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Barbara P. Lukert, Glucocorticoid Replacement—How Much Is Enough?, The Journal of Clinical Endocrinology & Metabolism, Volume 91, Issue 3, 1 March 2006, Pages 793–794, https://doi.org/10.1210/jc.2005-2737
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The physiological replacement of corticosteroids presents a difficult challenge. Replacing thyroid hormone is relatively straightforward because the half-life of T4 is long (days) and TSH secretion is not pulsatile; therefore, measuring TSH provides a reliable assessment of response. In comparison, the half-life of steroid hormones is relatively short (hours compared with days for T4), and ACTH secretion is pulsatile and cannot be used to monitor adequacy of glucocorticoid replacement. Adjusting the dose to suppress ACTH produces features of Cushing’s syndrome in patients with Addison’s disease. Avoiding overreplacement is problematic whether one is treating congenital adrenal hyperplasia (CAH), Addison’s disease, or pituitary insufficiency.
The relationship between excessive glucocorticoid replacement and osteoporosis has been reported repeatedly. Serum osteocalcin (a marker of bone formation) was suppressed and rose by 19% in a group of patients in whom the cortisol dose was reduced on the basis of peak cortisol and urine free cortisol measurements (1). Glucocorticoids cause rapid decline in bone mass through a variety of effects including inhibition of calcium absorption, suppression of gonadal hormone, and adrenal androgen secretion and, most importantly, direct effects on bone (2). Bone resorption is increased early after exposure to glucocorticoids due to enhanced expression of RANK ligand (RANK-L), collagenase-3, and colony-stimulating factor-1, and to inhibition of osteoprotegerin production by osteoblasts with consequent induction of osteoclastogenesis (3). Bone resorption eventually decreases due to a decline in the number of mature osteoblasts resulting in a decrease in osteoblastic signals required for osteoclastogenesis. The most profound and enduring effect of glucocorticoids is inhibition of bone formation secondary to a decrease in the number and activity of osteoblastic cells. The number of osteoblasts declines due to a decrease in differentiation of osteoblasts and a consequent increase in adipocytes along with an increase in apoptosis of mature osteoblasts and osteocytes (2). Osteoblast activity is reduced by glucocorticoid regulation of the IGF axis. Glucocorticoids inhibit transcription of IGF-I and IGF-binding protein-5, both of which normally promote bone formation (4, 5). Additional factors contributing to glucocorticoid-induced inhibition of bone formation include decreased activity of TGF-β and enhanced expression of dickkopf-1, which inhibits Wnt signaling (6, 7). All these glucocorticoid-induced alterations in bone metabolism cause the most rapid rates of bone loss observed in clinical medicine with the consequence of vertebral fractures in 30–50% of patients exposed to glucocorticoid excess.
