Inadequacies of glucocorticoid replacement and improvements by physiological circadian therapy

Abstract

Patients with adrenal insufficiency need lifelong glucocorticoid replacement, but many suffer from poor quality of life, and overall there is increased mortality. Moreover, it appears that use of glucocorticoids at the higher end of the replacement dose range is associated with increased risk for cardiovascular and metabolic bone disease. These data highlight some of the inadequacies of current regimes.The cortisol production rate is estimated to be equivalent to 5.7-7.4 mg/m 2 per day, and a major difficulty for replacement regimes is the inability to match the distinct circadian rhythm of circulating cortisol levels, which are low at the time of sleep onset, rise between 0200 and 0400 h, peaking just after waking and then fall during the day. Another issue is that current dose equivalents of glucocorticoids used for replacement are based on anti-inflammatory potency, and few data exist as to doses needed for equivalent cardiovascular and bone effects. Weight-adjusted, thrice-daily dosing using hydrocortisone (HC) reduces glucocorticoid overexposure and represents the most refined regime for current oral therapy, but does not replicate the normal cortisol rhythm. Recently, proof-of-concept studies have shown that more physiological circadian glucocorticoid therapy using HC infusions and newly developed oral formulations of HC have the potential for better biochemical control in patients with adrenal insufficiency. Whether such physiological replacement will have an impact on the complications seen in patients with adrenal insufficiency will need to be analysed in future clinical trials.

Nieradykalne (oszczędzające) operacje guzów nadnerczy

“…It is especially important among young people. It predisposes to early osteoporosis, arterial hypertension, diabetes, and hypoandrogenism in women [2,6,7].…”

“…30% report feeling constant tiredness and severely constrained activity. 48% of patients consider themselves to be handicapped [11,12].…”

“…Szczególnie ważne staje się to u młodych ludzi. Usposabia do przedwczesnej osteoporozy, nadciśnienia tętniczego, cukrzycy, hypoandrogenizmu u kobiet [2,6,7]. Wyważenie wszystkich czynników mających znaczenie i wpływ na ważne decyzje dotyczące czasu ingerencji operacyjnej, jak również jej zakresu oraz przyjęcia odpowiedniej taktyki postępowania, zwłaszcza w zmianach obustronnych, poszerza terapię chorób nadnerczy o wykonywanie operacji nieradykalnych.…”

“…U 30% występuje poczucie przewlekłego przemęczenia i znacząco wymuszonej aktywności życiowej. Czterdzieści osiem procent pacjentów uważa siebie za upośledzonych [11,12].…”

Recent advancements in the drug treatment of endocrine diseases

“…29 The traditional hydrocortisone replacement dose of 30 mg/day in patients with adrenal insufficiency is likely to result in over-replacement and increased risk for cardiovascular disease and bone loss. For example, it has been shown that bone mineral density (BMD) at the femoral neck and lumbar spine is reduced in patients with Addison's disease, indicating undesirable effects of the replacement therapy.…”