Laura Barbetta

Diagnosis and management of Addison’s disease during pregnancy

Although primary adrenal failure is considered a rare condition, recent epidemiological studies indicate a rising incidence of the disease owing to the increase of autoimmune disorders. Addison’s disease may be a life-threatening condition and the occurrence of pregnancy has been considered as a dangerous event. Nowadays, adrenal insufficiency during pregnancy is associated with high incidence of serious fetal and maternal complications, as fetal death in utero and post-partum adrenal crises, only if the disorder is not recognized and adequately treated. In this article pathophysiological aspects, clinical features and guidelines of management of pregnancy in Addison’s disease are reviewed.

Effects of dehydroepiandrosterone (DHEA) supplementation on hormonal, metabolic and behavioral status in patients with hypoadrenalism

Oral DHEA administration to patients with hypoadrenalism, in addition to glucocorticoid and mineralcorticoid replacement, may improve both well-being and hormonal/metabolic parameters. Twenty patients (13 men, 7 women, 26276 yr, 11 with Addison’s disease, 9 with central hypoadrenalism) were recruited in a placebocontrolled, randomized study. Hormone levels, carbohydrate and lipid parameters, bone metabolism, body composition and psychological parameters were evaluated at baseline and after treatment with DHEA 50 mg/day or placebo for 4 months. After 4 months of DHEA administration, serum DHEAS levels raised both in men (from 0.71±0.18 to 8.28±1.66 μmol/l, p<0.005) and in women (from 0.25±0.07 to 5.65±1.93 μmol/l, p<0.05). Only in hypoadrenal women an increase in testosterone (T; from 0.4±0.1 to 1.45±0.26 nmol/l, p<0.05) and androstenedione (A; from 0.86±0.34 to 2.05±0.29 nmol/l, p<0.05) levels was observed. In men no significant modifications in T and 17-hydroxyprogesterone (17-OHP) levels were found, whereas serum SHBG significantly decreased. As far as the metabolic parameters are concerned, only in patients with Addison’s disease a significant decrease in total cholesterol and in low-density lipoproteins after 4 months of DHEA administration was found. No changes in glucose metabolism and insulin sensitivity were observed. In basal conditions, mean serum osteocalcin (OC) was normal and significantly decreased after DHEA treatment. A significant reduction in body fat mass percentage (BF%) after DHEA administration was observed. As far as well-being is concerned, DHEA replacement did not cause any relevant variation of subjective health scales and sexuality in both sexes. Our study confirms that DHEA may be beneficial for female patients with hypoadrenalism, mainly in restoring androgen levels. Concerning the health status, more sensitive and specific instruments to measure the effects of DHEA treatment could be necessary.

Coexistence of 21-Hydroxylase and 11β-Hydroxylase Deficiency in Adrenal Incidentalomas and in Subclinical Cushing’s Syndrome

Objective: The prevalence of steroid secretion abnormalities was studied by evaluating the 17-hydroxyprogesterone (17-OHP) and 11-deoxycortisol (S) responses to adrenocorticotropic hormone (ACTH) stimulation in 48 patients with ‘nonfunctioning’ incidentalomas and in 10 patients with ‘subclinical’ Cushing’s syndrome. Methods: In all patients the cortisol, 17-OHP, and S levels were measured after ACTH test. Eight patients were reinvestigated after surgery. Results: In patients with nonfunctioning lesions, the ACTH test induced 17-OHP and S peaks higher than in normals (p < 0.005). In 10 cases an augmented rise of 17-OHP and S was observed. In patients with subclinical Cushing’s syndrome, the 17-OHP peak after ACTH was greater than in patients with nonfunctioning lesions and in normals (p < 0.005); the S peak was also higher than in controls (p < 0.005). In 7 of 8 operated patients, the exaggerated 17-OHP peak was normalized. Conclusions: A combined impairment of different enzyme activities is frequently present in adrenal incidentalomas; the alteration of enzymatic pathways can also coexist with the presence of partial cortisol autonomy.

Comparison of different regimens of glucocorticoid replacement therapy in patients with hypoadrenalism

Since the optimal glucocorticoid replacement needs to avoid over and under treatment, the adequacy of different daily cortisone acetate (CA) doses was assessed in 34 patients with primary and central hypoadrenalism. The conventional twice CA 37.5 mg/day dose was administered to all patients (A regimen: 25 mg at 07:00 h, 12.5 mg at 15:00 h), while in 2 subgroups of 12 patients the dose was shifted on 2 thrice daily regimens (B: 25 mg at 07:00, 6.25 mg at 12: 00, 6.25 mg at 17:00; C: 12.5 mg, 12.5 mg, 12.5 mg). In other 12 patients the conventional dose was reduced to a thrice 25 mg/day administration (D regimen: 12.5 mg, 6.25 mg, 6.25 mg). In all patients, urinary free cortisol (UFC) excretion and cortisol day curves were evaluated. During the CA 37.5 mg administration, nadir cortisol levels were significantly higher with the thrice daily regimens (143±31 on B and 151±34 nmol/l on C) than with the conventional twice (85±16 nmol/l). Moreover, UFC, morning cortisol levels and mean cortisol day curves were similar in each group. Finally, during D regimen nadir cortisol levels were higher than in A and similar to B and C regimens. No difference in UFC and in cortisol day curves by reducing the CA dose was found. In conclusion, the thrice daily cortisone regimens, in which more physiological cortisol levels are achieved, perform better as replacement therapy. The administration of 25 mg/day CA confirms that replacement therapy is more adequate with a lower dose, particularly in patients with central hypoadrenalism.

Baseline and CRH-stimulated ACTH and cortisol levels after administration of the peroxisome proliferator-activated receptor-γ ligand, rosiglitazone, in Cushing’s disease

The ability of acute rosiglitazone administration in influencing ACTH/cortisol secretion in basal conditions and after CRH stimulation was studied in patients with Cushing’s disease. Ten patients (8 women and 2 men, aged 18–65 yr) with Cushing’s disease were enrolled in the study: 6 of them had previously undergone unsuccessful surgery and 4 were untreated. Plasma ACTH and serum cortisol levels were evaluated at serial time points for 3 h during saline infusion and after the administration of rosiglitazone (8 mg, po) and for 1 h after the injection of CRH (1 μg/kg iv) given alone or 30 min following rosiglitazone administration. The 4 tests were performed in all subjects in randomized order on different days. No significant difference was observed between the pattern of hormone secretion during saline alone and after rosiglitazone, as evaluated by two-way analysis of variance (ANOVA). The integrated areas under the curves (AUCs) were also not significantly different (ACTH: 5683±1038 vs 6111±1007 pg/ml/180 min; cortisol: 2333±267 vs 2902±486 μg/dl/180 min). In addition, there was no difference for ACTH and cortisol responses to CRH given either alone or after rosiglitazone, when evaluated as peak, increment or AUC; the pattern of the responses analyzed by two-way ANOVA was also similar. In conclusion: 1) the administration of a single dose of rosiglitazone did not decrease ACTH/cortisol levels or blunt their response after CRH injection; 2) the activation of PPAR-γ receptors by rosiglitazone seems unable to affect ACTH and cortisol secretion, at least in acute conditions, in patients with ACTH-secreting pituitary adenomas.

Comparison between buserelin and dexamethasone testing in the assessment of hirsutism

Many hirsute women may present a form of functional ovarian hyperandrogenism (FOH), since they show an exaggerated 17-hydroxyprogesterone (17-OHP) response to GnRH agonists administration. As the failure of dexamethasone to reduce testosterone levels may be indicative of an ovarian source of androgen secretion, we evaluated the usefulness of dexamethasone suppression test, in comparison with buserelin challenge, in the assessment of hirsutism. Twenty-seven hirsute women (aged 15–42 yr) underwent ACTH and buserelin tests: 4 patients were heterozygotes for 21-OH deficiency and 8 patients were affected with FOH: 2 of the patients with hyperresponse to buserelin also had 21-hydroxylase deficiency. The results of the dexamethasone suppression test (2 mg/day for 7 days) were compared to those obtained after buserelin test. Basal T and Δ4 levels (mean±SE) were higher than in controls (4.2±0.5 vs 2.2±0.2 nmol/l and 10.9±0.9 vs 5.9±0.6 nmol/l, p<0.02), while no differences were found in 17-OHP and DHEAS levels. A significant reduction (p<0.001) in T (1.8±0.4 nmol/l), Δ4 (3.2±0.5 nmol/l) and DHEAS levels (2.4±0.3 μmol/l) was observed at the 3rd day of dexamethasone administration and no differences between sampling at 3rd, 5th and 7th day were found. Serum T was not suppressed in 6 cases, Δ? and DHEAS levels in 3 and 1 of them, respectively. Buserelin injection caused an excessive 17-OHP response in 8 patients, only 4 of them did not reduce T levels during dexamethasone. The sensitivity and specificity of the dexamethasone suppression test, with respect to the buserelin test, were 50% and 89%, respectively. In conclusion, 37% of hirsute patients had an abnormal responsiveness to buserelin and/or ACTH tests, indicating that hormonal investigations are mandatory. An ovarian origin of hirsutism was identified by buserelin test in 30% of patients and by dexamethasone in 22% of cases; only 4 of 8 patients showed concordant results to both tests. Therefore, buserelin challenge seems a more useful, cost-effective and less time consuming tool than dexamethasone administration in order to recognize the possible ovarian origin of hyperandrogenism.