Since the glucocorticoid receptor defect is partial, the elevated circulating cortisol appears to be sufficient to compensate for the end-organ insensitivity. However, the excess ACTH results in increased production of adrenal steroids with salt-retaining (mineralocorticoid) activity, such as DOC and corticosterone (3), and/or androgenic activity, such as Δ4-androstenedione, dehydroepiandrosterone (DHEA) and DHEA-sulfate (47) (Fig. 4). Clinical manifestations due to the excess of mineralocorticoids (including cortisol itself), acting on the intact mineralocorticoid receptor of the patients, are hypertension with or without hypokalemic alkalosis. The increased amount of androgens, on the other hand, lead to acne, hirsutism and male pattern baldness, menstrual irregularities (oligo-amenorrhea), oligo-anovulation, and infertility in women. In children, the early and excessive prepubertal adrenal androgen secretion has been associated with ambiguous genitalia and precocious puberty. In adult men, oligospermia and infertility have been observed, possibly as the result of interference with FSH feedback regulation by the excessive adrenal androgens and/or by the ACTH –induced intratesticular growth of adrenal rests, which may occur as they do in classic and “late-onset” congenital adrenal hyperplasia (20). Because of the excessive secretion of adrenal androgens, bone mass (BMD measurements) is usually high-normal to elevated in patients with glucocorticoid resistance, in contrast to Cushing’s syndrome where osteoporosis is the hallmark. However, the clinical spectrum of this disease is quite broad, ranging from completely asymptomatic to mild and to severe symptomatic conditions. In fact, most of the patients diagnosed up to now and several subjects in the course of family studies were asymptomatic with only biochemical changes.

Figure 4. Pathophysiology of the clinical manifestations of glucocorticoid resistance in humans. Because of loss-of-function GR mutations, the HPA axis is reset at higher levels. This induces the pituitary gland to secrete an increased amount of ACTH and consequently the adrenal glands to secrete more cortisol. The elevated cortisol is sufficient to compensate for the end-organ insensitivity, while the excess ACTH results in increased production of glucocorticoid precursors with mineralocorticoid activity (DOC, deoxycorticosterone; B, corticosterone) and adrenal androgens.