Prevalence, risk factors and evolution of diabetes mellitus after treatment in primary aldosteronism. Results from the SPAIN-ALDO registry.

PURPOSE: To evaluate the prevalence, risk factors and evolution of diabetes mellitus (DM) after targeted treatment in patients with primary aldosteronism (PA). METHODS: A retrospective multicenter study of PA patients in follow-up at 27 Spanish tertiary hospitals (SPAIN-ALDO Register). RESULTS: Overall, 646 patients with PA were included. At diagnosis, 21.2% (n = 137) had DM and 67% of them had HbA1c levels < 7%. In multivariate analysis, family history of DM (OR 4.00 [1.68-9.53]), the coexistence of dyslipidemia (OR 3.57 [1.51-8.43]) and advanced age (OR 1.04 per year of increase [1.00-1.09]) were identified as independent predictive factors of DM. Diabetic patients were on beta blockers (46.7% (n = 64) vs. 27.5% (n = 140), P < 0.001) and diuretics (51.1% (n = 70) vs. 33.2% (n = 169), p < 0.001) more frequently than non-diabetics. After a median follow-up of 22 months [IQR 7.5-63.0], 6.9% of patients developed DM, with no difference between those undergoing adrenalectomy and those treated medically (HR 1.07 [0.49-2.36], p = 0.866). There was also no significant difference in the evolution of glycemic control between DM patients who underwent surgery and those medically treated (p > 0.05). CONCLUSION: DM affects about one quarter of patients with PA and the risk factors for its development are common to those of the general population. Medical and surgical treatment provides similar benefit in glycemic control in patients with PA and DM.

The increased circulating prostate-specific antigen concentrations in women with hirsutism do not respond to acute changes in adrenal or ovarian function.

Serum prostate-specific antigen (PSA) is produced in several female tissues and appears to be up-regulated by androgens. We have studied serum PSA concentrations in women with different forms of hyperandrogenism, focusing on the influence of changes in ovarian and adrenal function on these concentrations. Thirty-seven hirsute women were studied in the follicular phase of the menstrual cycle. Basal and ACTH-stimulated plasma samples were obtained, and sampling was repeated 1 (gonadal stimulation) and 21 (gonadal suppression) days after receiving a single im 3.75-mg dose of triptorelin. Eleven nonhyperandrogenic women served as controls. Hirsute women had increased PSA levels compared to controls. When considering the source of the hyperandrogenism, ovarian patients (those with increased serum androgen levels that normalized during gonadal suppression) and adrenal patients (those with increased androgen levels that remained elevated during gonadal suppression) presented increased PSA values, whereas hirsute patients without hyperandrogenemia had normal PSA levels. PSA levels did not change during ovarian or adrenal stimulation or during gonadal suppression with respect to initial values. Basal PSA levels showed significant correlations with basal total testosterone (r = 0.59; P < 0.001), free androgen index (r = 0.68; P < 0.001), sex hormone-binding globulin (r = -0.58; P < 0.001), dehydroepiandrosterone sulfate (r = 0.39; P < 0.01), 17-hydroxyprogesterone (r = 0.32; P < 0.05), and age (r = -0.33; P < 0.05) when patients and controls were considered as a whole. In conclusion, basal PSA levels are increased in hirsute patients and correlate with the degree of hyperandrogenism when patients and controls are considered as a whole. The adrenal and the ovary do not appear to be the source of PSA, suggesting that hyperandrogenism induces PSA secretion in tissues other than the adrenal and the ovary.

Insulin resistance in patients with a recent diagnosis of coronary artery disease.

OBJECTIVE: To elucidate whether insulin resistance is present in coronary artery disease (CAD) at diagnosis and to study its relationship with other known cardiovascular risk factors. METHODS: We evaluated the incidence of insulin resistance in 40 newly diagnosed CAD patients. Fifteen healthy subjects were used as a control group. The patients and controls had no previous history of metabolic disorders, and were not being administered any medication that might have affected their insulin sensitivity. Immediately after diagnosis of CAD, a standard 75 g oral glucose-tolerance test (OGTT) and an insulin suppression test (IST) were performed on separate days. The IST consisted of a constant infusion of glucose, insulin and somatostatin for 150 min; insulin resistance was estimated by determining the steady-state plasma glucose (SSPG) concentrations during the last 60 min of the test. The insulin sensitivity index (ISI) was calculated by the formula ISI = (glucose infusion rate/SSPG]x10(3). RESULTS: Insulin resistance, defined by an ISI below the normal range derived from the control group, was present in 82.5% of the CAD patients. As a group, the patients with CAD displayed lower ISI (means +/- SD:29.23 +/- 11.23 versus 50.33 +/- 9.37 dl/kg per min, P < 0.001) than did controls. Serum triglycerides and uric acid were higher and high-density lipoprotein cholesterol levels were lower in patients than they were in controls. No differences were observed in fasting plasma insulin, glucose, total and low-density lipoprotein cholesterol concentration. An abnormal OGTT result was observed in 27 patients. The ISI was low in 88.8% of the patients with an abnormal OGTT result and in 69% of the 13 patients with a normal OGTT result. CONCLUSIONS: Insulin resistance and even impaired glucose tolerance are common findings in CAD at diagnosis. The changes in the lipid profile and in uric acid levels paralleled the changes in insulin sensitivity. These results suggest that insulin resistance might play a role in the development of coronary atherosclerosis and that its early diagnosis might be important in the prophylaxis of CAD.

Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist?

To study ovarian and adrenal steroid profiles of women with idiopathic hirsutism, we compared sex steroid and basal and corticotropin (ACTH)-stimulated adrenal steroid levels before and after ovarian suppression induced by a long-acting gonadotropin-releasing hormone agonist analog (GnRH-a) in 24 hirsute women without hyperandrogenemia. Twelve healthy women served as controls for basal and ACTH-stimulated adrenal steroid levels. Serum levels of testosterone (T), sex hormone-binding globulin (SHBG), estradiol (E2), basal and ACTH-stimulated 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), delta 4-androstenedione (delta 4-A), 11-deoxycortisol (S) and cortisol (F), and basal and luteinizing hormone-releasing hormone (LHRH)-stimulated gonadotropin levels were measured before and 21 days after 3.75 mg intramuscular triptorelin in hirsute women. Basal T levels and basal and ACTH-stimulated delta 4-A, DHEA, and DHEAS levels were not different in hirsute women with respect to controls. Basal and ACTH-stimulated 17OHP was elevated, and decreased to normal after ovarian suppression with triptorelin. Although basal and ACTH-stimulated delta 4-A levels were normal, the delta delta 4-A/delta F and delta delta 4-A/delta 17OHP ratios were elevated and remained elevated after ovarian suppression, suggesting enhanced adrenal delta 4-17,20-lyase activity. T, F, S, and DHEAS levels were not affected by ovarian suppression. Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids. We conclude that idiopathic hirsute women with normoandrogenemia show an increase in ovarian secretion of 17OHP and a minimally increased adrenal delta 4-17, 20-lyase activity, suggesting that mild forms of ovarian and adrenal functional hyperandrogenism may be present in these patients with otherwise unexplained hirsutism.

Circulating leptin concentrations in women with hirsutism.

OBJECTIVE: To evaluate serum leptin concentrations in hirsute women. DESIGN: Controlled clinical study. SETTING: Tertiary institutional hospital. PATIENT(S): Thirty-three hirsute women and 11 healthy female controls. INTERVENTION(S): Serum samples were obtained at baseline and on day 1 (gonadal stimulation) and day 21 (gonadal suppression) after the IM injection of a single 3.75-mg dose of triptorelin. MAIN OUTCOME MEASURE(S): Leptin, T, sex hormone-binding globulin (SHBG), insulin, and glucose levels and free androgen index. RESULT(S): Leptin levels were increased in hirsute women in comparison with control subjects at baseline and on day 1. Leptin levels increased on day 1 compared with baseline and then decreased to baseline by day 21. Leptin levels correlated with body mass index (r = 0.76), SHBG levels (r = -0.52), free androgen index (r = 0.38), insulin levels (r = 0.46), and the glucose/insulin ratio (r = -0.38). When the effect of obesity on these results was removed by analysis of covariance and partial correlation analysis, leptin levels remained elevated only on day 1 and the only correlations that remained significant were those of leptin with insulin (r = 0.24) and the glucose/insulin ratio (r = -0.24). CONCLUSION(S): The increased leptin levels found in hirsute women are related mainly to obesity and also to insulin resistance. Leptin levels increased during gonadal stimulation and returned to baseline during gonadal suppression, suggesting that leptin also is influenced by the gonadal axis.

Abnormalities in the serum insulin-like growth factor-1 axis in women with hyperandrogenism.

OBJECTIVE: To study the insulin-like growth factor-1 (IGF-1) axis in hirsute women. DESIGN: Controlled clinical study. SETTING: Tertiary care institutional hospital. PATIENT(S): Forty hirsute women and 17 women with normal menstrual cycles. INTERVENTION(S): Basal and ACTH-stimulated samples were obtained, and sampling was repeated 1 (gonadal stimulation) and 21 (gonadal suppression) days after a single 3.75-mg IM dose of triptorelin. Controls did not receive triptorelin for ethical reasons. MAIN OUTCOME MEASURE(S): Serum GH, IGF-1, IGF-binding protein-3 (IGFBP-3), insulin, glucose, total testosterone, sex hormone-binding globulin, E2, and gonadotropin levels. Basal and ACTH-stimulated steroid precursors were measured. RESULT(S): Patients with idiopathic hirsutism were identified by normal serum androgen levels (n=17). Those with functional ovarian hyperandrogenism (n=15) were identified by an increase in the serum testosterone level that normalized during gonadal suppression, whereas those with functional adrenal hyperandrogenism (n=8) were identified by an initial increase in the testosterone level that persisted during gonadal suppression. The adrenal hyperandrogenism group had increased IGF-1 levels compared with the control, idiopathic hirsutism, and ovarian hyperandrogenism groups. Patients with ovarian hyperandrogenism had normal TGF-1 concentrations, but their IGFBP-3 concentrations were lower than those of controls. No differences were observed in GH levels between any of the groups. These results persisted when the influence of age was corrected for. CONCLUSION(S): The IGF-1 axis appears to be involved in the pathogenesis of hyperandrogenism, especially in patients with adrenal hyperandrogenism, who have a clear increase in IGF-1 levels. Moreover, patients with ovarian hirsutism have decreased IGFBP-3 concentrations, which might enhance IGF-1 bioavailability.

Lack of an ovarian function influence on the increased adrenal androgen secretion present in women with functional ovarian hyperandrogenism.

OBJECTIVE: To evaluate whether ovarian function might have an influence on the adrenal hyperandrogenism present in patients with functional ovarian hyperandrogenism. DESIGN: Controlled clinical study. SETTING: Tertiary institutional hospital. PATIENT(S): Twenty-nine hirsute women with functional ovarian hyperandrogenism and 12 normal controls. INTERVENTION(S): The ACTH and GnRH tests were performed before and during triptorelin-induced ovarian suppression in patients. The normal women served as controls for the ACTH test. MAIN OUTCOME MEASURE(S): Basal and ACTH-stimulated steroid values. RESULT(S): All patients presented elevated T and free androgen index, which normalized after triptorelin. Patients with functional ovarian hyperandrogenism and adrenal hyperandrogenism, defined by elevated basal DHEAS (n = 10), presented enhanced delta 4-17, 20-lyase activity, which persisted during ovarian suppression. delta 4-17,20-lyase activity was normal in the functional ovarian hyperandrogenism patients without adrenal hyperandrogenism (n = 19). No correlation was observed between the any of the indexes of the adrenal enzymatic activities evaluated and plasma E2 or T. CONCLUSION(S): Increased adrenal delta 4-17,20-lyase activity is present in functional ovarian hyperandrogenism women with adrenal hyperandrogenism. No influence of the excess ovarian androgens or estrogens was found on any of the adrenal enzymatic pathways explored.

Methimazole has no dose-related effect on the serum concentrations of soluble class I major histocompatibility complex antigens, soluble interleukin-2 receptor, and beta 2-microglobulin in patients with Graves' disease.

Soluble class I major histocompatibility antigens (sHLA), beta 2-microglobulin (beta 2-M), and soluble interleukin-2 receptor (sIL-2R), are secreted by B and T lymphocytes upon activation, and have been used as markers of immune activation in several diseases. Thirty-two Graves' disease patients were randomly assigned to three methimazole (MMI) regimens of treatment: (1) low-dose, starting with 45 mg/day, and lowering the dose thereafter to maintain normal serum thyroid hormones; (2) MMI 60 mg/day + levothyroxine, and (3) MMI 30 mg/day + levothyroxine. Serum sHLA, beta 2-M, sIL-2R, TSH receptor antibodies (TSH-R Ab), T3, and free T4 (fT4) were measured at diagnosis and at weeks 4, 12, and 24 (end of treatment). Patients were followed-up after treatment for at least 24 weeks (24 to 89). At diagnosis, serum levels of sIL-2R, beta 2-M, sHLA, and TSH-R Ab were elevated. Serum sIL-2R, beta 2-M, sHLA, and TSH-R Ab decreased with treatment. No effect of the varying MMI regimens on these parameters was observed. Soluble IL-2R correlated positively with T3, fT4, beta 2-M, sHLA, and TSH-R Ab. Statistically significant, but weak, correlations (r < 0.35) were observed between beta 2-M, sHLA, and TSH-R Ab, between beta 2-M, T3, and fT4, and between TSH-R Ab and T3. Recurrence rates were not associated either with the MMI regimen or any of the parameters studied, with the exception of elevated initial TSH-R Ab levels. Serum sHLA, beta 2-M, and sIL-2R are increased in untreated Graves' disease, and decrease during treatment. No MMI dose-related differences were observed in these parameters, and in the recurrence rate. Unfortunately, sHLA, beta 2-M, and sIL-2R were not useful predictors of prolonged remission after MMI treatment.

Isolated adrenocorticotropic hormone deficiency due to probable lymphocytic hypophysitis in a man.

We report a male patient who presented with severe fasting hypoglycemia in which extensive pituitary and adrenal investigations were diagnostic of isolated ACTH deficiency of pituitary origin. The finding of autoimmune subclinical primary hypothyroidism strongly suggested an autoimmune etiology of the pituitary disease. Lymphocytic hypophysitis, although very rare in male patients, has to be kept in mind when studying patients with pituitary failure of unknown origin, especially when other autoimmune endocrinopathy is present.

Evolution of insulin resistance in coronary artery disease patients on four different pharmacological therapies.

The objective of the study was to examine the evolution of insulin sensitivity in a group of patients with stable coronary artery disease receiving one of four different pharmacological therapies. Insulin sensitivity was evaluated using an insulin suppression test in 40 newly diagnosed patients with coronary artery disease and no previous history of metabolic disorders, who were not taking any medication which might affect insulin sensitivity. The insulin suppression test consisted of a constant infusion of glucose, insulin and somatostatin for 150 min; insulin resistance was estimated by determining the steady-state plasma glucose concentrations during the last 60 minutes of the test. The insulin sensitivity index was calculated by the formula: insulin sensitivity index = (glucose infusion rate/steady state plasma glucose concentrations) x 10(3). A second insulin suppression test was performed after 6 months' therapy with either isosorbide mononitrate, atenolol, diltiazem or captopril in 30 of the 40 patients. There were no differences between any of the groups before therapy was initiated. After 6 months, patients treated with captopril and, to a lesser extent, those treated with diltiazem showed statistically significantly decreased steady state plasma glucose concentrations and increased insulin sensitivity index compared to basal values. No statistically significant differences were found in the other two groups. We conclude that captopril and, to a lesser extent, diltiazem improve insulin sensitivity in patients with stable coronary artery disease.

Insulin resistance, dehydroepiandrosterone sulfate and sex hormone-binding globulin in essential hypertension.

OBJECTIVE: To evaluate insulin sensitivity, and serum levels of sex hormone-binding globulin (SHBG) and dehydroepiandrosterone sulfate (DHEA-sulfate), in patients with essential hypertension. DESIGN AND METHODS: In 15 non-treated hypertensive patients, insulin resistance was measured by an insulin suppression test (IST). Serum levels of DHEA-sulfate and SHBG were measured at the beginning and at the end of the IST. The results were compared to those of a control group of 10 healthy normotensive subjects matched for age, sex and body mass index (BMI).

Relationship between insulin sensitivity and dehydroepiandrosterone sulfate in patients with ischemic heart disease.

Insulin resistance has been related to the pathogenesis and development of ischemic heart disease (IHD). Dehydroepiandrosterone sulfate (DHEA-S) has been suggested as the possible link between these two entities. The aim of this study was to clarify the relationship between insulin resistance and DHEA-S in patients with IHD. Thirty-two male patients with newly-diagnosed IHD and without known metabolic disorders and 11 healthy matched controls were included in this study. Insulin sensitivity was assessed by an insulin suppression test, and DHEA-S levels were measured before the test (basal) and at the end of the test (during hyperinsulinemia). Insulin resistance, defined as an insulin sensitivity index (ISI) below the normal range derived from the control group, was present in 78% of IHD patients; they also displayed, as a group, lower ISI (P < 0.0001) than controls. DHEA-S levels were lower in IHD than in controls, both basal and during hyperinsulinemia (P < 0.05). DHEA-S levels decreased when hyperinsulinemia was achieved, both in IHD patients and controls (P < 0.0005). The magnitude of the decrease was the same in both groups. No correlation between ISI and DHEA-S levels was found. In conclusion, insulin sensitivity is lower in patients with IHD, even when major metabolic abnormalities associated with insulin resistance are excluded. These patients also show decreased DHEA-S levels, which are further reduced when acute induced hyperinsulinemia is achieved, although, as the decline was similar to that of controls, there does not seem to be resistance to this particular action of insulin.