsulinemia and insulin resistance and the postoperative lowering of insulin levels and improved insulin sensitivity may have contributed to the preoperative lowering and then postoperative rise of serum ghrelin levels we found in our patients. Mounting evidence suggests that insulin is an important regulator of circulating ghrelin concentration (9). In a recent study, insulin administration during maintained euglycemia suppressed ghrelin levels (9). In another study, however, one insulin injection did not seem to alter ghrelin levels in healthy subjects (23). Others have shown that fasting insulin and ghrelin levels are negatively correlated (5); in another disease state characterized by hyperinsulinemia, polycystic ovary syndrome, insulin resistance and serum ghrelin levels were negatively correlated (24). However, hyperinsulinemia alone does not seem to explain all of the variability in circulating ghrelin levels because, after adjustment for insulin levels, BMI still correlates negatively with circulating ghrelin levels (5) and diabetes mellitus itself does not appear to dramatically alter ghrelin levels when controlled for body weight (25). Interestingly, ghrelin administration to healthy humans led to a rise in serum glucose followed by a reduction in insulin levels, suggesting also a possible role for ghrelin in the regulation of endogenous insulin secretion (26).
Insulin resistance is a common metabolic abnormality in patients with active acromegaly. Many of these patients have elevated basal insulin levels and/or exaggerated insulin responses to oral glucose administration (27, 28, 29). With successful surgical treatment, insulin resistance may resolve (29, 30). The cause of insulin resistance in acromegaly appears to be multifactorial because both impaired insulin-induced suppression of glucose output and insulin-stimulated glucose uptake can occur (30, 31, 32, 33, 34). GH-induced stimulation of lipolysis-increasing free fatty acid levels may be another cause of insulin resistance in acromegaly (27, 35). In our patients with active acromegaly, fasting serum insulin levels and the HOMA score, an estimate of insulin resistance, correlated negatively with serum ghrelin levels. Another recent report also suggested that those patients with acromegaly with more severe insulin resistance have lower ghrelin levels (12). In our study, the postoperative rise in serum ghrelin was accompanied by a fall in serum insulin levels, suggesting also a role for insulin in the regulation and dysregulation of ghrelin secretion in acromegaly.
Ghrelin is also thought to be an important regulator of food intake and body weight. Ghrelin levels have been shown to vary with states of nutritional sufficiency; levels are elevated in fasting and fall with food intake. In healthy humans, ghrelin administration stimulates appetite and food intake (36). Ghrelin levels vary negatively with body weight; they are higher in lean humans (25) and fall with weight gain in patients with anorexia nervosa (4), whereas they are low in obesity and rise with weight loss (5, 6, 7, 8). As predicted by the known metabolic effects of GH, patients with acromegaly are known to have marked body composition changes (37, 38). In general, studies have demonstrated that patients with active acromegaly have decreased central body fat, but increased soft tissue mass and extracellular and total body water (37, 38, 39, 40). With therapy, body composition abnormalities of acromegaly tend to reverse, with an increase in trunk and intraabdominal adipose tissue and a decrease in lean body mass (37, 39, 41, 42).
Interestingly, also, the strong relationship between ghrelin levels and BMI or weight seen in the nonacromegaly population (5) was not present in patients with active acromegaly, suggesting that other factors, possibly hyperinsulinemia leading to ghrelin dysregulation, could mask this relationship in active acromegaly. However, after therapy in the surgically treated group, when ghrelin physiology should be normalized, serum ghrelin correlated negatively with weight, as would be expected based on other studies in the nonacromegaly population (5, 7). This finding, along with the rise in fasting ghrelin levels to values similar to those in healthy subjects, suggests some restoration of normal ghrelin physiology in these patients. In our study, although the amount of weight gained was very variable, the surgically treated patients all gained weight postoperatively. It might have been expected, on the basis of the negative correlation of ghrelin levels with BMI that has been reported in the general population, that ghrelin levels would fall postoperatively in our patients who gained weight. It is interesting to speculate that postoperative changes in ghrelin levels could play a role in the weight gain noted after successful treatment of acromegaly.
In this study, we have also shown, as have others, that oral glucose ingestion suppresses serum ghrelin levels. In other studies, ghrelin levels have been reported to fall on average by 28% (23) or to a mean of 66% of baseline values (25) after oral glucose in healthy subjects. In another recent study, however, suppression of ghrelin after oral glucose was reduced in patients with acromegaly (12). The mechanism for suppression of ghrelin levels after glucose ingestion is not clear, but it may relate to the rise in insulin that follows glucose administration (9).
We have also shown, as others have recently reported, that administration of long-acting octreotide persistently suppresses serum ghrelin levels in active acromegaly. Somatostatin-14 administration acutely lowered circulating ghrelin levels in healthy young men (43) and sc octreotide (17) and long-acting octreotide suppressed serum ghrelin levels in patients with acromegaly (44). The mechanism for ghrelin suppression by octreotide may be a direct effect on ghrelin-secreting gastric cells. Somatostatin receptors are present on GI tract neuroendocrine cells (45, 46), and with these receptors octreotide suppresses many GI tract peptides, gastric motility, and acid secretion (45) and could also suppress gastric ghrelin secretion. In our patients, ghrelin suppression seemed to occur without relationship to the degree of GH or IGF-I suppression on long-acting octreotide. The fall in insulin levels in most patients on octreotide therapy could be explained in part by a direct octreotide effect or improved insulin sensitivity on octreotide therapy. It is also not known whether changes in ghrelin levels could have effects on pituitary tumor GH secretion. Somatotroph tumors express ghrelin receptor, and in vitro, administration of ghrelin to GH-secreting tumors led to their secretion of GH (22, 47, 48). Thus, factors altering ghrelin secretion in acromegaly could potentially affect pituitary tumor GH secretion.
In summary, we have found that fasting serum ghrelin levels rise postoperatively in patients with acromegaly. This rise in ghrelin levels was associated with postoperative lowering of GH, IGF-I, and insulin levels, suggesting a possible role for one or a combination of these hormones in the regulation of circulating ghrelin levels in acromegaly. We have also confirmed other reports demonstrating persistent suppression of serum ghrelin levels on long-acting octreotide therapy for acromegaly. In our patients with acromegaly, the rise in serum ghrelin levels postoperatively was associated with weight gain, but suppression of ghrelin levels by octreotide did not produce a consistent pattern of weight change. It is clear that many factors are involved in determining body composition in acromegaly, and it remains to be determined whether changes in circulating ghrelin concentrations in acromegaly and the differential effects of our therapies could also be relevant to body composition changes in patients with acromegaly.
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Footnotes |
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Abbreviations: BMI, Body mass index; CV, coefficient of variation; GI, gastrointestinal; HOMA, homeostasis model assessment; IRMA, immunoradiometric assay; OGTT, oral glucose tolerance testing.
Received November 6, 2002.
Accepted February 10, 2003.
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) and after surgical cure (•). B, Serum ghrelin levels during OGTT in patients with active acromegaly before octreotide therapy (