Postoperative IGF-I predicts

F Vogel and others 184:6 813–821

Clinical Study outcome of Cushing-associated
myopathy

Patients with low IGF-I after curative surgery

for Cushing’s syndrome have an adverse
long-term outcome of
hypercortisolism-induced myopathy
Frederick Vogel 1, Leah Braun1, German Rubinstein1, Stephanie Zopp1,
Sarina Benedix1, Holger Schneider1, Katrin Ritzel1, Katharina Schilbach1,
Ralf Schmidmaier1, Felix Beuschlein 1,2, Martin Bidlingmaier1 and Martin Reincke1 Correspondence
should be addressed
1
Medizinische Klinik und Poliklinik IV, LMU Klinikum, Ludwig-Maximilians-Universität München, Munich, Bayern, to M Reincke
Germany and 2Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, UniversitätsSpital Zürich, Email
Zurich, Switzerland Martin.Reincke@med.
uni-muenchen.de

Abstract
European Journal of Endocrinology

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.

European Journal of
Endocrinology
(2021) 184, 813–821

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

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Clinical Study F Vogel and others
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
European Journal of Endocrinology
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
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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
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Table 1 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.

European Journal of Endocrinology

*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.

electrodes were attached to the dorsum of hand and foot. Statistical analysis
All impedance measurements were taken after fasting,
Statistical analysis was performed using SPSS 26 (IBM).
the arms relaxed at the sides without touching the body.
Descriptive data are presented as median and interquartile
The measurements were performed by the same skilled
range (IQR). For comparison between different time points
investigator in a standardized manner.
Wilcoxon signed rank test was used. Differences between
groups were analyzed using a nonparametric Mann–
Laboratory analysis Whitney U-test. The leading hypothesis was that IGF-I
concentrations or the IGF-I to IGFBP 3 molar ratio before
In all patients, blood samples were taken after overnight
or after surgery might be associated with muscle function
fast at the time of diagnosis and as part of the regular
and could be predictive for long-term myopathy outcome.
follow-up visits after successful surgery. Venous blood
Therefore, correlations between these biochemical and
samples were drawn, centrifuged and stored at −80°C. IGF-I
biometric parameters were determined using Spearman’s
measurements were performed using a multidiscipline
rank correlation coefficient (rs). P values below 0.05 were
automated system (IDS iSYS; Immunodiagnostic Systems,
considered to indicate statistical significance.
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 Results
15,000 subjects (38). s.d. scores (SDS) of IGF-I and IGF
Patient characteristics and muscle strength
binding protein 3 (IGFBP 3) were calculated according to
previous analyses (38, 39). The calculation of IGF-I to IGFBP All 31 patients included in this study (74 % with pituitary
3 molar ratio was done after conversion into nanomoles CS and 26 % with adrenal CS) underwent successful
per liter (IGF-I: ng/mL × 0.1307  = nmol/L; IGFBP 3: surgery leading to biochemical remission and had regular
ng/mL × 0.03478 = nmol/L) (39). Acid labile subunit (ALS) follow-up studies until 3 years postoperatively. Ninety
was measured using an in-house immunofluorescence percent of patients received glucocorticoid replacement
immunoassay (FIA) as described previously (40). therapy at 6 months, 77% at 12 months, 68% at

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Clinical Study F Vogel and others
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).
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
European Journal of Endocrinology
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).
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
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Figure 1
(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.
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).
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
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Figure 2
European Journal of Endocrinology
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.
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
Postoperative IGF-I predicts
184:6 817
outcome of Cushing-associated
myopathy
Figure 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.
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
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Clinical Study F Vogel and others
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
European Journal of Endocrinology
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).
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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
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 Postoperative IGF-I predicts
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outcome of Cushing-associated
myopathy
Forschungsgemeinschaft (DFG, German Research Foundation) – project
number MA 2186/14-1.
References
1 Pecori Giraldi F, Moro M, Cavagnini F & Study Group on the
Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of
Endocrinology, Study Group on the Hypothalamo-Pituitary-
Adrenal Axis of the Italian Society. Gender-related differences in
the presentation and course of Cushing’s disease. Journal of Clinical
Endocrinology and Metabolism 2003 88 1554–1558. (https://doi.
org/10.1210/jc.2002-021518)
2 Berr CM, Stieg MR, Deutschbein T, Quinkler M, Schmidmaier R,
Osswald A, Reisch N, Ritzel K, Dimopoulou C, Fazel J et al.
Persistence of myopathy in Cushing’s syndrome: evaluation of the
German Cushing’s Registry. European Journal of Endocrinology 2017
176 737–746. (https://doi.org/10.1530/EJE-16-0689)
3 Geer EB, Shen W, Strohmayer E, Post KD & Freda PU. Body
composition and cardiovascular risk markers after remission of
Cushing’s disease: a prospective study using whole-body MRI. Journal
of Clinical Endocrinology and Metabolism 2012 97 1702–1711. (https://
doi.org/10.1210/jc.2011-3123)
4 Vogel F, Braun LT, Rubinstein G, Zopp S, Kunzel H, Strasding F,
Albani A, Riester A, Schmidmaier R, Bidlingmaier M et al. Persisting
European Journal of Endocrinology
muscle dysfunction in Cushing’s syndrome despite biochemical
remission. Journal of Clinical Endocrinology and Metabolism 2020 105.
(https://doi.org/10.1210/clinem/dgaa625)
5 Dirks-Naylor AJ & Griffiths CL. Glucocorticoid-induced apoptosis
and cellular mechanisms of myopathy. Journal of Steroid Biochemistry
and Molecular Biology 2009 117 1–7. (https://doi.org/10.1016/j.
jsbmb.2009.05.014)
6 Pereira RM & Freire de Carvalho J. Glucocorticoid-induced
myopathy. Joint Bone Spine 2011 78 41–44. (https://doi.org/10.1016/j.
jbspin.2010.02.025)
7 Webster JM, Fenton CG, Langen R & Hardy RS. Exploring the
interface between inflammatory and therapeutic glucocorticoid
induced bone and muscle loss. International Journal of Molecular
Sciences 2019 20 5768. (https://doi.org/10.3390/ijms20225768)
8 Frystyk J, Schou AJ, Heuck C, Vorum H, Lyngholm M, Flyvbjerg A &
Wolthers OD. Prednisolone reduces the ability of serum to activate
the IGF1 receptor in vitro without affecting circulating total or free
IGF1. European Journal of Endocrinology 2013 168 1–8. (https://doi.
org/10.1530/EJE-12-0518)
9 Casanueva FF, Burguera B, Muruais C & Dieguez C. Acute
administration of corticoids: a new and peculiar stimulus of growth
hormone secretion in man. Journal of Clinical Endocrinology and
Metabolism 1990 70 234–237. (https://doi.org/10.1210/jcem-70-1-
234)
10 Pekic S, Doknic M, Djurovic M, Damjanovic S, Petakov M,
Miljic D, Dieguez C, Casanueva FF & Popovic V. The influence
of serum cortisol levels on growth hormone responsiveness to
GH-releasing hormone plus GH-releasing peptide-6 in patients
with hypocortisolism. Hormones 2003 2 243–249. (https://doi.
org/10.14310/horm.2002.11106)
11 Mazziotti G & Giustina A. Glucocorticoids and the regulation of
growth hormone secretion. Nature Reviews: Endocrinology 2013 9
265–276. (https://doi.org/10.1038/nrendo.2013.5)
12 Tzanela M, Karavitaki N, Stylianidou C, Tsagarakis S &
Thalassinos NC. Assessment of GH reserve before and after successful
treatment of adult patients with Cushing’s syndrome. Clinical
Endocrinology 2004 60 309–314. (https://doi.org/10.1046/j.1365-
2265.2004.01976.x)
13 Magiakou MA, Mastorakos G, Gomez MT, Rose SR & Chrousos GP.
Suppressed spontaneous and stimulated growth hormone secretion
in patients with Cushing’s disease before and after surgical cure.
184:6 819
Journal of Clinical Endocrinology and Metabolism 1994 78 131–137.
(https://doi.org/10.1210/jcem.78.1.7507118)
14 Pecori Giraldi F, Andrioli M, De Marinis L, Bianchi A, Giampietro A,
De Martin M, Sacco E, Scacchi M, Pontecorvi A & Cavagnini F.
Significant GH deficiency after long-term cure by surgery in adult
patients with Cushing’s disease. European Journal of Endocrinology
2007 156 233–239. (https://doi.org/10.1530/eje.1.02329)
15 Palmieri S, Morelli V, Salcuni AS, Eller-Vainicher C, Cairoli E,
Zhukouskaya VV, Beck-Peccoz P, Scillitani A & Chiodini I. GH
secretion reserve in subclinical hypercortisolism. Pituitary 2014 17
470–476. (https://doi.org/10.1007/s11102-013-0528-7)
16 Formenti AM, Maffezzoni F, Doga M, Mazziotti G & Giustina A.
Growth hormone deficiency in treated acromegaly and active
Cushing’s syndrome. Best Practice and Research: Clinical Endocrinology
and Metabolism 2017 31 79–90. (https://doi.org/10.1016/j.
beem.2017.03.002)
17 Veldman RG, Frolich M, Pincus SM, Veldhuis JD & Roelfsema F.
Growth hormone and prolactin are secreted more irregularly in
patients with Cushing’s disease. Clinical Endocrinology 2000 52
625–632. (https://doi.org/10.1046/j.1365-2265.2000.00994.x)
18 Hotta M, Shibasaki T, Masuda A, Imaki T, Sugino N, Demura H,
Ling N & Shizume K. Effect of human growth hormone-releasing
hormone on GH secretion in Cushing’s syndrome and non-
endocrine disease patients treated with glucocorticoids. Life Sciences
1988 42 979–984. (https://doi.org/10.1016/0024-3205(88)90427-4)
19 Katznelson L, Laws ER, Jr, Melmed S, Molitch ME, Murad MH, Utz A,
Wass JA & Endocrine Society. Acromegaly: an endocrine society
clinical practice guideline. Journal of Clinical Endocrinology and
Metabolism 2014 99 3933–3951. (https://doi.org/10.1210/jc.2014-
2700)
20 English K, Chikani V, Dimeski G & Inder WJ. Elevated insulin-like
growth factor-1 in Cushing’s disease. Clinical Endocrinology 2019 91
141–147. (https://doi.org/10.1111/cen.13974)
21 Borges MH, Pinto AC, DiNinno FB, Camacho-Hubner C, Grossman A,
Kater CE & Lengyel AM. IGF-I levels rise and GH responses to GHRH
decrease during long-term prednisone treatment in man. Journal of
Endocrinological Investigation 1999 22 12–17. (https://doi.org/10.1007/
BF03345472)
22 Bang P, Degerblad M, Thoren M, Schwander J, Blum W & Hall K.
Insulin-like growth factor (IGF) I and II and IGF binding protein
(IGFBP) 1, 2 and 3 in serum from patients with Cushing’s syndrome.
Acta Endocrinologica 1993 128 397–404. (https://doi.org/10.1530/
acta.0.1280397)
23 Ramshanker N, Aagaard M, Hjortebjerg R, Voss TS, Moller N,
Jorgensen JOL, Jessen N, Bjerring P, Magnusson NE, Bjerre M et al.
Effects of prednisolone on serum and tissue fluid IGF-I receptor
activation and post-receptor signaling in humans. Journal of Clinical
Endocrinology and Metabolism 2017 102 4031–4040. (https://doi.
org/10.1210/jc.2017-00696)
24 Schakman O, Kalista S, Barbe C, Loumaye A & Thissen JP.
Glucocorticoid-induced skeletal muscle atrophy. International Journal
of Biochemistry and Cell Biology 2013 45 2163–2172. (https://doi.
org/10.1016/j.biocel.2013.05.036)
25 Inder WJ, Jang C, Obeyesekere VR & Alford FP. Dexamethasone
administration inhibits skeletal muscle expression of the androgen
receptor and IGF-1 – implications for steroid-induced myopathy.
Clinical Endocrinology 2010 73 126–132. (https://doi.org/10.1111/
j.1365-2265.2009.03683.x)
26 Frost RA & Lang CH. Regulation of insulin-like growth factor-I in
skeletal muscle and muscle cells. Minerva Endocrinologica 2003 28
53–73.
27 Gayan-Ramirez G, Vanderhoydonc F, Verhoeven G & Decramer M.
Acute treatment with corticosteroids decreases IGF-1 and IGF-2
expression in the rat diaphragm and gastrocnemius. American Journal
of Respiratory and Critical Care Medicine 1999 159 283–289. (https://
doi.org/10.1164/ajrccm.159.1.9803021)
https://eje.bioscientifica.com
Downloaded from Bioscientifica.com at 07/03/2022 06:11:02PM
via free access
 Postoperative IGF-I predicts
Clinical Study F Vogel and others
outcome of Cushing-associated
myopathy
28 Li BG, Hasselgren PO & Fang CH. Insulin-like growth factor-I
inhibits dexamethasone-induced proteolysis in cultured L6
myotubes through PI3K/Akt/GSK-3beta and PI3K/Akt/mTOR-
dependent mechanisms. International Journal of Biochemistry
and Cell Biology 2005 37 2207–2216. (https://doi.org/10.1016/j.
biocel.2005.04.008)
29 Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y,
Lin HC, Yancopoulos GD & Glass DJ. Insulin-like growth factor-1
(IGF-1) inversely regulates atrophy-induced genes via the
phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin
(PI3K/Akt/mTOR) pathway. Journal of Biological Chemistry 2005 280
2737–2744. (https://doi.org/10.1074/jbc.M407517200)
30 Sacheck JM, Ohtsuka A, McLary SC & Goldberg AL. IGF-I stimulates
muscle growth by suppressing protein breakdown and expression
of atrophy-related ubiquitin ligases, atrogin-1 and MuRF1. American
Journal of Physiology:. Endocrinology and Metabolism 2004 287
E591–E601. (https://doi.org/10.1152/ajpendo.00073.2004)
31 Tomas FM. The anti-catabolic efficacy of insulin-like growth
factor-I is enhanced by its early administration to rats receiving
dexamethasone. Journal of Endocrinology 1998 157 89–97. (https://
doi.org/10.1677/joe.0.1570089)
32 Tomas FM, Knowles SE, Owens PC, Chandler CS, Francis GL, Read LC
& Ballard FJ. Insulin-like growth factor-I (IGF-I) and especially IGF-I
variants are anabolic in dexamethasone-treated rats. Biochemical
Journal 1992 282 91–97. (https://doi.org/10.1042/bj2820091)
European Journal of Endocrinology
33 Kanda F, Takatani K, Okuda S, Matsushita T & Chihara K.
Preventive effects of insulinlike growth factor-I on steroid-
induced muscle atrophy. Muscle and Nerve 1999 22 213–217.
(https://doi.org/10.1002/(sici)1097-4598(199902)22:2<213::aid-
mus9>3.0.co;2-m)
34 Fournier M, Huang ZS, Li H, Da X, Cercek B & Lewis MI. Insulin-like
growth factor I prevents corticosteroid-induced diaphragm muscle
atrophy in emphysematous hamsters. American Journal of Physiology:
Regulatory, Integrative and Comparative Physiology 2003 285 R34–R43.
(https://doi.org/10.1152/ajpregu.00177.2002)
35 Braun LT, Riester A, Osswald-Kopp A, Fazel J, Rubinstein G,
Bidlingmaier M, Beuschlein F & Reincke M. Toward a diagnostic
score in Cushing’s syndrome. Frontiers in Endocrinology 2019 10 766.
(https://doi.org/10.3389/fendo.2019.00766)
36 Mathiowetz V, Kashman N, Volland G, Weber K, Dowe M & Rogers S.
Grip and pinch strength: normative data for adults. Archives of
Physical Medicine and Rehabilitation 1985 66 69–74.
37 Mathiowetz V, Wiemer DM & Federman SM. Grip and pinch
strength: norms for 6- to 19-year-olds. American Journal of
Occupational Therapy 1986 40 705–711. (https://doi.org/10.5014/
ajot.40.10.705)
38 Bidlingmaier M, Friedrich N, Emeny RT, Spranger J, Wolthers OD,
Roswall J, Korner A, Obermayer-Pietsch B, Hubener C, Dahlgren J
et al. Reference intervals for insulin-like growth factor-1 (IGF-I) from
birth to senescence: results from a multicenter study using a new
automated chemiluminescence IGF-I immunoassay conforming
to recent international recommendations. Journal of Clinical
Endocrinology and Metabolism 2014 99 1712–1721. (https://doi.
org/10.1210/jc.2013-3059)
39 Friedrich N, Wolthers OD, Arafat AM, Emeny RT, Spranger J,
Roswall J, Kratzsch J, Grabe HJ, Hubener C, Pfeiffer AF et al. Age- and
sex-specific reference intervals across life span for insulin-like growth
factor binding protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 ratio
measured by new automated chemiluminescence assays. Journal of
Clinical Endocrinology and Metabolism 2014 99 1675–1686. (https://
doi.org/10.1210/jc.2013-3060)
40 Morrison KM, Bidlingmaier M, Stadler S, Wu Z, Skriver L &
Strasburger CJ. Sample pre-treatment determines the clinical
usefulness of acid-labile subunit immunoassays in the diagnosis of
growth hormone deficiency and acromegaly. European Journal of
https://eje.bioscientifica.com
184:6 820
Endocrinology 2007 156 331–339. (https://doi.org/10.1530/EJE-06-
0592)
41 Schiaffino S & Mammucari C. Regulation of skeletal muscle growth
by the IGF1-Akt/PKB pathway: insights from genetic models. Skeletal
Muscle 2011 1 4. (https://doi.org/10.1186/2044-5040-1-4)
42 Forcina L, Miano C, Scicchitano BM & Musaro A. Signals from
the niche: insights into the role of IGF-1 and IL-6 in modulating
skeletal muscle fibrosis. Cells 2019 8 232. (https://doi.org/10.3390/
cells8030232)
43 Schakman O, Gilson H, de Coninck V, Lause P, Verniers J, Havaux X,
Ketelslegers JM & Thissen JP. Insulin-like growth factor-I gene
transfer by electroporation prevents skeletal muscle atrophy in
glucocorticoid-treated rats. Endocrinology 2005 146 1789–1797.
(https://doi.org/10.1210/en.2004-1594)
44 Ma K, Mallidis C, Bhasin S, Mahabadi V, Artaza J, Gonzalez-
Cadavid N, Arias J & Salehian B. Glucocorticoid-induced skeletal
muscle atrophy is associated with upregulation of myostatin
gene expression. American Journal of Physiology: Endocrinology
and Metabolism 2003 285 E363–E371. (https://doi.org/10.1152/
ajpendo.00487.2002)
45 Cappola AR, Bandeen-Roche K, Wand GS, Volpato S & Fried LP.
Association of IGF-I levels with muscle strength and mobility in
older women. Journal of Clinical Endocrinology and Metabolism 2001
86 4139–4146. (https://doi.org/10.1210/jcem.86.9.7868)
46 Bian A, Ma Y, Zhou X, Guo Y, Wang W, Zhang Y & Wang X.
Association between sarcopenia and levels of growth hormone
and insulin-like growth factor-1 in the elderly. BMC Musculoskeletal
Disorders 2020 21 214. (https://doi.org/10.1186/s12891-020-03236-y)
47 Ferrari U, Schmidmaier R, Jung T, Reincke M, Martini S, Schoser B,
Bidlingmaier M & Drey M. IGF-I/IGFBP3/ALS deficiency in
sarcopenia: low GHBP suggests GH resistance in a subgroup of
geriatric patients. Journal of Clinical Endocrinology and Metabolism
2021 106 e1698–e1707. (https://doi.org/10.1210/clinem/dgaa972)
48 Gotherstrom G, Elbornsson M, Stibrant-Sunnerhagen K,
Bengtsson BA, Johannsson G & Svensson J. Muscle strength in
elderly adults with GH deficiency after 10 years of GH replacement.
European Journal of Endocrinology 2010 163 207–215. (https://doi.
org/10.1530/EJE-10-0009)
49 Diez JJ, Sangiao-Alvarellos S & Cordido F. Treatment with growth
hormone for adults with growth hormone deficiency syndrome:
benefits and risks. International Journal of Molecular Sciences 2018 19
893. (https://doi.org/10.3390/ijms19030893)
50 Janssen YJ, Doornbos J & Roelfsema F. Changes in muscle volume,
strength, and bioenergetics during recombinant human growth
hormone (GH) therapy in adults with GH deficiency. Journal of
Clinical Endocrinology and Metabolism 1999 84 279–284. (https://doi.
org/10.1210/jcem.84.1.5411)
51 Clemmons DR. The relative roles of growth hormone and IGF-1 in
controlling insulin sensitivity. Journal of Clinical Investigation 2004
113 25–27. (https://doi.org/10.1172/JCI20660)
52 Aleidi SM, Shayeb E, Bzour J, Abu-Rish EY, Hudaib M, Al Alawi S &
Bustanji Y. Serum level of insulin-like growth factor-I in type 2 diabetic
patients: impact of obesity. Hormone Molecular Biology and Clinical
Investigation 2019 39. (https://doi.org/10.1515/hmbci-2019-0015)
53 Ketha H & Singh RJ. Clinical assays for quantitation of insulin-
like-growth-factor-1 (IGF1). Methods 2015 81 93–98. (https://doi.
org/10.1016/j.ymeth.2015.04.029)
54 Brick DJ, Gerweck AV, Meenaghan E, Lawson EA, Misra M, Fazeli P,
Johnson W, Klibanski A & Miller KK. Determinants of IGF1 and
GH across the weight spectrum: from anorexia nervosa to obesity.
European Journal of Endocrinology 2010 163 185–191. (https://doi.
org/10.1530/EJE-10-0365)
55 Gibney J, Wolthers T, Johannsson G, Umpleby AM & Ho KK. Growth
hormone and testosterone interact positively to enhance protein
and energy metabolism in hypopituitary men. American Journal
Downloaded from Bioscientifica.com at 07/03/2022 06:11:02PM
via free access
 Postoperative IGF-I predicts
Clinical Study F Vogel and others 184:6 821
outcome of Cushing-associated
myopathy

of Physiology: Endocrinology and Metabolism 2005 289 E266–E271.
(https://doi.org/10.1152/ajpendo.00483.2004)
56 Ohlsson C, Mohan S, Sjogren K, Tivesten A, Isgaard J, Isaksson O,
Jansson JO & Svensson J. The role of liver-derived insulin-like
growth factor-I. Endocrine Reviews 2009 30 494–535. (https://doi.
org/10.1210/er.2009-0010)
57 Hjortebjerg R & Frystyk J. Determination of IGFs and their
binding proteins. Best Practice and Research: Clinical Endocrinology
and Metabolism 2013 27 771–781. (https://doi.org/10.1016/j.
beem.2013.08.010)
58 Ragnarsson O, Olsson DS, Papakokkinou E, Chantzichristos D,
Dahlqvist P, Segerstedt E, Olsson T, Petersson M, Berinder K,
Bensing S et al. Overall and disease-specific mortality in patients
with Cushing disease: a Swedish nationwide study. Journal of Clinical
Endocrinology and Metabolism 2019 104 2375–2384. (https://doi.
org/10.1210/jc.2018-02524)

Received 7 December 2020

Revised version received 23 March 2021
Accepted 7 April 2021
European Journal of Endocrinology

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