Therapeutic strategies in adrenal insufficiency.

Severe chronic adrenal insufficiency (primary or secondary) is a potentially lethal disorder, unless the patient is regularly substituted with glucocorticoids, usually with hydrocortisone (15-25 mg/day) and with 9 alpha-fluor-hydrocortisone (0.05-0.2 mg/day) in addition in patients with the primary adrenal disorder (Addison's disease). In stressful situations and in febrile disorders, the glucocorticoid dosage must be increased prophylactically in order to prevent an "adrenal crisis". Most women with adrenal insufficiency will profit from the additional substitution of dehydroepiandrosterone (DHEA) with regard to well-being and sexual function. A patient with acute adrenal insufficiency will die if the diagnosis is missed and high-dose glucocorticoid treatment is not instituted immediately. Acute adrenal insufficiency developing de novo in an intensive care patient (e.g. from adrenal hemorrhage or adrenal vein thrombosis) is a most challenging diagnosis. In these patients, however, survival not only depends on glucocorticoid substitution but also on the underlying disease.

Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure.

Endogenous 17 beta-estradiol (E2) and low parenteral doses of exogenous E2 are vasodilators. High dose estrogens, especially ethinylestradiol (EE) and mestranol, stimulate the synthesis of hepatic proteins including coagulation factors, sex hormone binding globulin, and angiotensinogen (Aogen). In the steady state, high plasma levels of Aogen produce only a very small increase of angiotensin II (AII) and plasma renin activity, because AII inhibits the secretion of renin and lowers plasma renin concentration. However, the increase in AII is sufficient for a slight reduction in renal blood flow and a slight increase in exchangeable sodium and blood pressure; in susceptible women, blood pressure may rise considerably. Effects of estrogens on the brain may also be involved in blood pressure changes. Endogenous progesterone is a mineralocorticoid receptor antagonist. Endogenous or exogenous progesterone leads to sodium loss and a compensatory increase in renin secretion, plasma renin activity, AII, and plasma aldosterone, e.g. in the second half of the menstrual cycle. Synthetic progestogens are commonly devoid of the mineralocorticoid receptor antagonistic effect of progesterone, and some are weak estrogen receptor agonists. Combined use of EE and synthetic progestogens may therefore enhance estrogen effects on body sodium and blood pressure. A new progestogen (Drospirenone) with an antimineralocorticoid effect like that of progesterone is described that slightly lowers body weight and blood pressure in a contraceptive formulation together with EE. An almost ideal oral contraceptive would be progestogen like Drospirenone together with a low dose natural estrogen that does not stimulate Aogen synthesis. Since most oral formulations for postmenopausal estrogen replacement also stimulate hepatic protein synthesis (including Aogen) to some extent, the transdermal route of E2 application for contraceptive purposes should also be investigated, since it has reduced potential for undesirable side effects.

Ascorbate depletion prevents aldosterone stimulation by sodium deficiency in the guinea pig.

The concentration of ascorbic acid (vitamin C) in the adrenal cortex is higher than in any other organ. The role of vitamin C in the adrenal cortex is unknown, but data obtained with bovine adrenocortical cells in vitro favour its role as an antioxidant that especially protects aldosterone synthesis from damaging lipid peroxides. Alternatively, vitamin C could act as part of an auxiliary electron transport system for the last step of aldosterone synthesis. The effects of vitamin C depletion on adrenocortical function cannot be studied in the human for ethical reasons, so we subjected different groups of guinea pigs to vitamin C depletion, sodium depletion and combined vitamin C and sodium depletion. Other groups of animals on normal or vitamin C-deficient diets received high-dose adrenocorticotrophin (ACTH) injections for 3 days before sacrifice. Fifteen days of a vitamin C-free diet led to very low vitamin C levels in adrenals, liver and plasma without clear signs of scurvy. At this time, plasma aldosterone and aldosterone secretion by isolated adrenal cells were stimulated significantly by sodium deficiency. Simultaneous vitamin C depletion completely abolished the rise in aldosterone in vivo and in vitro, significantly reduced the conversion of [3H]deoxycorticosterone to [3H]aldosterone and impaired renal sodium conservation. Plasma renin activity (PRA), plasma ACTH and serum potassium were not different in the sodium-depleted and sodium plus vitamin C-depleted groups. Sodium depletion did not affect cortisol. Vitamin C depletion led to a significant increase in plasma cortisol without an increase in ACTH, while in vitro secretion of cortisol was slightly decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and therapy surveillance in Addison's disease: rapid adrenocorticotropin (ACTH) test and measurement of plasma ACTH, renin activity, and aldosterone.

The rapid ACTH injection test is an indirect screening test for adrenocortical insufficiency. As a supplement to this test, we evaluated the practicability of single measurements of plasma cortisol, ACTH, aldosterone, and PRA as a definitive diagnostic test of primary adrenocortical insufficiency (PAI). We also tested the value of PRA measurements during treatment with hydro- and fludrocortisone (HC and FC) as a guide for correct mineralocorticoid substitution. In 45 patients with PAI, results of the rapid ACTH test and single measurements of the four hormones (all tests between 0800-0900 h) were compared. Single hormone measurements were also made in 55 normal subjects and 46 patients with pituitary disease (cortisol and ACTH only), most of them with mild to severe secondary adrenocortical insufficiency (SAI). The rapid ACTH test was abnormal in 100% of 41 patients with PAI tested. Plasma ACTH, PRA, and the ratios of ACTH/cortisol and PRA/plasma or urinary aldosterone were clearly elevated in 100% of the patients with PAI. The ACTH/cortisol ratio also distinguished 100% of patients with PAI from those with SAI, but not always control subjects from those with SAI. Thus, dynamic tests (CRH or insulin tests) are indicated if SAI is suspected. PAI and involvement of zona fasciculata and glomerulosa function can be diagnosed with high reliability by measuring cortisol, ACTH, aldosterone, and PRA either together with the rapid ACTH test or later, after a short interval of steroid substitution. PRA measurements during treatment with HC and FC correlated better with the mineralocorticoid dose than plasma potassium and sodium levels. PRA measurement is a valuable guide for FC replacement therapy. It should be titrated into the upper normal range to avoid under- and overtreatment.