Genetic Variations of Glucocorticoid Receptor May Explain Loss of Muscle Strength in Cushing’s, Study Says

Genetic variations in the glucocorticoid receptor may explain why some patients with Cushing’s syndrome lose muscle strength, a study suggests.

The study, “Glucocorticoid receptor polymorphisms influence muscle strength in Cushing’s syndrome,” was published in The Journal of Clinical Endocrinology & Metabolism.

Cushing’s syndrome is caused by the excessive production of the glucocorticoid hormone cortisol by the adrenal glands, which sit on top of the kidneys. The disease can be caused by external factors, including some medications, or by tumors that lead to the excessive production of cortisol.

Regardless of the underlying cause, the abnormally high levels of glucocorticoids in the body may lead to severe proximal myopathy, in which muscles become progressively weaker, especially in the legs.

Glucocorticoids seem to have this effect on muscles by promoting the destruction of proteins necessary for muscle function and, at the same time, by preventing the production of new proteins.

However, not all patients with Cushing’s end up developing proximal myopathy, despite having high levels of cortisol, suggesting that other factors may play a key role in the onset of muscle disease.

One of these factors may be the glucocorticoid receptor (GR) — the protein that interacts with cortisol and other glucocorticoids in the body — itself, since variations in the genetic sequence of this receptor have been shown to change the way it responds to glucocorticoid hormones.

“The two polymorphisms N363S (rs56149945) and BclI (rs41423247) have been shown to increase glucocorticoid sensitivity, leading to an increased prevalence of abdominal obesity, a higher body mass index, dyslipidemia [high lipid levels] and increased levels of morning serum cortisol. On the contrary, the ER22/23EK (rs6189/rs6190) and A3669G (rs6198) polymorphisms are associated with decreased glucocorticoid sensitivity and relative glucocorticoid resistance,” the researchers said in the study.

In this study, these investigators from the Charité Universitätsmedizin Berlin in Germany set out to explore if certain genetic variants of GR could be linked to the development of myopathy in people with Cushing’s.

The study involved 205 people with Cushing’s syndrome and 125 individuals who did not have the disease used as controls. All study participants were asked to use a hand-held dynamometer — a device that measures force — to determine their handgrip strength and to perform the chair rising test (CRT) to assess their leg strength.

Investigators also collected blood samples from the participants to isolate their DNA and analyze the gene sequence of their GR.

Analyses showed that, in patients with active Cushing’s, normal values of grip strength were more frequent among individuals carrying the A3669G variant, which had been associated with low glucocorticoid sensitivity, than among those carrying the normal version of the GR gene.

However, among those who were in remission and those who did not have Cushing’s, the researchers found no differences in grip strength between individuals who had the rare A3669G variant and those who had the more common version of the gene.

Investigators also found that men with Cushing’s who had the rare ER22/23EK variant had stronger handgrip strength than those with the normal version of the gene.

The two remaining GR variants — N363S and BclI — did not seem to affect grip strength. None of the GR variants had an effect on participants’ performance on CRT.

“We detected that muscle strength of GR A3669G … carriers is protected against glucocorticoid excess. Therefore, GR SNPs [genetic variants] might explain interindividual differences in glucocorticoid induced myopathy in states of high endogenous cortisol levels,” the researchers said.

“Interestingly, the polymorphisms [variations] that increase GR signaling do not worsen myopathy in our study. This suggests that CS [Cushing’s syndrome] myopathy might depend on a threshold effect: if excessive GR signaling is already existing, having even more GR signaling by certain polymorphisms might not further stimulate GR effects and might not make a significant difference. Such a conclusion although speculative should be tested in future studies,” they added.