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BRIEF REPORT |
Department of Medical and Surgical Sciences, Endocrinology Unit (P.S., E.Z., S.B., B.M., F.S., F.M., C.S.) and Internal Medicine Second Chair (F.B., A.P.), and Department of Pediatrics (G.P., N.G.), University of Padova, 35128 Padova, Italy
Address all correspondence and requests for reprints to: C. Scaroni, M.D., via Ospedale 105, University of Padova, 35128 Padova, Italy. E-mail: carla.scaroni{at}unipd.it.
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Abstract |
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Objective: The objective of the study was to evaluate glucose metabolism, lipid profile, IMT of the abdominal aorta, right and left common carotids, carotid bulbs, and common femoral arteries in adult CAH patients.
Subjects: Nineteen (10 females, nine males; 28 ± 3.5 yr) patients (12 salt wasting and seven simple virilizing) and 19 (10 females, nine males) healthy subjects matched for anthropometric parameters (age, sex, body mass index, smoking habit, waist to hip ratio, and blood pressure).
Methods: Glucose metabolism was studied using the oral glucose tolerance test and the homeostasis model assessment-insulin resistance. The echo-Doppler was used for arterial ultrasound. 17-Hydroxyprogesterone, androstenedione, testosterone, ACTH, plasma renin activity, total and high-density lipoprotein cholesterol, and triglycerides were measured.
Results: CAH patients had significantly higher fasting plasma insulin (11.6 ± 6.20 µU/ml vs 5.18 ± 2.4 µU/ml; P < 0.0001) and homeostasis model assessment-insulin resistance than controls (2.46 ± 1.92 vs 1.12 ± 0.58; P = 0.0033). IMT of the studied arteries was higher in CAH patients than controls. There was no correlation between IMT and cumulative glucocorticoid doses and androgen levels.
Conclusion: A reduced insulin sensitivity and increased IMT were demonstrated in adults with CAH, who consequently need a follow-up for cardiovascular risk.
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Introduction |
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Higher body mass index (BMI) (4, 5), body fat mass (6), insulin (7), and blood pressure (BP) levels (8) have been described in children or adolescents with CAH. Because patients survive into adulthood now, long-term complications have become an important issue.
There is increasing evidence that endothelial dysfunction and increased intima-media thickness (IMT) are precursors of clinically detectable atherosclerosis (9) and are associated with higher cardiovascular risk (10).
This study was designed to test cardiovascular risk indexes and signs of precocious arterial disease in 19 adult patients with classic 21OHD. We measured IMT at different arterial sites [right and left carotid bulbs (CBR-L), right and left common carotids (CCR-L), right and left common femoral arteries (CFR-L), abdominal aorta (AAo)] and evaluated patients’ metabolic data, comparing them with controls.
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Subjects and Methods |
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We considered 19 patients (10 females, nine males; 28 ± 3.5 yr); 12 of them (seven males and five females) had CAH classified as salt wasting (SW); the other seven (two males and five females) were diagnosed as simple virilizing (SV). The diagnosis of 21OHD was confirmed by genotype in 16 patients. With regard to the remaining three cases, two of them, one male and one female, presented with a SW phenotype, elevated 17-hydroxyprogesterone (17OHP), K+, ACTH, testosterone (T), androstenedione (
4-A), plasma renin activity, and low serum cortisol and aldosterone; the female also presented ambiguous genitalia. The third patient (one female) presented SV phenotype with ambiguous genitalia; hormonal data showed elevated 17OHP and low cortisol levels with normal potassium.
All patients received glucocorticoid replacement therapy with hydrocortisone (mean dose 25.2 ± 2 mg) or dexamethasone (0.4 ± 0.1 mg), and 12 patients also assumed mineralocorticoid therapy (9
-flurohydrocortisone, 0.12 ± 0.02 mg). The adequacy of therapy was monitored periodically on the basis of clinical and laboratory data, in accordance with current guidelines (11). None of the patients used additional medication.
Nineteen healthy volunteers subjects (10 females and nine males) matched for age, sex, BMI, waist to hip ratio (WHR), BP levels, smoking habit, and socioeconomic status (all subjects were Caucasians and enrolled in the same town) were enrolled and considered as the control group. None of them were taking any medication.
This study was conducted in accordance with the guidelines in The Declaration of Helsinki and was approved by the local ethical committee. All participants gave their informed consent.
Clinical study
Height, weight, BMI, WHR, and BP levels were evaluated using standard methods. A BMI between 25 and 29.9 kg/m2 was classified as overweight, a BMI of 30 kg/m2 or more as obesity. The average of three BP measurements taken with a sphygmomanometer on separate occasions was considered. WHR was measured as the ratio between the circumferences of the waist (the narrowest part of the torso between the 12th rib and the iliac crest) and hip (the maximal extension of the buttocks) (12).
Glucocorticoid dosages were expressed as the cumulative dose per body surface (gram per square meter) and calculated over 1 and 3 yr before the study. All the glucocorticoid dosages used were converted into a hydrocortisone dosage for the purpose of normalization (30 mg hydrocortisone = 0.75 mg dexamethasone).
Fasting plasma determinations of total (TOT C) and high-density lipoprotein cholesterol (HDL C) and triglycerides (TGC) were performed in patients and controls.
The oral glucose tolerance test (OGTT) was performed after an overnight fast of at least 10 h; a fasting blood sample was obtained at time 0 (between 0800 and 0900 h) for measurement of glucose and insulin levels; other samples were obtained 60 and 120 min after oral administration of 75 g glucose. Glucose tolerance was evaluated using the criteria of the World Health Organization. Insulin resistance (IR) was estimated using the homeostasis model assessment (HOMA) method according to the formula: IR = insulin (microunits per milliliter) x glucose (millimoles per liter)/22.5 (13).
Assays
Plasma glucose was measured using a glucose oxidase method on a glucose analyzer. Plasma insulin was measured by polyclonal RIA and TOT C, HDL C, and TGC by enzymatic methods.
Serum concentrations of 17-OHP and T were measured by RIA (Bridge; Adaltis, Guidonia Montecello, Rome, Italy) with intraassay coefficients of variation less than 10%. Concentrations of 4-A and upright plasma renin activity were detected by RIA (Radim, Pomezia, Rome, Italy) with intraassay variation less than 7%. Plasma levels of ACTH were determined by immunoradiometric assay (Adaltis) with intraassay variation less than 8%.
Vascular study
Patients underwent echo color Doppler ultrasonography (US) of the CCR-L, CBR-L, CFR-L, and AAo, using an Apogee 800 Plus (Advanced Technology Laboratories, Cherry Hill, NJ) with 8.5- and 3.5-MHz probes for B-mode echography and a 6-MHz probe for pulsed Doppler.
Patients laid on the couch with necks rotated by 45°. All arteries were studied in both longitudinal and transversal sections. The CCR-L, CBR-L, and CFR-L were examined at a 60° angle of incidence. The AAo was examined midway between the origins of the celiac tripod and iliac arteries.
One US operator performed the tests, which were all videotaped and reassessed by another operator for validation. Conflicting results were further evaluated blindly by a senior expert. The interobserver variability of the US assessment of IMT was: kappa = 0.88; 95% confidence interval, 0.77–0.99.
The presence of plaque was evaluated in all segments considered. Fluximetric and colorimetric analyses were also carried out. The echo color Doppler study was used to check atherosclerotic plaque, define the degree of stenosis in accordance with the North American Symptomatic Carotid Endarterectomy Trial study (14), and measure the IMT of the vessel wall (15).
Statistical analysis
We compared CAH patients and controls for lipid and glucose profile and IMT data using Student’s t test.
Kappa statistics were used to assess interobserver variability of the US assessment of IMT. Simple linear regression analysis, nonparametric analysis and multiple regression analysis were used to correlate IMT with various variables. Statistical significance was accepted at a level of P < 0.05. Statistical analyses were performed on a personal computer with the SAS system (SAS Institute, Cary, NC).
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Results |
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. Fasting insulin and HOMA-IR were significantly higher in patients (P < 0.05). All subjects in both groups had a normal blood glucose response to the OGTT and there were no significant differences in lipid profile.
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). No significant correlation was found between IMT and fasting glucose, insulin or post-OGTT glucose and insulin levels, cumulative doses of glucocorticoid (1–3 yr), 17-OHP, T, and 4-A levels. CCR-L and CBR-L IMT correlated significantly and positively with age (CCR-IMT: r2 = 0.74, P = 0.0002; CCL-IMT: r2 = 0.56, P = 0.0091; CBR-IMT: r2 = 0.54, P = 0.01; CBL-IMT: r2=0.64, P = 0.0021); CCR-L IMT, CBR-L IMT, and CFL correlated significantly and positively with BMI (CCR-IMT: r2 = 0.49, P = 0,027; CCL-IMT: r2 = 0.53, P = 0.016; CBR-IMT r2 = 0.64, P = 0.0020; CBL-IMT r2 = 0.62, P = 0.0033 CFL-IMT: r2 = 0.46, P = 0.0462). There were no differences related to gender, disease phenotype, or smoking habit.
No significant correlations emerged between fasting and post-OGTT insulin and 17-OHP, T, and 4-A levels and cumulative doses of glucocorticoids.
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Discussion |
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Although our patients showed no signs of any progression from an increased IMT to plaque formation, this condition is an independent predictor of vascular events. Our findings thus suggest that CAH might be at higher risk of developing coronary, cerebrovascular and peripheral vascular disease, as demonstrated by population studies (9).
Previous studies have reported a greater risk of obesity and a greater degree of IR among children and adolescents with classic CAH due to 21OHD (5, 7). It has been suggested that high insulin combined with increase leptin concentrations in CAH children (16) might be due to the chronic adrenomedullary hypofunction observed in these patients. In fact, a lower catecholaminergic tone leads to a loss of inhibition of insulin and leptin secretion by ß-adrenergic receptors (7).
The close relationship between hyperandrogenemia and hyperinsulinemia is also well known (17), but few studies exist in patients with CAH. No significant correlations emerged in our patients between androgen levels and glucose metabolism parameters but we cannot say for sure whether a nonoptimal control of androgen production over the previous years had any negative influence. High insulin levels in patients with classic CAH may have a number of adverse effects on the course of the disease and consequent important implications for their management. Hyperinsulinism may alter the activity of enzymes participating in adrenal steroidogenesis and results in a further increase in androgen production and onset of polycystic ovary and metabolic syndrome with related atherosclerotic cardiovascular disease in adult life (18).
The significantly higher basal insulin and HOMA-IR in patients probably do not reflect any exogenous hypercortisolism or adrenal hyperandrogenism, judging from the lack of any correlation between IR index and cumulative glucocorticoid doses, or endocrine parameters such as 4-A, T, and 17-OHP levels.
It has been reported, moreover, that children with SW 21OHD have high 24-h ambulatory arterial BP measurements (8). It could be that any increased cardiovascular morbidity in CAH patients is attributable wholly to their higher BP, BMI, and insulin levels. Our findings suggest that the increased IMT is independent of any cardiovascular risk factors such as BMI, high BP, or lipid profile disruption. We did not find more severe metabolic profiles and arterial damage in SW than SV forms.
Unlike the pediatric agenda which focuses on optimizing final height, the common strategy in adults is to administer the minimum effective dose of glucocorticoid (19).
Because overweight and an increase in fat mass are associated with metabolic syndrome and a higher cardiovascular risk, weight control and the administration of low-dose glucocorticoids should be given appropriate attention in the follow-up of CAH. Adequate monitoring of the treatment in adults with CAH thus demands a multidisciplinary approach to the metabolic and cardiovascular aspects of the disease to optimize the long-term outcome for this condition.
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Footnotes |
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First Published Online January 2, 2007
Abbreviations: AAo, Abdominal aorta; 4-A, androstenedione; BMI, body mass index; BP, blood pressure; CAH, congenital adrenal hyperplasia; CB, carotid bulb; CBR-L, right and left carotid bulbs; CC, common carotid; CCR-L, right and left common carotids; CF, common femoral; CFR-L, right and left common femoral arteries; HDL C, high-density lipoprotein cholesterol; HOMA, homeostasis model assessment; IMT, intima-media thickness; IR, insulin resistance; OGTT, oral glucose tolerance test; 21OHD, 21-hydroxylase deficiency; 17OHP, 17-hydroxyprogesterone; SV, simple virilizing; SW, salt wasting; T, testosterone; TGC, triglycerides; TOT C, total cholesterol; US, ultrasonography; WHR, waist to hip ratio.
Received August 8, 2006.
Accepted December 27, 2006.
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  D. P. Merke Approach to the Adult with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 653 - 660. [Abstract] [Full Text] [PDF]
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