These constitute the most commonly reported systemic adverse effects [23]. The HPA axis is a finely regulated, interlinked system of hormones with widespread effects on body metabolism including maintenance of blood glucose levels and response to stress. Almost all TC molecules have the ability to suppress the HPA axis; however, the menace is more with the class I molecules especially clobetasol (0.05% ointment) which can cause suppression at doses as less as 2 g/day within a few days of use. Continuous use leads to increase in bodyweight, development of moon face, buffalo hump, striae, delayed wound healing, and other features of Cushing’s syndrome. Exogenous TC molecules suppress the release of CRH and ACTH leading to decreased stimulation of the adrenal glands and consequent low levels of endogenously produced cortisol. This results in a form of secondary adrenal insufficiency. Sudden stoppage of TC application in such patients may lead to Addisonian crisis. Recovery of the HPA axis occurs spontaneously once the TC application stops. The recovery period of HPA axis suppression was reported to be 3.49 ± 2.92 and 3.84 ± 2.51 months in children and adult, respectively [23]. Laboratory investigations recommended for assessment of HPA axis function are enlisted in Table 25.3.

Growth retardation and delayed puberty are seen in children especially those with atopic dermatitis who are exposed to long duration of TC therapy [7]. Delayed puberty and decreased bone age are often because of low growth hormone (GH) and thyroid hormone levels as a result of a generalized suppression of hypothalamic and pituitary function. However, premature closure of the epiphyses resulting in a small but significant diminution of final height has been reported in children exposed to systemic corticosteroid [7].

In adults, glucocorticoid-induced osteoporosis mostly affects the cancellous bones; hence, vertebral bodies and ribs are most commonly affected. Vertebral fractures and hip fracture may occur after several years of therapy with large amounts of potent TC [27, 28]. Females especially postmenopausal, geriatric patients and those with concurrent disease like COPD are at higher risk of developing such complications [7]. The mechanism of corticosteroid-induced bone loss is complex and is schematically depicted in Fig. 25.1.

High level of systemic glucocorticoids is one of the most important causes of avascular bone necrosis (AVN) or osteonecrosis [29]. It involves bones with a single terminal blood supply and leads to progressive destruction of the bone as a result of compromise of bone vasculature, the femoral head being the most commonly affected. The mechanism of glucocorticoid-induced AVN is not fully understood till date. Several hypotheses exist which include fat cell hypertrophy, fat embolization, intravascular coagulation, and osteocyte apoptosis, all resulting in compromise of bone vasculature and marrow, leading to ischemic necrosis of the femoral head and subsequent collapse of the bone [29].

Glucocorticoid causes muscle atrophy due to overall catabolic effect on muscles [30]. It inhibits glucose uptake and utilization by the skeletal muscles and also increases the breakdown of muscle proteins and decreases protein synthesis. The effect is more pronounced in the proximal muscle groups with the muscles around the hip joint and quadriceps being more severely involved [31].

Glucocorticoids can induce diabetes in previously nondiabetic patients or may worsen the glycemic control in persons with preexisting diabetes [7]. It works synergistically with glucagon pathway, inhibits insulin release from the beta cells of pancreas, and promotes insulin resistance resulting in decreased glucose uptake and utilization in target organs (muscles and fatty tissue) [32].