Abstract
Context
Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in regulating body composition and glucose homeostasis.
Objective
The purpose of our study was to investigate body composition including ectopic lipids, measures of glucose homeostasis, and gonadal steroids in patients with active acromegaly compared with age-, body mass index (BMI)−, and sex-matched controls and to determine changes in these parameters after biochemical control of acromegaly.
Design
Cross-sectional study of 20 patients with active acromegaly and 20 healthy matched controls. Prospective study of 16 patients before and after biochemical control of acromegaly.
Main Outcome Measures
Body composition including ectopic lipids by magnetic resonance imaging/proton magnetic resonance spectroscopy; measures of glucose homeostasis by an oral glucose tolerance test; gonadal steroids.
Results
Patients with active acromegaly had lower mean intrahepatic lipid (IHL) and higher mean fasting insulin and insulin area under the curve (AUC) values than controls. Men with acromegaly had lower mean total testosterone, sex hormone−binding globulin, and estradiol values than male controls. After therapy, homeostasis model assessment of insulin resistance, fasting insulin level, and insulin AUC decreased despite an increase in IHL and abdominal and thigh adipose tissues and a decrease in muscle mass.
Conclusions
Patients with acromegaly were characterized by insulin resistance and hyperinsulinemia but lower IHL compared with age-, BMI-, and sex-matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass.
Acromegaly is characterized by insulin resistance but lower hepatic lipids compared with healthy controls. Biochemical control of acromegaly improves IR but leads to less favorable body composition.
Acromegaly is characterized by growth hormone (GH) and insulinlike growth factor-1 (IGF-1) hypersecretion, and GH and IGF-1 play important roles in the regulation of body composition and glucose homeostasis (1). GH exerts lipolytic actions and causes insulin resistance (2), and patients with active acromegaly frequently present with impaired glucose tolerance and type 2 diabetes mellitus (T2DM) (1). In addition, GH excess in acromegaly is associated with reduced fat mass, especially visceral adipose tissue (VAT), and increased lean mass (3, 4), which represent a more favorable anthropometric phenotype for metabolic risk. GH excess also has beneficial effects on inflammatory markers (5).
Insulin resistance is associated with ectopic lipid deposits in the liver [intrahepatic lipids (IHLs)] and skeletal muscle [intramyocellular lipids (IMCLs)] (6). Ectopic lipid deposits can be quantified noninvasively using proton magnetic resonance spectroscopy (1H-MRS) (7, 8). We previously demonstrated an inverse association between peak stimulated GH and ectopic lipids (IHL and IMCL) in obese but otherwise healthy subjects (9), such that relative GH deficiency was associated with higher quantities of lipid accumulation in both liver and skeletal muscle. Moreover, administration of GH for 6 months reduced IHL in men with obesity, but it increased insulin resistance at 6 weeks (10). Similarly, a previous study showed that patients with acromegaly had lower IHL than controls (11); in one study, abdominal subcutaneous and visceral fat and IHL increased after surgical cure of acromegaly (12), whereas in another study, no change in IHL was found (11).
Furthermore, hypogonadism is highly prevalent in patients with acromegaly because of mass effects from the pituitary adenoma, an adenoma cosecreting GH and prolactin that results in hyperprolactinemia and/or GH excess itself (13). Gonadal steroids are important modulators of body composition and glucose homeostasis, and hypogonadism is associated with central obesity, insulin resistance, and increased cardiometabolic risk in men (14, 15) and women (16–18).
The purpose of our study was to investigate body composition, including ectopic lipid deposits, and measures of glucose homeostasis in patients with active acromegaly compared with age-, body mass index (BMI)−, and sex-matched controls and to determine changes in these parameters shortly after biochemical control of acromegaly. In addition, we aimed to investigate changes in insulin resistance, IGF-1 level, and gonadal steroids as potential mediators of changes in body composition. We hypothesized that patients with active acromegaly would have increased insulin resistance associated with increased ectopic lipid depositions compared with age-, BMI- and sex-matched controls and that these changes would improve after cure of acromegaly. We also hypothesized that these changes might be mediated in part by normalization of gonadal steroids.
Materials and Methods
Our study was institutional review board approved and complied with Health Insurance Portability and Accountability Act guidelines. Written informed consent was obtained from all subjects after the nature of the procedures was fully explained.
Subjects
Our study was performed at the Clinical Research Center at Massachusetts General Hospital. We studied 40 subjects (22 men, 18 women; mean age, 47 ± 16 years), 20 subjects with active acromegaly (11 men, nine women), and 20 age- sex-, and BMI-matched controls. Healthy control subjects were matched by sex, age ±2 years, and BMI ±2 kg/m2 to patients with active acromegaly. Five women with acromegaly and five controls were perimenopausal/postmenopausal. Two subjects with acromegaly were taking medications for T2DM, and one subject was taking glucocorticoid replacement therapy (prednisone, 5 mg/d). None of the men with acromegaly were receiving testosterone replacement therapy. None of the controls had chronic disease, including cancer, hypertension, or diabetes mellitus. Exclusion criteria for both groups included pregnancy and contraindications to magnetic resonance imaging (MRI), such as the presence of a pacemaker or metallic implant. None of the patients had a history of liver disease.
After baseline assessment, 16 subjects (nine men, seven women) with active acromegaly were evaluated after treatment and biochemical control of acromegaly. The four subjects who were not available for follow-up included one man who was claustrophobic and elected not to undergo follow-up MRI, one woman who became pregnant, one woman who was actively trying to become pregnant, and one man in whom acromegaly was not controlled. Of the 16 patients available for follow-up, 15 subjects underwent transsphenoidal surgical resection with pathological confirmation of a GH-secreting pituitary adenoma, one subject received medical therapy alone with cabergoline, and five subjects required medical therapy after surgery. Of the five patients who received medical therapy after surgery, four received lanreotide and one received lanreotide and cabergoline. Patients with acromegaly were reexamined once they had achieved biochemical control, defined as normalization of IGF-1 levels, but not <3 months after surgery. The mean follow-up period was 8 months (range, 3 to 22 months).
Endocrine testing
All subjects underwent the following fasting blood tests: IGF-1 [Liquid chromatography–mass spectrometry (LC/MS); Quest Diagnostics, San Juan Capistrano, CA], total (LC/MS; Mayo, Rochester, MN) and free testosterone (equilibrium dialysis; Mayo), estradiol (LC/MS; Brigham Research Assay Core, Boston, MA), and sex hormone-binding globulin (SHBG; Access Chemiluminescent Immunoassay; Brigham Research Assay Core). A standard oral glucose tolerance test (OGTT) with 75 g of glucose load was performed in subjects without T2DM (n = 38), and serum glucose, insulin, and GH levels (immunoassay; Quest) were assessed. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated, and the GH nadir was determined.
Body composition and ectopic lipid assessment
Body composition and ectopic lipid deposits were quantified using a 3.0 Tesla (Siemens Trio; Siemens Medical Systems, Erlangen, Germany) MRI system after an overnight fast.
Body composition
Fat and muscle cross-sectional areas (CSAs) were determined by axial MRI. A triplane gradient echo localizer pulse sequence [repetition time (TR) of 49.0 ms; echo time (TE) of 1.6 ms] was performed, and axial T1-weighted images (fast spin-echo pulse sequence, 10-mm slice thickness, 40-cm field of view; TR of 300 ms; TE of 12 ms; echo train of 4; 512 × 512 matrix; one number of acquisitions) were prescribed through the abdomen at the level of L1-2, the midportion of L4, and the proximal and mid femur. Subcutaneous adipose tissue (SAT), VAT, and muscle CSAs were determined on the basis of offline analysis of tracings obtained using commercial software (VITRAK; Merge eFilm, Milwaukee, WI).
Liver 1H-MRS
Liver 1H-MRS was performed as previously described (8, 19). Briefly, a breath-hold true fast imaging with steady precession (True FISP) sequence of the liver was obtained, and a voxel measuring 20 × 20 × 20 mm (8 mL) was placed within the peripheral portion of the right hepatic lobe, avoiding the diaphragm, vessels, and artifact. For each voxel placement, automated optimization of gradient shimming was performed. The voxel placement was registered using screen captures to enable similar placement in the follow-up examination. Breath-hold single-voxel 1H-MRS data were acquired in midexpiration using point-resolved single-voxel spectroscopy pulse sequence without water suppression (TR of 1500 ms; TE of 30 ms; eight averages; 1024 data points; and receiver bandwidth, 2000 Hz) (8). The coefficient of variation of 1H-MRS for IHL quantification at 6 weeks was 5.9% and at 6 months was 18.7% (20).
1H-MRS of the soleus muscle
1H-MRS of the soleus muscle was performed as previously described (19). Briefly, axial T1-weighted images of the proximal two-thirds of the calf were obtained, and a voxel measuring 15 × 15 × 15 mm (3.4 mL) was placed on the axial T1-weighted slice with the largest CSA of the soleus muscle, avoiding visible interstitial tissue, fat, and vessels. Single-voxel 1H-MRS data were acquired by using a point-resolved single-voxel spectroscopy pulse sequence (TR of 3000 ms; TE of 30 ms; 64 acquisitions; 1024 data points; and receiver bandwidth of 1000 Hz). For each voxel placement, automated optimization of gradient shimming, water suppression, and transmit-receive gain were performed, followed by manual adjustment of gradient shimming, targeting water line widths of 12 to 14 Hz. The coefficient of variation of 1H-MRS for IMCL quantification was 6%.
1H-MRS data analysis
Fitting of all 1H-MRS data was performed using LCModel (version 6.3-0K; Stephen Provencher, Oakville, ON, Canada) (21). All spectra had standard deviation of the peak fit of <5%, which represents the acceptable error of fit of the software.
Data were transferred from the scanner to a Linux workstation, and metabolite quantification was performed using eddy current correction and water scaling. A customized fitting algorithm for IHL analysis (LCModel “liver”) provided estimates for the lipid signals at 0.9, 1.3, and 2.0 ppm and are expressed in lipid/water ratio.
For the soleus muscle, IMCL (1.3 ppm) methylene estimates were automatically scaled to the creatine peak (3.0 ppm) and expressed in arbitrary units.
Statistical analysis
JMP Statistical Database Software (version 11.0; SAS Institute, Cary, NC) was used for statistical analyses. Variables were tested for normality of distribution by using the Shapiro-Wilk test. When variables were nonnormally distributed, nonparametric tests were performed. Differences between patients with acromegaly and controls and between patients with acromegaly after biochemical control of acromegaly and controls were made using the t test for normally distributed data or the Mann-Whitney U test for nonnormally distributed data. Changes within the acromegaly group before and after biochemical control of acromegaly were assessed using a two-sided paired t test for normally distributed data or the Wilcoxon signed rank test for nonnormally distributed data. Linear correlation analyses between gonadal steroids and measures of glucose homeostasis and body composition were performed, and nonparametric Spearman rank correlation coefficients were reported. Data are shown as mean ± standard deviation for normally distributed data and as median (interquartile range) for nonnormally distributed data. Statistical significance was defined as a two-tailed P < 0.05.
Results
Clinical characteristics of study subjects are provided in Table 1. As expected, the group of patients with active acromegaly had a higher mean IGF-1 level and a higher mean GH nadir than controls. Patients with active acromegaly had normal thyroid hormone levels (mean thyroxine levels, 1.17 ± 0.23 ng/dL) and normal renal function (mean serum creatinine level, 0.78 ± 0.18 mg/dL; mean calculated creatinine clearance, 148 ± 54 mL/min). Patients with acromegaly had a higher mean fasting insulin levels and insulin area under the curve. Of note, the two acromegaly subjects with T2DM did not undergo the OGTT and were not included in the analyses of measures of glucose homeostasis.
Table 1.
Clinical Characteristics of Patients With Acromegaly Before and After Biochemical Control of Acromegaly and of Controls
| Variable | Acromegaly Pretherapy (n = 20) | Acromegaly Posttherapy (n = 16) | Controls (n = 20) | P Value Acromegaly Pretherapy vs Controls | P Value Acromegaly Pretherapy vs Posttherapy | P Value Acromegaly Posttherapy vs Controls |
|---|---|---|---|---|---|---|
| Age, y | 47 ± 16 | 47 ± 17 | 1.0 | |||
| Male/female, n | 11/9 | 9/7 | 11/9 | 1.0 | ||
| Weight, kg | 92.1 ± 22.8 | 92.7 ± 24.2 | 91.0 ± 23.1 | 0.9 | 0.3 | 0.8 |
| BMI, kg/m2 | 30.4 ± 5.4 | 30.8 ± 6.5 | 30.5 ± 5.9 | 0.9 | 0.2 | 0.9 |
| GH nadir, ng/mLa | 8.3 (4.3, 10.9) | 0.2 (0.1, 0.45) | 0.05 (0.05, 0.1) | <0.0001 | 0.0001 | 0.0001 |
| IGF-1, ng/mLa | 787 (641, 1099) | 249 (191, 317) | 174 (110, 209) | <0.0001 | <0.0001 | 0.002 |
| IGF-1, standard deviation score | 4.3 ± 0.9 | 1.3 ± 0.7 | 0.2 ± 0.8 | <0.0001 | <0.0001 | 0.0002 |
| HOMA-IRa | 1.81 (1.55, 3.73) | 0.98 (0.49, 1.53) | 1.35 (0.57, 2.51) | 0.08 | 0.01 | 0.3 |
| Fasting glucose, mg/dL | 92 ± 13 | 89 ± 14 | 90 ± 12 | 0.5 | 0.8 | 1.0 |
| Glucose AUC, mg/dL × 120 min | 17614 ± 5123 | 17468 ± 5193 | 14792 ± 2757 | 0.06 | 0.6 | 0.08 |
| Fasting insulin, μU/mLa | 9 (7, 17) | 5 (2, 8) | 6 (3, 12)±5 | 0.045 | 0.003 | 0.5 |
| Insulin AUC, μU/mL × 120 mina | 6828 (5152, 8196) | 3098 (2094, 4272) | 3827 (1854, 4580) | 0.004 | 0.008 | 0.8 |
Data are presented as mean ± standard deviation for normally distributed data and as median (interquartile range) for nonnormally distributed data. P values in boldface are significant.
Abbreviation: AUC, area under the curve.
Nonnormally distributed data.
Gonadal steroid levels in men and women are provided in Table 2. Men with acromegaly had lower mean total testosterone, estradiol, and SGBH levels than male controls. There were no significant differences in gonadal steroids between women with acromegaly and female controls.
Table 2.
Gonadal Steroid Levels in Patients With Acromegaly Before and After Biochemical Control of Acromegaly and in Controls
| Variable | Acromegaly Pretherapy (n = 20) | Acromegaly Posttherapy (n = 16) | Controls (n = 20) | P Value Acromegaly Pretherapy vs Controls | P Value Acromegaly Pretherapy vs Posttherapy | P Value Acromegaly Posttherapy vs Controls |
|---|---|---|---|---|---|---|
| Free testosterone, ng/dL, men | 8.8 (5.4, 11.8) | 10.9 (7.6, 15.1) | 10.0 (8.6, 13.1) | 0.2 | 0.2 | 0.9 |
| Free testosterone, ng/dL, women | 0.5 (0.4, 0.7) | 0.4 (0.2, 0.5) | 0.3 (0.1, 0.5) | 0.1 | 0.2 | 0.9 |
| Total testosterone, ng/dL, men | 220 (143, 294) | 321 (243, 429) | 431 (274, 583) | 0.01 | 0.07 | 0.2 |
| Total testosterone, ng/dL, women | 29 (17, 51) | 18 (9, 30) | 25 (15, 33) | 0.5 | 0.8 | 0.4 |
| Estradiol, pg/mL, men | 17 (14, 20) | 20 (16, 28) | 29 (26, 42) | 0.02 | 0.9 | 0.03 |
| Estradiol, pg/mL, women | 33 (7, 70) | 8 (7, 36) | 16 (6, 139) | 0.9 | 0.8 | 0.6 |
| SHBG, nmol/L, men | 13 (10, 17) | 17 (12, 25) | 28 (18, 43) | 0.003 | 0.1 | 0.07 |
| SHBG, nmol/L, women | 40 (25, 62) | 34 (29, 61) | 62 (42, 102) | 0.1 | 0.5 | 0.06 |
Data are presented as mean ± standard deviation for normally distributed data and as median (interquartile range) for nonnormally distributed data. Data are presented as median (interquartile range). P values in boldface are significant.
Body composition measures and ectopic lipids of study subjects are provided in Table 3. There was no statistical difference in fat and muscle mass and IMCL between patients with active acromegaly and controls. Patients with active acromegaly had lower mean IHL content than healthy controls despite similar BMIs.
Table 3.
Body Composition of Patients With Acromegaly Before and After Biochemical Control of Acromegaly and of Controls
| Variable | Acromegaly Pretherapy (n = 20) | Acromegaly Posttherapy (n = 16) | Controls (n = 20) | P Value Acromegaly Pretherapy vs Controls | P Value Acromegaly Pretherapy vs Posttherapy | P Value Acromegaly Posttherapy vs Controls |
|---|---|---|---|---|---|---|
| BMI, kg/m2 | 30.4 ± 5.4 | 30.8 ± 6.5 | 30.5 ± 5.9 | 0.9 | 0.2 | 0.9 |
| SAT CSA at L1-2, cm2a | 130 (66, 219) | 169 (118, 229) | 199 (89, 322) | 0.2 | 0.0006 | 0.6 |
| VAT CSA at L1-2, cm2a | 74 (49, 204) | 113 (73, 229) | 138 (55, 229) | 0.4 | 0.0002 | 0.9 |
| SAT CSA at L4, cm2a | 217 (170, 365) | 275 (225, 419) | 293 (174, 489) | 0.3 | 0.002 | 0.9 |
| VAT CSA at L4, cm2a | 96 (62, 188) | 122 (76, 213) | 140 (56, 208) | 0.5 | <0.0001 | 0.9 |
| Proximal femur muscle CSA, cm2 | 240 ± 62 | 232 ± 77 | 216 ± 46 | 0.2 | 0.09 | 0.4 |
| Proximal femur SAT CSA, cm2a | 238 (166, 276) | 273 (155, 294) | 263 (190, 337) | 0.3 | 0.03 | 0.5 |
| Midfemur muscle CSA, cm2 | 162 ± 38 | 154 ± 45 | 158 ± 40 | 0.9 | 0.002 | 0.8 |
| Midfemur SAT CSA, cm2a | 96 (56, 113) | 100 (58, 130) | 113 (68, 133) | 0.09 | 0.006 | 0.5 |
| Intrahepatic lipids, lipid/watera | 0.02 (0.01, 0.04) | 0.03 (0.01, 0.30) | 0.06 (0.02, 0.22) | 0.03 | 0.03 | 0.6 |
| IMCL/SOL, AUa | 8.2 (3.9, 11.2) | 8.3 (6.4, 11.6) | 10.7 (6.4, 14.1) | 0.2 | 0.9 | 0.3 |
Data are presented as mean ± standard deviation for normally distributed data and as median (interquartile range) for nonnormally distributed data. P values in boldface are significant.
Abbreviations: AU, arbitrary unit; SOL, soleus muscle.
Nonnormally distributed data.
Clinical characteristics and hormone levels of patients with acromegaly before and after achievement of biochemical control and comparisons with those of healthy controls are provided in Table 1. After biochemical control of acromegaly, there was an expected decrease in GH nadir, IGF-1 levels, and IGF-1 standard deviation scores. There was no significant change in weight or BMI during the short duration of the study. HOMA-IR, fasting insulin level, and insulin area under the curve after biochemical control of acromegaly decreased to levels similar to those of healthy controls (Table 1). One patient with T2DM who was taking sitagliptin and metformin before therapy was able to discontinue sitagliptin after biochemical control of acromegaly was achieved. The other patient with T2DM was not available for follow-up. There was no difference in change in BMI, body composition (including ectopic lipids), or measures of glucose homeostasis between subjects with acromegaly who did (n = 6) and did not (n = 10) receive medical therapy (P = 0.1 to 1.0) (Supplemental Table 1). When the five patients who received lanreotide were excluded, the decrease in HOMA-IR and fasting insulin level after biochemical control of acromegaly remained significant (Supplemental Table 2).
There were no significant changes in gonadal steroid levels before therapy compared with those after therapy (Table 2).
Body composition measures and ectopic lipid levels of patients with acromegaly before and after biochemical control are provided in Table 3. There was a significant increase in abdominal SAT and VAT and thigh SAT, similar to levels of controls, whereas midfemoral muscle mass decreased compared with baseline levels, similar to levels of controls (Fig. 1). In addition, there was an increase in mean IHL (Fig. 2) similar to that of controls, although there was no significant change in IMCL level.
Figure 1.
Axial T1-weighted images of the abdomen at the level of L1-2 and L4 and the proximal and midthigh of a 75-year-old woman with acromegaly (A) before and (B) after biochemical control of the disease. After therapy, there was an increase in abdominal and thigh subcutaneous adipose tissue (black asterisks) and visceral adipose tissue (+) and a decrease in muscle mass (white asterisks).
Figure 2.
Proton magnetic resonance spectroscopy of the right hepatic lobe in a 56-year-old man with acromegaly obtained (A) before and (B) after biochemical control of the disease. IHL increased after therapy. For purposes of visual comparison, the amplitudes of unsuppressed water are scaled identically.
There were no associations between change in gonadal steroids and measures of glucose homeostasis and body composition in men or women except for an inverse association between change in SHBG and HOMA-IR in women and an inverse association between change in SHBG and femoral muscle CSA in men (Supplemental Table 3).
Discussion
Our study shows that despite decreased insulin sensitivity and hyperinsulinemia, patients with active acromegaly had lower IHL than age-, BMI-, and sex-matched controls. Biochemical control in patients with active acromegaly did not change BMI in the short term but led to a less favorable anthropometric phenotype with increased IHL and visceral and subcutaneous adiposity and decreased muscle mass, despite improvement in insulin sensitivity.
GH is an important modulator of body composition and cardiometabolic risk. GH stimulates lipolysis and lipid turnover, resulting in reduced adipose tissue mass (2). Furthermore, GH has anabolic actions on skeletal muscle with stimulation of protein synthesis (22, 23). However, increased lipolysis results in increased plasma free fatty acids, which have been implicated in GH-induced insulin resistance (2, 24). Therefore, despite increased lean body mass (6) and decreased fat mass (7), patients with acromegaly exhibit insulin resistance and an increased risk of T2DM (2, 8, 9).
Ectopic lipid deposits in the liver (IHL) and muscle (IMCL) are observed in conditions associated with insulin resistance and have been implicated in the development of insulin resistance and T2DM (25, 26). 1H-MRS is a reliable noninvasive method to quantify IHL and IMCL (27). We previously showed inverse associations between IHL and IMCL and peak stimulated GH levels in subjects with obesity (9), and administration of GH reduced IHL in men with obesity (10).
Only a few studies have assessed ectopic fat depots in patients with acromegaly. Winhofer et al. (11) assessed IHL by 1H-MRS in 10 patients with active acromegaly compared with matched controls. IHL were lower in patients with active acromegaly than in controls, despite hyperinsulinemia and insulin resistance in the acromegaly group. After biochemical control of seven patients with acromegaly, IHL increased, but the change was not significant (11). In our study, patients with active acromegaly also demonstrated lower IHL than matched controls. However, mean IHL increased significantly after biochemical control of acromegaly. Given our larger number of subjects (n = 16), our study may have had more power to detect a significant change than the study by Winhofer et al. (n = 7). Moreover, it is possible that the patients in our study had more severe acromegaly and achieved better control, thus facilitating the significant increase in IHL. Reyes-Vidal et al. (12) performed 1H-MRS to assess IHL and IMCL levels in 14 patients with acromegaly before and 6 months to 2 years after surgery. IHL increased 1 year after surgery, whereas there was no change in IMCL, which was similar to findings in our study. MRI performed for assessment of fat and muscle mass showed that abdominal SAT and VAT increased and muscle mass decreased 6 months, 1 year, and 2 years after surgery (12). This is consistent with results of our study, in which abdominal SAT and VAT and thigh fat increased and muscle mass decreased after biochemical control of acromegaly. However, the study by Reyes-Vidal et al. (12) did not include a control group to determine whether body composition and ectopic lipids were similar to those of healthy controls.
Madsen et al. (28) assessed IHL and IMCL by 1H-MRS in patients with acromegaly who were well controlled on a somatostatin analogue and who were randomized to unchanged monotherapy or reduction of somatostatin analogue dose and cotreatment with pegvisomant. Cotreatment with pegvisomant and reduced somatostatin analogue dose increased IHL and decreased IMCL (28). In our study, no patients received pegvisomant. Compared with patients who did not receive medical therapy, patients receiving medical therapy (lanreotide and cabergoline, n = 6) did not demonstrate differences in changes in body composition or measures of glucose homeostasis.
Men with active acromegaly had lower testosterone, estradiol, and SHBG levels than healthy BMI- and age-matched men. In contrast, testosterone, estradiol, and SHBG levels did not differ between women with active acromegaly and age- and BMI-matched controls, and levels did not significantly change after therapy. Hypogonadism is highly prevalent in patients with acromegaly (13), and gonadal steroids are important modulators of body composition and glucose homeostasis (14, 16, 18). We hypothesized that gonadal steroids might mediate some of the changes in body composition observed after treatment of acromegaly. However, contrary to our hypothesis, there were no significant associations between changes in gonadal steroids and body composition or measures of glucose homeostasis, except for an inverse association between change in SHBG and HOMA-IR in women and an inverse association between change in SHBG and femoral muscle CSA in men.
Strengths of our study include the detailed assessment of body composition and ectopic lipids by MRI and 1H-MRS and a carefully matched control group, which also allowed comparison of posttreatment data with those of healthy controls. A limitation of our study is the relatively small number of patients, which did not allow determination of sex-specific outcomes. Moreover, we assessed glucose homeostasis by OGTT and HOMA-IR, which excluded two patients with T2DM. A glucose clamp would have been more accurate in assessing glucose homeostasis, especially hepatic insulin resistance.
In conclusion, acromegaly is a unique condition characterized by insulin resistance and hyperinsulinemia but a more favorable anthropometric phenotype than that of matched healthy controls. Biochemical control of acromegaly improved insulin resistance but led to a less favorable anthropometric phenotype with increased IHL and abdominal adiposity and decreased muscle mass despite similar BMIs.
Supplementary Material
Acknowledgments
Financial Support: This study was supported by an investigator-initiated grant from Ipsen.
Disclosure Summary: The authors have nothing to disclose.
Abbreviations
- 1H-MRS
proton magnetic resonance spectroscopy
- AUC
area under the curve
- BMI
body mass index
- CSA
cross-sectional area
- GH
growth hormone
- HOMA-IR
homeostasis model assessment of insulin resistance
- IGF-1
insulinlike growth factor-1
- IHL
intrahepatic lipid
- IMCL
intramyocellular lipid
- MRI
magnetic resonance imaging
- OGTT
oral glucose tolerance test
- SAT
subcutaneous adipose tissue
- SHBG
sex hormone-binding globulin
- T2DM
type 2 diabetes mellitus
- VAT
visceral adipose tissue.
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