Abstract
Background
Glucocorticoid excess leads to muscle atrophy and weakness in patients with endogenous Cushing’s syndrome. Insulin-like growth factor I (IGF-I) is known to have protective effects on muscle loss. We hypothesized that individual serum IGF-I concentrations might be predictive for long-term myopathy outcome in Cushing’s syndrome.
Patients and methods
In a prospective longitudinal study of 31 patients with florid Cushing’s syndrome, we analyzed IGF-I and IGF binding protein 3 (IGFBP 3) concentrations at the time of diagnosis and following surgical remission over a period of up to 3 years. We assessed muscle strength by grip strength measurements using a hand grip dynamometer and muscle mass by bio-impedance measurements.
Findings
Individual serum IGF-I concentrations in the postoperative phase were strongly predictive of long-term grip strength outcome (rs = 0.696, P ≤ 0.001). Also, lower IGF-I concentrations were associated with a lower muscle mass after 3 years (rs = 0.404, P = 0.033). While patients with high IGF-I s.d. scores (SDS; >1.4) showed an improvement in grip strength within the follow-up period (P = 0.009), patients with lower IGF-I SDS (≤−0.4) had a worse outcome with persisting muscle dysfunction. In contrast, preoperative IGF-I concentrations during the florid phase of Cushing’s syndrome did not predict long-term muscle function outcome (rs = 0.285, P = 0.127).
Conclusion
Lower individual IGF-I concentrations 6 months after curative surgery for Cushing’s syndrome are associated with adverse long-term myopathy outcome and IGF-I might be essential for muscle regeneration in the early phase after correction of hypercortisolism.
Introduction
Proximal muscle atrophy and weakness due to glucocorticoid excess is a common comorbidity in patients with Cushing’s syndrome (CS) (1). Impaired muscle function and reduced skeletal muscle mass can persist even after years of successful surgical cure (2, 3). Indeed, in a recently published longitudinal multicenter study from the German Cushing’s Registry, we observed a persisting muscle dysfunction up to 4 years after curative surgery for CS. As predictors for long-term myopathy outcome, we identified age, HbA1c and waist-to-hip ratio at the time of diagnosis (4). The underlying mechanisms are incompletely understood. Anabolic factors like growth hormone (GH) and insulin-like growth factor I (IGF-I) are known to influence myopathy induced by exogenous glucocorticoids (5, 6, 7). The catabolic effects of glucocorticoids on muscle tissue are likely mediated, at least in part, by reduced biological activity of IGF-I during glucocorticoid excess (8). While acute exposure to glucocorticoids is followed by an increase in GH (9), prolonged glucocorticoid excess has inhibitory effects on GH secretion (10, 11). Whether GH secretion recovers by achieving long-term remission in patients with endogenous CS remains controversial (12, 13, 14, 15). Furthermore, it is still uncertain whether patients with florid CS or those following successful surgery benefit from GH replacement therapy (16). Due to the hypercortisolism-associated suppression of GH, which is the main hormone-regulating IGF-I gene expression, rather decreased serum IGF-I might be expected in patients with CS (13, 17, 18, 19). Interestingly, English et al. recently reported elevated serum IGF-I concentrations in patients with florid pituitary CS (20), consistent with other observations of increased serum IGF-I in response to endogenous and exogenous glucocorticoid excess (21, 22, 23). However, in muscle tissue, local IGF-I production has been reported to be inhibited by glucocorticoids, resulting in an increased muscle protein breakdown and decreased protein synthesis (24, 25, 26, 27). Muscle IGF-I downregulates proteolytic systems, the expression of genes involved in atrophy and, thus, suppresses glucocorticoid-induced muscle cell atrophy in vitro (28, 29, 30). Furthermore, systemic administration of IGF-I showed protective effects on glucocorticoid-induced muscle atrophy in rats and hamsters (31, 32, 33, 34). On the basis of these preclinical examinations, the aim of this study was to investigate serum IGF-I concentrations in patients with endogenous CS before and after curative surgery and its relation to hypercortisolism-induced muscle dysfunction.
Patients and methods
Patients
We performed a prospective longitudinal study on hypercortisolism-induced myopathy and its relationship to serum IGF-I concentrations. We, therefore, included 31 patients with endogenous CS diagnosed between 2012 and 2017 at Ludwig-Maximilian-University Munich. All patients had typical signs and symptoms of CS at the time of diagnosis. Twenty-three patients (74%) had pituitary CS (Cushing’s disease) and eight patients (26%) had adrenal CS. Diagnosis and subtype differentiation of CS were done as reported earlier according to the current guidelines and recommendations (2, 35).
The patients were studied at diagnosis of Cushing’s syndrome prior to surgery. Following surgical remission, the patients were re-examined clinically and biochemically in regular follow-up visits 6, 12, 24 and 36 months after surgery at our institution. Due to missing follow-up visits of individual patients, the exact numbers of patients at the respective time points are as follows: florid CS (preoperative) n = 31, 6 months n = 29, 1 year n = 29, 2 years n = 27, 3 years n = 31.
The patients remained in clinical and biochemical remission during the follow-up period. They received standard glucocorticoid replacement therapy during the adrenal insufficiency phase following successful surgery, consisting of 20–25 mg hydrocortisone per day. Patients who had subclinical hypercortisolism, ectopic CS or postoperatively developed insufficiencies of other pituitary axes (pituitary-thyroid and pituitary-gonadal axis) were excluded. Also, no patient in the study cohort received adrenostatic therapy or radiotherapy. The German Cushing’s Registry was approved by the LMU ethics committee, and all patients gave written informed consent.
Muscle strength measurements
Muscle function was assessed by hand grip strength measurements in a standardized manner. The measurements were performed in a sitting position with the JAMAR hydraulic hand dynamometer (Patterson Medical, Nottinghamshire, UK). Mean grip strength (kg) for dominant and non-dominant hand was calculated out of three repetitions per visit. The hand with the better performance at the time of diagnosis was defined as the dominant hand. To adjust for age and gender (normalized grip strength), grip strength was standardized to the manufacturer’s information on normative grip strength data (36, 37). Mean normalized grip strength was determined from the mean value of dominant and non-dominant grip strength according to age and gender.
Estimation of muscle mass
Lean body cell mass was estimated as surrogate parameter for muscle mass by using a bio-impedance measuring device at 50 kHz with 400 µA by Data Input (Poecking, Germany) according to the manufacturer’s information. Two pairs of current-introducing and voltage-sensing electrodes were attached to the dorsum of hand and foot. All impedance measurements were taken after fasting, the arms relaxed at the sides without touching the body. The measurements were performed by the same skilled investigator in a standardized manner.
Laboratory analysis
In all patients, blood samples were taken after overnight fast at the time of diagnosis and as part of the regular follow-up visits after successful surgery. Venous blood samples were drawn, centrifuged and stored at −80°C. IGF-I measurements were performed using a multidiscipline automated system (IDS iSYS; Immunodiagnostic Systems, Bolden, UK). All samples were analyzed in one batch at the end of the observational period. IGF-I results were compared to method specific gender and age-adjusted reference intervals derived from a study in more than 15,000 subjects (38). s.d. scores (SDS) of IGF-I and IGF binding protein 3 (IGFBP 3) were calculated according to previous analyses (38, 39). The calculation of IGF-I to IGFBP 3 molar ratio was done after conversion into nanomoles per liter (IGF-I: ng/mL × 0.1307 = nmol/L; IGFBP 3: ng/mL × 0.03478 = nmol/L) (39). Acid labile subunit (ALS) was measured using an in-house immunofluorescence immunoassay (FIA) as described previously (40).
Statistical analysis
Statistical analysis was performed using SPSS 26 (IBM). Descriptive data are presented as median and interquartile range (IQR). For comparison between different time points Wilcoxon signed rank test was used. Differences between groups were analyzed using a nonparametric Mann–Whitney U-test. The leading hypothesis was that IGF-I concentrations or the IGF-I to IGFBP 3 molar ratio before or after surgery might be associated with muscle function and could be predictive for long-term myopathy outcome. Therefore, correlations between these biochemical and biometric parameters were determined using Spearman’s rank correlation coefficient (rs). P values below 0.05 were considered to indicate statistical significance.
Results
Patient characteristics and muscle strength
All 31 patients included in this study (74 % with pituitary CS and 26 % with adrenal CS) underwent successful surgery leading to biochemical remission and had regular follow-up studies until 3 years postoperatively. Ninety percent of patients received glucocorticoid replacement therapy at 6 months, 77% at 12 months, 68% at 24 months and 58% at 36 months. Table 1 summarizes the clinical and biochemical characteristics at the time of diagnosis and 6 months after surgery. Biochemical remission led to the expected reduction in BMI and HbA1c (Table 1). Age- and gender-corrected grip strength (normalized grip strength) was decreased after surgery (69% of normal controls at 6 months), with a subsequent improvement in the 2 year (P = 0.045) and 3 year follow-up studies (P = 0.003; Supplementary Fig. 1, see section on supplementary materials given at the end of this article), as shown previously (4).
Preoperative (Florid CS) and 6 months follow-up characteristics of patients with CS. Data are given as median and 25th and 75th percentile in brackets. Comparisons were performed by a Wilcoxon signed rank test.
| Patient characteristics | Reference interval | Florid CS (n = 31) | 6 months remission (n = 29) | P value* |
|---|---|---|---|---|
| Sex, n (%) | — | |||
| Female | 21 (68%) | |||
| Male | 10 (32%) | |||
| Age, years | 47 (38, 58) | — | ||
| Diagnosis | — | |||
| Pituitary | 23 (74%) | |||
| Adrenal | 8 (26%) | |||
| BMI, kg/m2 | 29 (26, 34) | 28 (25, 32) | ≤0.001 | |
| HbA1c, % | 6.2 (5.4, 6.9) | 5.5 (5.2, 6.5) | ≤0.001 | |
| Insulin, µlU/mL | 3.2–16.3 | 13.5 (7.3, 22.6) | 9.6 (4.9, 20.6) | 0.370 |
| FPG, mg/dL | 60–99 | 99 (86, 125) | 92 (87, 104) | 0.191 |
| TSH, µU/mL | 0.27–4.20 | 1.1 (0.6, 1.4) | 1.8 (0.7, 2.4) | ≤0.001 |
| UFC, µg/24h | ≤83.0 | 686 (356, 847) | 22 (13, 45) | ≤0.001 |
| LNSC, ng/mL | ≤1.5 | 7.9 (3.2, 15.4) | 0.7 (0.3, 1.4) | ≤0.001 |
| LDDST, µg/dL | ≤2.0 | 11.9 (8.1,; 19.5) | 0.9 (0.7, 1.6) | 0.008 |
| ACTH, pg/mL | 4–50 | |||
| In pituitary CS (n = 23) | 60 (34, 83) | 9 (3, 15) | ≤0.001 | |
| In adrenal CS (n = 8) | 4 (2, 5) | 13 (5, 19) | 0.063 |
Bold P-values indicates statistical significance.
*Florid CS vs 6 months remission.
ACTH, adrenocorticotropic hormone; CS, Cushing’s syndrome; FPG, fasting plasma glucose; HbA1c, hemoglobin A1c; LDDST, low dose (1 mg) dexamethasone suppression test; LNSC, late night salivary cortisol; TSH, thyroid-stimulating hormone; UFC, urinary free cortisol.
Postoperative IGF-I concentrations following remission correlate with muscle function outcome
IGF-I SDS at 6 months follow-up correlated with normalized grip strength after 1 year (rs = 0.574, P = 0.003), 2 years (rs = 0.531, P = 0.005) and 3 years (rs = 0.696, P ≤ 0.001, Fig. 1A) in remission. IGF-I SDS additionally correlated with the relative change in grip strength at 3 years in relation to grip strength at 6 months follow-up (rs = 0.378, P = 0.048; data not shown). Figure 2 shows the course of grip strength in patients with CS in remission when dividing the patient cohort into three groups depending on serum IGF-I concentrations 6 months after curative surgery. Compared to patients with low IGF-I SDS (≤ −0.4, n = 10), patients with high IGF-I SDS (>1.4, n = 10) showed a better grip strength already after 1 year in remission (86 % of normal controls vs 56 % in patients with low IGF-I SDS, P = 0.009), and overall an improvement in grip strength within the period of observation (97 % of normal controls at 3 years vs 72 % at 6 months, P = 0.009, Fig. 2). Patients with low IGF-I SDS at 6 months, on the other hand, showed no improvement during remission and an adverse outcome with continued pronounced muscle dysfunction after 3 years (68 % of normal controls at 3 years vs 66 % at 6 months, P = 0.594, Fig. 2).
(A) Relationship between IGF-I SDS 6 months after surgical cure of Cushing’s syndrome (CS) and age and gender corrected grip strength (normalized grip strength, % of normal controls) after 3 years in remission. Line indicates estimated linear regression line. n = 29, Spearman‘s coefficient 0.696, R2 = 0.446, P ≤ 0.001. (B) Relationship between IGF-I SDS 6 months after surgery and lean body cell mass as surrogate for muscle mass measured by bio-impedance after 3 years in remission. Line indicates estimated linear regression line. n = 28, Spearman‘s coefficient 0.404, R2 = 0.126, P = 0.033.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
(A) Relationship between IGF-I SDS 6 months after surgical cure of Cushing’s syndrome (CS) and age and gender corrected grip strength (normalized grip strength, % of normal controls) after 3 years in remission. Line indicates estimated linear regression line. n = 29, Spearman‘s coefficient 0.696, R2 = 0.446, P ≤ 0.001. (B) Relationship between IGF-I SDS 6 months after surgery and lean body cell mass as surrogate for muscle mass measured by bio-impedance after 3 years in remission. Line indicates estimated linear regression line. n = 28, Spearman‘s coefficient 0.404, R2 = 0.126, P = 0.033.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
(A) Relationship between IGF-I SDS 6 months after surgical cure of Cushing’s syndrome (CS) and age and gender corrected grip strength (normalized grip strength, % of normal controls) after 3 years in remission. Line indicates estimated linear regression line. n = 29, Spearman‘s coefficient 0.696, R2 = 0.446, P ≤ 0.001. (B) Relationship between IGF-I SDS 6 months after surgery and lean body cell mass as surrogate for muscle mass measured by bio-impedance after 3 years in remission. Line indicates estimated linear regression line. n = 28, Spearman‘s coefficient 0.404, R2 = 0.126, P = 0.033.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
Course of age and gender corrected grip strength (normalized grip strength, % of normal controls) in patients after curative surgery for Cushing’s syndrome (mo = months; y = years). Division into three groups was made according to the IGF-I SDS at the time of 6 months after surgery (High IGF-I SDS: IGF-I SDS > 1.4, n = 10; Intermediate IGF-I SDS: IGF-I SDS < 1.4 and > −0.4, n = 9; Low IGF-I SDS: IGF-I SDS ≤ −0.4, n = 10). n = 29. Comparisons were performed by Mann–Whitney-U-Test and Wilcoxon signed rank test. Higher percentage indicates greater muscle strength. Data are given as mean ± s.e.m.; P < 0.05 was considered statistically significant. *P < 0.05 High IGF-I SDS vs Low IGF-I SDS, #P < 0.05 3 years follow-up vs 6 months follow-up.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
Course of age and gender corrected grip strength (normalized grip strength, % of normal controls) in patients after curative surgery for Cushing’s syndrome (mo = months; y = years). Division into three groups was made according to the IGF-I SDS at the time of 6 months after surgery (High IGF-I SDS: IGF-I SDS > 1.4, n = 10; Intermediate IGF-I SDS: IGF-I SDS < 1.4 and > −0.4, n = 9; Low IGF-I SDS: IGF-I SDS ≤ −0.4, n = 10). n = 29. Comparisons were performed by Mann–Whitney-U-Test and Wilcoxon signed rank test. Higher percentage indicates greater muscle strength. Data are given as mean ± s.e.m.; P < 0.05 was considered statistically significant. *P < 0.05 High IGF-I SDS vs Low IGF-I SDS, #P < 0.05 3 years follow-up vs 6 months follow-up.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
Course of age and gender corrected grip strength (normalized grip strength, % of normal controls) in patients after curative surgery for Cushing’s syndrome (mo = months; y = years). Division into three groups was made according to the IGF-I SDS at the time of 6 months after surgery (High IGF-I SDS: IGF-I SDS > 1.4, n = 10; Intermediate IGF-I SDS: IGF-I SDS < 1.4 and > −0.4, n = 9; Low IGF-I SDS: IGF-I SDS ≤ −0.4, n = 10). n = 29. Comparisons were performed by Mann–Whitney-U-Test and Wilcoxon signed rank test. Higher percentage indicates greater muscle strength. Data are given as mean ± s.e.m.; P < 0.05 was considered statistically significant. *P < 0.05 High IGF-I SDS vs Low IGF-I SDS, #P < 0.05 3 years follow-up vs 6 months follow-up.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
Furthermore, we observed a significant association between serum IGF-I concentrations at 6 months and lean body cell mass as surrogate for muscle mass measured by bio-impedance at 3 years (rs = 0.404, P = 0.033, Fig. 1B). In line with these observations, IGF-I to IGFBP 3 molar ratio at 6 months correlated with normalized grip strength after 1, 2 and 3 years as well as with lean body cell mass after 2 and 3 years (data not shown). Changes of individual IGF-I SDS from the time of florid hypercortisolism to 6 months after surgery also correlated with normalized grip strength at 3 years (rs = 0.493, P = 0.007; Supplementary Fig. 2). Serum testosterone, sex hormone binding globulin (SHBG), androstenedione and dehydroepiandrosteronesulfat (DHEAS) concentrations had no relevant influence on grip strength outcomes in our patients with CS in remission (data not shown).
IGF-I and IGFBP 3 concentrations after curative surgery
IGF-I and IGFBP 3 SDS are shown in Fig. 3A and B, respectively. Compared to the preoperative phase of florid hypercortisolism, IGFBP 3 SDS increased over time (Fig. 3B), and the IGF-I to IGFBP 3 molar ratio decreased accordingly after achieving remission (Fig. 3C). In contrast to the postoperative IGF-I concentrations, neither IGF-I nor the IGF-I to IGFBP 3 molar ratio during florid hypercortisolism correlated with grip strength outcome (Supplementary Table 1). Individual IGF-I concentrations in the postoperative phase up to 6 months after surgery changed markedly in both directions in relation to IGF-I concentrations during hypercortisolism, and remained mostly constant afterwards (Supplementary Fig. 3).
SDS of (A) IGF-I and (B) IGFBP 3 in patients with Cushing’s syndrome (CS) preoperative during hypercortisolism (gray shaded) and after curative surgery (mo = months; y = years). (C) IGF-I to IGFBP 3 molar ratio (nmol/L)/(nmol/L) and (D) ALS (mU/mL) during hypercortisolism (gray shaded) and after curative surgery. Box and whiskers (10–90 percentile), Florid CS: n = 31, 6 months: n = 29, 1 year: n = 29, 2 years: n = 27, 3 years: n = 31. Comparisons were performed by a Wilcoxon signed rank test; P < 0.05 was considered statistically significant. * P < 0.05 vs Florid CS.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
SDS of (A) IGF-I and (B) IGFBP 3 in patients with Cushing’s syndrome (CS) preoperative during hypercortisolism (gray shaded) and after curative surgery (mo = months; y = years). (C) IGF-I to IGFBP 3 molar ratio (nmol/L)/(nmol/L) and (D) ALS (mU/mL) during hypercortisolism (gray shaded) and after curative surgery. Box and whiskers (10–90 percentile), Florid CS: n = 31, 6 months: n = 29, 1 year: n = 29, 2 years: n = 27, 3 years: n = 31. Comparisons were performed by a Wilcoxon signed rank test; P < 0.05 was considered statistically significant. * P < 0.05 vs Florid CS.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
SDS of (A) IGF-I and (B) IGFBP 3 in patients with Cushing’s syndrome (CS) preoperative during hypercortisolism (gray shaded) and after curative surgery (mo = months; y = years). (C) IGF-I to IGFBP 3 molar ratio (nmol/L)/(nmol/L) and (D) ALS (mU/mL) during hypercortisolism (gray shaded) and after curative surgery. Box and whiskers (10–90 percentile), Florid CS: n = 31, 6 months: n = 29, 1 year: n = 29, 2 years: n = 27, 3 years: n = 31. Comparisons were performed by a Wilcoxon signed rank test; P < 0.05 was considered statistically significant. * P < 0.05 vs Florid CS.
Citation: European Journal of Endocrinology 184, 6; 10.1530/EJE-20-1285
Discussion
Cushing’s syndrome-associated myopathy is a prevalent and severe comorbidity with adverse prognosis causing impaired quality of life. In this study, we identified a close relationship between postoperative IGF-I concentrations and long-term muscle function outcome. Lower IGF-I concentrations 6 months after successful surgery correlated with lower muscle mass and with adverse long-term muscle function outcomes. These data are novel, identify an important pathophysiologic mechanism and a potentially druggable target in patients with endogenous CS.
IGF-I is known as a crucial factor mediating the regulation of anabolic muscle homeostasis in myofibers. By the suppression of proteolysis and activation of muscle protein synthesis through an activation of the mammalian target of rapamycin (mTOR) signaling pathway (41), IGF-I promotes muscle protein anabolism and increases muscle mass (7). Through the stimulation of myoblast proliferation and by modulating muscle environment, IGF-I plays a key role in promoting muscle regeneration (42). In muscle tissue, glucocorticoid administration leads to a decrease in IGF-I signaling and an increase in negative regulators of the mTOR pathways (27, 34). Interestingly, local overexpression of IGF-I protein was shown to prevent skeletal muscle atrophy in glucocorticoid-treated rats (43). Moreover, early and prophylactic IGF-I infusion therapy was more effective than delayed treatment in a rat model of glucocorticoid-induced myopathy (31). These results, in accordance with our findings, indicate that the biological action of IGF-I has a great impact on the further course of hypercortisolism-induced myopathy. The critical mechanisms of glucocorticoid-associated myopathy are still incompletely understood, and further research is necessary to clarify the role of IGF-I pathway and negative regulators of the IGF-I pathway such as myostatin (44), fibroblast growth factors and transforming growth factor beta (TGFβ).
A positive correlation of serum IGF-I and muscle function as well as muscle mass has already been described in patients with sarcopenia and advanced age (45, 46, 47). Furthermore, growth hormone therapy in patients with growth hormone deficiency is associated with an increase in muscle mass and muscle strength (48, 49, 50). In a recently published longitudinal multicenter study with 88 patients with endogenous CS (4), we reported on a persisting muscle dysfunction despite biochemical remission over 4 years, assessed by hand grip strength and the chair rising test. Chair rising test performance improved initially after achieving remission of CS, most likely as a result of weight reduction, but remained at a reduced level in the long term. The chair rising test is subject to many influencing factors such as BMI and age, and hand grip strength therefore in our opinion a more suitable outcome parameter to assess muscle function in this context. Strength measurements of individual muscle groups would be desirable in the future to better characterize hypercortisolism-induced muscle dysfunction. Grip strength measurements showed a temporary worsening in the postoperative phase that may be influenced by glucocorticoid withdrawal during this period. However, interestingly, the improvement of muscle function from this time to 3 years after curative surgery is strongly correlated to serum IGF-I concentrations in the postoperative phase (Fig. 2). In our previous study, we identified age, HbA1c and waist-to-hip ratio at the time of diagnosis as clinical factors associated with myopathy long-term outcome (4). Decreasing serum IGF-I over the life span (38) could provide an explanation for the worse myopathy outcome in older patients. Because of the known insulin-like effect of IGF-I with stimulation of glucose uptake (51), lower IGF-I concentrations could also explain a pronounced diabetic metabolic state and thus the observed adverse effects of a high HbA1c on myopathy outcome (4). In the present study, IGF-I concentrations during hypercortisolism correlated inversely with HbA1c as well as with fasting glucose concentrations (data not shown). In line with this observation, type 2 diabetes mellitus was previously associated with lower concentrations of IGF-I, regardless of obesity (52).
Sex steroids are known to have an impact on serum IGF-I concentrations. Estradiol inhibits hepatic IGF-I production and testosterone was shown to increase IGF-I (53, 54, 55, 56). In our analyses of sex steroids, testosterone, SHBG, androstenedione and DHEAS showed no correlation with serum IGF-I and muscle function outcome. Estradiol showed an inverse correlation with IGF-I SDS at the 3-years follow-up (data not shown). Moreover, IGF-I concentrations at the time of diagnosis or afterwards showed no relationship to the level of hypercortisolism or to the subtype of CS (data not shown). Since the assay methodology for quantification of IGF-I is challenging, and IGF-I concentrations are affected by age, sex, BMI and assay characteristics, interpretation of IGF-I quantitation should be done with caution (53, 54, 57). Furthermore, the observations should be interpreted carefully as our cohort consisted of only 31 patients, a limitation of this study.
Taken together, our data point toward an important role of individual serum IGF-I concentrations in the postoperative phase after glucocorticoid excess on reversing the catabolic effects on skeletal muscle. Therefore, in those patients who have low IGF-I concentrations postoperatively, the administration of GH or IGF-I could be beneficial and should be considered in a prospective trial. Noteworthy, a recent nation-wide Swedish cohort study reported a positive association of GH treatment and reduced long-term mortality in Cushing’s disease (58). As glucocorticoid-associated myopathy is the most common type of drug-induced myopathy with a frequency of up to 60% (6), a pharmacologic intervention might also be effective in this context. Further research is needed to investigate the crosstalk between glucocorticoid and IGF-I signaling as well as beneficial effects in patients with endogenous CS or long-term glucocorticoid treatment.
Conclusion
Serum IGF-I following remission of endogenous CS strongly correlated with muscle function outcome highlighting its potential impact on muscle regeneration after glucocorticoid excess.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EJE-20-1285.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
This work is part of the German Cushing’s Registry CUSTODES and has been supported by a grant from the Else Kröner-Fresenius Stiftung to M R (2012_A103 and 2015_A228). F B and M R are supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, Projektnummer: 314061271-TRR 205). L T B is supported by the Clinician Scientist Program RISE (Rare Important Syndromes in Endocrinology), supported by the Else-Kröner-Fresenius Stiftung and Eva Luise und Horst Köhler Stiftung. H S is supported by the Clinician Scientist PRogram In Vascular MEdicine (PRIME) funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project number MA 2186/14-1.
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