Time course of 21-hydroxylase antibodies and long-term remission of subclinical autoimmune adrenalitis after corticosteroid therapy: case report.

Subclinical Addison's disease is characterized by the presence of adrenal autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21OHAb) with or without adrenal function failure. In our previous longitudinal study some patients with high titers of ACA and at stage 2 of subclinical adrenocortical failure showed disappearance of ACA with recovery of normal adrenocortical function after corticosteroid treatment for Graves' ophthalmopathy. To investigate whether corticosteroid-induced modification of the adrenal autoimmune markers can also involve 21OHAb and to evaluate whether the remission of subclinical adrenocortical failure can persist over a long period of time, we followed-up for 100 months the levels of 21OHAb and ACA as well as the metabolic markers of adrenal function in one patient with Graves' ophthalmopathy and at stage 2 of subclinical adrenocortical failure before and after corticosteroid therapy. A 34-yr-old woman with Graves' disease and active ophthalmopathy who was found to be positive for ACA and to have high PRA, low aldosterone levels, and normal basal ACTH and cortisol levels, but impaired cortisol response to ACTH was studied. The patient was treated with oral corticosteroid therapy for 6 months. After corticosteroid therapy, 21OHAb, initially positive, became negative in concomitance with the disappearance of ACA and the restoration of normal adrenal function. The disappearance of both 21OHAb and ACA and their prolonged absence during the follow-up suggest that corticosteroid treatment can induce long-term remission of subclinical adrenal insufficiency and prevent the onset of the clinical phase of the disease. Our pilot study may pave the way to future trials aimed at preventing the onset of the clinical signs of Addison's disease in ACA/21OHAb-positive patients.

Association of arginine vasopressin-secreting cell, steroid-secreting cell, adrenal and islet cell antibodies in a patient presenting with central diabetes insipidus, empty sella, subclinical adrenocortical failure and impaired glucose tolerance.

A 36-year-old woman with central diabetes insipidus (DI), diagnosed when she was 7, was referred to our Endocrine Unit in January 1993 for further hormonal investigations. Clinical and laboratory findings confirmed the diagnosis of central DI. Cranial computed tomography and magnetic resonance imaging showed only an empty sella. Moreover, we noted impaired glucose tolerance and unusual findings of subclinical adrenocortical failure, i.e. high plasma renin activity with normal aldosterone levels, high ACTH despite normal basal and ACTH-stimulated cortisol levels. Immunological study of the patient's serum showed the presence of arginine vasopressin (AVP)-secreting cell antibodies (Abs), steroid-producing cell Abs, adrenal and islet cell Abs. The following aspects of our case are stressed and discussed: (1) the presence of AVP-secreting cell Abs 29 years after the diagnosis of DI; (2) the association between DI, empty sella and subclinical autoimmune adrenocortical failure with unusual hormonal findings, and (3) impaired glucose tolerance with islet cell antibody positivity.

Lymphocyte subsets in major depressive patients. Influence of anxiety and corticoadrenal overdrive.

We studied 26 inpatients (17 females; mean age +/- SD: 41.2 +/- 14.3 years) who met the DSM III criteria for a major depressive episode and had a mean (+/- SD) Hamilton Depression Score of 19.3 +/- 8.0. All patients were drug free and medically healthy at the time of experimentation. We found a significant correlation between the CD4/CD8 ratio and the Hamilton Anxiety Score (r = 0.57, p less than 0.005). When splitting our sample in dexamethasone suppression test suppressors (DST-S) and nonsuppressors (DST-NS), this relationship appeared only in DST-NS (DST-NS: r = 0.81, p less than 0.005; DST-S: r = 0.20, p = NS). These results are discussed in terms of heterogeneity among major depressive disorders and possible relationships between catecholaminergic activity and the immune system.

[ACTH secretion in adrenocortical disorders].

Secretion of cortisol is under stimulatory regulation by ACTH, and cortisol secreted, in turn, inhibits ACTH secretion by the pituitary. Therefore, measurement of plasma ACTH is indispensable in the diagnosis of the adrenocortical diseases. The adrenal cortex is included in the hypothalamo-adenohypophysial-adrenocortical system, and the pathogenesis of these disorders must be evaluated. An interaction between the hypothalamo-adenohypophysial-adrenal system and the immune system have been suggested. We studied the effect of interleukin-1 (IL-1) on ACTH secretion by cultured rat pituitary cells in vitro. Our results suggest that IL-1 stimulates the ACTH secretion by enhancing its synthesis by the pituitary, rather than ACTH release.

Familial Cushing's syndrome due to nodular adrenocortical dysplasia is an inherited disease of immunological origin.

Circulating immunoglobulins may be involved in the pathogenesis of familial Cushing's syndrome due to nodular adrenocortical dysplasia. The disease may also be part of a complex including cutaneous and cardiac myxomas, spotty pigmentation of the skin, and other signs of endocrine overactivity. In the present study of two sisters treated by complete adrenalectomy for Cushing's syndrome due to nodular adrenocortical dysplasia, and of their first-degree relatives, no evidence of associated disorders was present. However, the serum of both girls and of their mother contained immunoglobulins capable of stimulating adrenal DNA synthesis and cortisol production in vitro. The study supports the theory that familial Cushing's syndrome due to adrenocortical dysplasia is an inherited disease of immunological origin.

Anti-corticosteroid antibodies in AIDS patients.

Patients suffering from AIDS tend to have symptoms that resemble those encountered in adrenocortical insufficiency. Serum sodium concentrations and blood pressure values were monitored and found to be subnormal, despite the fact that renin activity and aldosterone levels were either normal or elevated. We report the presence of autoantibodies directed against hydrocortisone among such AIDS patients. Indirect immunofluorescence technique using patients' sera and adrenal glands from AIDS patients as antigen showed antibodies to adrenocortical cells in sera from 9 of the 12 AIDS patients and in none from patients with autoimmune diseases and viral diseases or healthy blood donors. No similar reaction was seen in normal human or monkey adrenal glands. An ELISA technique was developed using hydrocortisone as antigen and using this technique 45% of the AIDS patients were found to have antibodies to hydrocortisone. It is possible that anti-corticosteroid antibodies (ACSA) may play a role in the pathophysiology of the Addison's like syndrome seen in terminal phases of AIDS.

Immunoglobulins of patients with Cushing's syndrome due to pigmented adrenocortical micronodular dysplasia stimulate in vitro steroidogenesis.

The putative stimulation of adrenal steroid production by immunoglobulins (Igs) of five patients with pigmented adrenocortical micronodular dysplasia and clinical Cushing's syndrome was investigated. Ascorbate depletion, a process linked to steroid production, was measured by a cyto-chemical bioassay employing guinea pig adrenal explants in organ culture and exposed to IgG from the patients and normal subjects. We also measured cortisol production by these segments during a 5-h culture period using a RIA. For positive reference values we studied the effects of ACTH-(1-39), ACTH-(1-24), ACTH-(11-24), and ACTH-(18-39) on in vitro ascorbate depletion and cortisol production. Both ACTH-(1-39) and ACTH-(1-24) depleted ascorbate and stimulated cortisol production in adrenal cells. The dose-response kinetics of the peptides were bell-shaped; maximal responses were reached in both instances at 1 fmol/L to 10 pmol/L. In all tests, stimulation of in vitro cortisol production was paralleled by ascorbate depletion. ACTH-(18-39) also stimulated ascorbate depletion and cortisol production, but at one concentration only (100 fmol/L), and TSH and LH had no effect. Protein-A-Sepharose-purified IgG preparations of the five patients stimulated ascorbate depletion and/or cortisol production in a dose-dependent fashion; however, the responses occurred over a narrow concentration range (15-150 micrograms IgG/mL culture fluid). These observations support the hypothesis that the hypercortisolism of the syndrome of pigmented adrenocortical micronodular dysplasia is due to circulating Igs that stimulate adrenal steroidogenesis.

Familial Cushing's syndrome due to nodular adrenocortical dysplasia. A putative receptor-antibody disease?

Two sisters aged 13 and 19 years suffering from familial Cushing's syndrome due to nodular adrenocortical dysplasia are described. Pituitary adrenocortical function tests indicated the presence of adrenal autonomy. Adrenal scintigraphy showed bilateral symmetrical uptake indicating the bilateral character of the autonomous process. Complete adrenalectomy was performed in both girls. The adrenals were of about normal weight showing numerous dark brown pigmented nodules and small perivascular lymphocytic infiltrates. Serum immunoglobulin preparations obtained from both girls stimulated adrenocortical cell growth in a cytochemical bioassay system. It is proposed that circulating growth factors may be involved in the pathogenesis of the disease.