Advances in glucocorticoid therapy target congenital adrenal hyperplasia
HALIFAX, Nova Scotia — Novel formulations and delivery of steroids are producing better short-term outcomes for the treatment of congenital adrenal hyperplasia in clinical trials, according to a presenter here.
Adequate suppression of excess androgen requires cortisol replacement, but excessive replacement can result in adverse effects, such as obesity, short stature and lack of adequate growth in children, said Deborah Merke, MD, MS, a pediatric endocrinologist and senior investigator at the NIH Clinical Center in Bethesda, Maryland.
Further, insufficient cortisol replacement can result in hyperandrogenism, which can lead to short stature, infertility in either sex, tumor formation, and hirsutism and amenorrhea in women, Merke said.
“There is poor quality of life on both sides of the equation,” Merke told Endocrine Today. “Endocrinologists tend to find these patients challenging to treat. It’s a difficult balancing act between two undesirable states.”
Current therapies, such as hydrocortisone, prednisone and dexamethasone, do not provide replacement of cortisol that is physiologic, she said.
“Prednisone and dexamethasone both have a long half-life, and hydrocortisone has a short half-life,” Merke said. “If you are on three times a day cortisone, the cortisol replacement is not physiologic at all.”
A new oral preparation of hydrocortisone called Chronocort (Diurnal), available in a modified-release capsule formulation, delivers cortisone in such a way as to imitate the body’s natural 24-hour hormone cycle and respond to cortisol deficiency, according to Merke.
“The concept is to replace cortisol in a more physiologic manner. The medication is the same, but the formulation is different, and it results in a delayed and slow release. We are approximating physiologic cortisol secretion at either lower or similar doses in half of the patients. We were able to lower the dose of glucocorticoids and achieve better control of androgens and biomarkers of disease control,” she said.
A phase 2 study demonstrated that cortisol profiles were similar to physiologic cortisol secretion in patients with congenital adrenal hyperplasia. Six months of Chronocort led to a drop in hydrocortisone dose when compared with conventional therapy. The therapy also produced improvements in body composition.
“We saw an increase in muscle mass in females and a decrease in fat in males,” Merke said, noting a phase 3 study is in the planning stages.
Another investigation looked at the delivery of hydrocortisone with the use of a pump for continuous infusion, and investigators achieved curves that looked similar to physiologic secretion of cortisol, according to Merke.
“The pump is for patients who have challenges with oral therapy or comorbidities,” such as patients with gastrointestinal intolerance, she said. – by Louise Gagnon
Merke D, et al. Advances in glucocorticoid therapy in the treatment of congenital adrenal hyperplasia. Presented at: Canadian Pediatric Endocrine Group Scientific Meeting; Feb. 19-21, 2015; Halifax, Nova Scotia, Canada.
Disclosure: Merke reports no relevant financial relationships. Funding for the phase 2 Chronocort study was provided by Diurnal, the manufacturer of Chronocort, through an agreement with NIH. Medtronic donated pumps for the administration of hydrocortisone via pump.