The conventional glucocorticoid replacement therapy in congenital adrenal hyperplasia (CAH) renders the cortisol levels unphysiological, which may cause symptoms and long-term complications. Glucocorticoid replacement is technically feasible by continuous subcutaneous hydrocortisone infusion (CSHI), and can mimic the normal diurnal cortisol rhythm. This method was recently applied to treat a patient through a critical phase of puberty. This is a clinical trial aiming to evaluate CSHI treatment in patients with CAH. The main objective is to determine the effects of CSHI on metabolic parameters (androstenedione and 17-hydroxyprogesterone profiles, and testosterone,adrenocorticotropic hormone(ACTH), cortisol, and bone markers), and to determine the required glucocorticoid doses. Secondary objectives are to determine effects on clinical status, body weight, blood pressure and other metabolic parameters, as well as on subjective health status (AddiQoL, SF36).

CAH patients are treated with glucocorticoids and mineralocorticoids. Ideally, the glucocorticoid doses should be sufficient to suppress the elevated ACTH secretion, and hence attenuate the increase in androgen levels. Because of this, CAH patients use higher steroid doses than patients with autoimmune adrenal insufficiency (Addison's disease) and therefore are in higher risk of developing glucocorticoid side effects. The natural glucocorticoids, hydrocortisone (cortisol) or cortisone acetate, are preferred during childhood because of the growth suppressive effects of the longer acting synthetic glucocorticoids, prednisolone and dexamethasone. There is no consensus as to which type of glucocorticoid and which doses should be used for adult CAH patients. Glucocorticoids display a typical diurnal variation, which the current therapy does not restore, leading to both to over- or undertreatment. Some CAH patients experience symptoms that may be due to unphysiological glucocorticoid replacement therapy.

For selected CAH patients with poor response to conventional replacement therapy, or with problematic side effects such as impaired growth, weight gain, metabolic syndrome, and osteoporosis, continuous subcutaneous hydrocortisone infusion (CSHI) might become a treatment option. CSHI treatment would also be facilitated by the use of the small disposable pumps now developed for insulin treatment.

CSHI: Pharmacodynamics, Pharmacokinetics, and safety Hydrocortisone is identical to cortisol; the pharmacodynamics does not depend on mode of delivery. A hydrocortisone solution can be safely applied for three days in the insulin pump without major day-to-day variation. A daily dose of 10 mg/m2 body surface area/day restores normal levels of saliva cortisol in most patients. Thus, it is possible to mimic the physiological diurnal cortisol variation seen in healthy subjects.

The study will compare two glucocorticoid replacement modalities in randomised order within each patient. Prior to Baseline there will be a period of dose adjustment for pump treatment. Patients will be educated in groups, and dose adjustments will be co-ordinated with regular visits at the outpatient clinic/telephone consultation combined with laboratory analyses.

The patients will be assigned a participation number and randomised to any of two treatment sequences (A-B or B-A). Should the need for an extra glucocorticoid dose occur (intercurrent illness) during the study, the patients should administer their previous glucocorticoid replacement for safety reasons. Extra doses should be recorded in the patient diary. Treatment A is current treatment, i.e. glucocorticoid and mineralocorticoid replacement according to best clinical judgement. Treatment B is CSHI with the initial standard dose of 10mg/m2/24hrs. Body surface area will be calculated according to the nomogram from the formula of Du Bois and Du Bois.

After 7 days after initiating pump therapy the patient should be reassessed with blood dots (17-hydroxyprogesterone) and saliva cortisol and saliva 17-hydroxyprogesterone measurements in the morning (0800-0900) and in the evening (2300-2400). Based on results of this testing the dose will be changed at the discretion of the investigator. The further new testing should be done within 7-10 days.

When the final dose is established a 24h urine measurement, blood test in the morning (17-hydroxyprogesterone and cortisol) and a salivary sample full profile (full profile Hrs. 0800, 0930, 1100, 1230, 1700, 2100, 2400, 0300), will be done before entering the study. The dose adjustment period will be unlimited but will take minimally 4 weeks (aiming to obtain normal range levels of morning serum cortisol (160- 620 nmol/l), and 3-4 times increase in morning serum 17-hydroxyprogesterone (0,3-8,6 nmol/l for females, 0,9-6,6 nmo/l for males), and midnight (24:00) saliva cortisol (<2,8 nmol/l) and a circadian pattern as indicated in figure 1.

Afterwards it will 4 weeks wash out period before starting, wash out period between treatments modalities will take 2 months.

Inclusion Criteria:

• verified salt-wasting CAH and simple virilizing CAH, on single prednisone, or hydrocortisone therapy.
• In case of concomitant endocrine/autoimmune diseases these should be on stable treatment during the study period.

Exclusion Criteria:

• Patients with diabetes mellitus on insulin pump treatment will not be included in this study
• cardiovascular disease, active malignant disease and pregnancy, and pharmacological treatment with glucocorticoids or drugs that interfere with cortisol metabolism (antiepileptics, rifampicin, St. Johns wart).