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Departments of Endocrinology, Metabolism, and Diabetes (H.Fa., M.T.), Molecular Medicine and Surgery (H.Fa., A.N., M.T.), and Paediatric Surgery (A.N.), Astrid Lindgren Children’s Hospital, Department of Women and Child Health (K.H.), Karolinska University Hospital and Karolinska Institute, SE-171 76 Stockholm, Sweden; Department of Paediatric Surgery (G.H.), Queen Silvia Children’s Hospital, Gothenburg SE-416 85, Sweden; and Departments of Endocrinology (H.Fi.) and Obstetrics and Gynaecology (P.-O.J.), Sahlgrenska University Hospital and Sahlgrenska Academy, SE-413 45 Gothenburg, Sweden
Address all correspondence and requests for reprints to: Dr. Henrik Falhammar, Department of Endocrinology, Metabolism, and Diabetes, D2:04, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. E-mail: henrik.falhammar{at}karolinska.se.
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Abstract |
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Objective: Our aim was to assess risk factors for cardiovascular disease and diabetes in CAH women.
Subjects, Methods, and Design: We compared 61 women, 18–63 yr, with CAH due to 21-hydroxylase deficiency with 61 age- and sex- matched controls. Twenty-seven were younger than 30 yr, and 34 were 30 yr or older. Anthropometry, fat and lean mass measured by dual-energy x-ray absorptiometry, serum lipids, insulin, and adrenocortical steroids were studied.
Main Outcome Measure: Body composition and cardiovascular risk factors were the main outcome measures.
Results: Younger patients and controls had similar waist to hip ratio, lean and fat mass, and insulin. Older patients had higher waist to hip ratio, lean mass, and insulin than controls. Fat mass was similar to controls but higher than in younger patients. Lipid profiles were slightly more favorable in older patients than controls. Gestational diabetes was more common in patients (21% of pregnancies vs. 0, P < 0.026). Few older patients had hypertension, cardiovascular disease, or diabetes. Despite moderate glucocorticoid doses, most patients had suppressed androgens.
Conclusions: No clear evidence of unfavorable cardiovascular risk factors were found. Increased fat mass and higher insulin levels were, however, found in patients older than 30 yr. High frequency of gestational diabetes is a risk marker for future diabetes. Lifelong follow-up, lifestyle modifications, and attempts to adjust and reduce the glucocorticoid doses seem important.
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Introduction |
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The therapeutic spectrum of glucocorticoids is narrow, and supraphysiological doses, often needed to suppress adrenal androgens, bring a risk for adiposity, insulin resistance and osteoporosis. Indeed, a progressive increase in fat mass during childhood has been reported in CAH patients (6). Few studies have addressed the consequences of long-term glucocorticoid therapy on metabolic risk factors and morbidity in cardiovascular disease and diabetes during adult life. Studies have been small, consisting mainly of young adults; none of the studies have included more than 15 females (7, 8, 9). One recent study (10) included 26 adult females; its main concern was, however, bone mineral density but body mass index (BMI) was reported. The aim of the present work was to investigate a larger cohort of adult CAH women and relate the findings to those in controls. Furthermore, young adults were compared with older patients to disclose possible changes appearing after long-term treatment.
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Subjects and Methods |
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Sixty-one CAH females aged 18 yr or older were recruited by an appeal to all Swedish Departments of Gynaecology, Endocrinology, and Internal Medicine; advertisement in the Journal of the Swedish Medical Association; and information to the national CAH patient organization. Diagnoses were verified by review of original pediatric and adult records including genital examinations, laboratory reports of adrenal steroids, and mutation analyses of the CYP21A2 gene (11).
The data were subdivided into two groups, those younger than 30 and 30 yr of age or older. Female controls born on the same date as the CAH patients were recruited from local population registries. The controls were examined within 1 yr from their age-matched patients.
The study was approved by the research ethics committees of the Karolinska Institute, Stockholm, and the Gothenburg University, Gothenburg, Sweden. All participants gave written informed consent.
Study protocol
From October 2002 to January 2005, patients and controls were studied as outpatients at the Department of Endocrinology, Metabolism, and Diabetes, Karolinska University Hospital, Stockholm, Sweden (n = 50), or the Department of Obstetrics and Gynaecology, Sahlgrenska University Hospital, Gothenburg, Sweden (n = 11).
Anthropometric methods and body composition. Measurements included height, weight, waist and hip circumference. BMI was calculated as weight/height2 (kilograms per square meter). BMI 25–29.9 kg/m2 was defined as overweight, 30 kg/m2 or greater as obesity. Waist was measured halfway between the costal edge and the iliac crest, and hip circumference over the widest part of the gluteal region. Blood pressure supine and standing was registered and signs of hypo/hypercortisolism and hyperandrogenism were recorded. Hirsutism was evaluated according to a modified Ferriman-Gallwey scoring method (12).
Total and regional body fat and lean mass were estimated by dual-energy x-ray absorptiometry (DXA) in 57 patients and 60 control subjects using a Lunar model DPX-L or Prodigy equipment (Lunar Radiation, Madison, WI) using a standard procedure previously described (13). The two instruments were calibrated. Three patients were assessed using Hologic QDR 4500 (Hologic Inc., Waltham, MA) and were excluded from the statistical analysis. To adjust for the difference in body height between patients and controls, lean and fat mass were divided by height2 (kilograms per square meter).
Endocrinological and metabolic investigations. Blood samples were collected in the morning after an overnight fast for measurements of serum lipids [total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol], electrolytes, insulin, IGF-binding protein (IGFBP)-1, testosterone, dehydroepiandrostendione sulfate (DHEAS), androstenedione, and plasma glucose in all participants. Serum 17-hydroxyprogesterone (17-OH-P), plasma ACTH, renin, and 24-h urinary pregnanetriol were measured in the patients.
Biochemical assays
Serum DHEAS and plasma ACTH were measured on an Advantage automatic immune analyzer and plasma renin by immunoradiometric assay (both from Nichols Institute Diagnostics, San Clemente, CA). ACTH had reference limits 2.0–10 pmol/liter and renin in standing position 4–46 ng/liter. Serum cholesterol, triglycerides, and HDL were measured on SYNCHRON LX Systems (Beckman Coulter Inc., Fullerton, CA). LDL concentration was calculated as suggested by Friedewald et al. (14). Serum insulin and testosterone were measured by fluoroimmunoassay (AutoDelfia; Wallac Inc, Turku, Finland). The reference value for fasting insulin was less than 20 mU/liter. RIA methods were used for the determination of serum IGFBP-1 (15), 17-OH-P (CIS BioInternational, Gif-sur-Yvette, France), and androstenedione (DiaSorin S.p.A., Saluggia, Italy). The reference limits for 17-OH-P were 0.6–2.5 nmol/liter (follicular phase), 2.2–6.5 nmol/liter (midcycle phase), 2.5–10 nmol/liter (luteal phase), and 0.5–2.0 nmol/liter (menopause). Urinary pregnanetriol was determined by gas chromatography and gas chromatography-mass spectrometry (16). The reference limits were less than 6 µmol per 24 h (follicular phase) and less than 8 µmol per 24 h (luteal phase). Sodium, potassium, creatinine, and glucose were measured using routine assays.
Statistics
Results are presented as mean ± SEM if not otherwise stated. Comparisons between groups were carried out with unpaired t test when normally distributed values. Otherwise, the Mann-Whitney rank-sum test was used and in these cases median and range are described. When 2 x 2 frequency tables calculations were performed, 
2 with Yates correction was used or when the expected frequency were small (<5), Fisher’s exact test. Correlations between variables were assessed using least squares linear and multiple regression analysis. IGFBP-1, insulin, ACTH, testosterone, androstenedione, DHEAS, 17-OH-P, and pregnanetriol values were log transformed before analysis to obtain a more closely approximated Gaussian distribution. Statistical significance was set at P < 0.05. Statistical analyses were performed using SigmaStat for Windows (Jandel Scientific, Erkarath, Germany).
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Results |
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All patients with the SW phenotype were diagnosed during the first weeks of life with salt-losing crisis in the presence of ambiguous external genitalia. Age at diagnosis in SV patients was 0–15 yr, and all had virilized external genitals with mild or absent SW, whereas NC patients were diagnosed between 6 and 32 yr of age and had nonambiguous external genitals with no history SW. The presenting signs and symptoms of NC patients were premature pubarche (n = 4), infertility (n = 1), and hirsutism (n = 1). The CYP21A2 gene mutations in SW were: null/null (n = 13), I2splice (n = 12), and I172N (n = 2); in SV: I172N (n = 23), I2splice (n = 3), L308F (n = 1, new mutation), and prom P30L (n = 1); in NC: V281L (n = 4), P105L+P453S (n = 1), and R233G (n = 1, new mutation).
All patients received glucocorticoids. About half of them had prednisolone, a third hydrocortisone, and the remainder cortisone acetate, dexamethasone, or a combination of two glucocorticoids (Table 1
). Daily doses of prednisolone and hydrocortisone were 6.3 ± 0.32 and 33.3 ± 2.1 mg. Fludrocortisone was taken by 82% (mean dose 0.09 ± 0.01 mg) including five of the six NC patients. The dose was higher in SW (0.12 ± 0.01 mg), compared with SV (0.07 ± 0.01 mg) or NC (0.07 ± 0.02 mg) patients (P = 0.014 and 0.019).
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Anthropometry and body composition
CAH women were shorter than controls (159.9 vs. 166.7 cm) (P < 0.001). Very short individuals (<155 cm), were more common in the patients, compared with controls (14 vs. 1, P < 0.001) (Fig. 1). The three patients who were shorter than 150 cm were diagnosed at birth and 3 and 7 yr, respectively. Height was similar in younger and older patients and both groups were shorter than their controls (Table 2).
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). Body composition measured by DXA demonstrated similar percentage body fat and total and regional fat mass in patients and controls in both age groups. Older patients had higher values than younger ones, whereas no difference was found between older and younger controls.
Total lean mass and regional lean mass in arms adjusted for height were higher in older patients, compared with both age-matched controls and younger patients (Table 2).
Cardiovascular morbidity
One patient had suffered from a minor myocardial infarction at the age of 45 yr. Another aged 63 yr had been diagnosed with angina pectoris. There was no history of cardiovascular disease in the control subjects.
Three patients 30 yr old or older but no control received antihypertensive therapy. With those excluded, three patients and four controls, all in the older group, had moderate hypertension (>140/90 mm Hg supine), the highest systolic and diastolic pressure being 160 and 95 mm Hg. There was no difference in supine systolic, supine diastolic, and standing systolic blood pressure between patients and controls in the two age groups. The only difference between older and younger patients was a higher standing diastolic pressure in the older patients, whereas blood pressure was similar in older and younger controls (Table 2).
Metabolic evaluation
Two patients 30 yr old or older had lipid-lowering medication and were therefore excluded from the statistical analysis of lipids. Total, HDL, and LDL cholesterol, HDL to LDL ratio, and triglycerides were similar in younger patients and controls. Older patients had higher HDL to LDL ratios and a tendency to higher HDL (P = 0.074), compared with controls. Total and HDL cholesterol were higher in older than younger patients. Total and LDL cholesterol were higher in older than younger controls (Table 3).
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). IGFBP-1 concentrations were not significantly different between the groups. The expected negative relationship between IGFBP-1 and insulin was found both in patients and controls (r = –0.422; P < 0.001 and r = –0.279; P = 0.031) and was maintained when younger and older patients and controls were analyzed separately. Relationships between lean body mass and other variables
In the patients, correlations were found between total lean mass/height2 and total fat mass/height2 (r = 0.661; P < 0.001) (Fig. 2) and IGFBP-1 (r = –0.402; P = 0.002) and insulin (r = 0.367; P = 0.006). Correlations persisted even when the two patients with the highest lean mass were excluded. In controls, only the correlation between total lean mass/height2 and total fat mass/height2 (r = 0.448; P < 0.001) was found (Fig. 2). When in multiple regression analysis of all patients adding IGFBP-1 and insulin as explaining variables together with total fat mass/height2, only total fat mass/height2 was significant (P < 0.001) in relationship to total lean mass/height2 (r = 0.673). This association was stronger when only the older patients were studied (r = 0.738; P < 0.001). Similar associations were seen for the whole (r = 0.462; P = 0.004) and the older control group (r = 0.494; P = 0.036).
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Two patients, both in the younger group, received antiandrogen therapy (bicalutamide) and were excluded from statistical analysis of androgens. In the remainder, serum testosterone, androstenedione, and DHEAS concentrations were significantly (P < 0.001) lower in the patients, compared with the controls, and a substantial number of patients had subnormal values (Fig. 3). Concentrations were similar in older and younger patients. The younger controls had higher androstenedione (P = 0.019) and DHEAS (P = 0.009) levels than the older ones, whereas testosterone was similar. Three patients were poorly controlled, with elevated serum testosterone, androstenedione, DHEAS, and urinary pregnanetriol.
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). There was no difference between the younger and older patients with respect to pregnanetriol, 17-OH-P, and ACTH. Plasma ACTH was correlated with 17-OH-P (r = 0.802; P < 0.001), testosterone (r = 0.520; P < 0.001), androstenedione (r = 0.616; P < 0.001), DHEAS (r = 0.472; P < 0.001), and urinary pregnanetriol (r = 0.546; P < 0.001). Similar correlations were found between 17-OH-P and testosterone, androstenedione, and DHEAS but not urinary pregnanetriol.
Plasma renin varied to a large extent and was together with potassium lower in younger patients in whom higher doses of fludrocortisone had been recorded (Table 3). Serum sodium was higher in all the patients, compared with controls (data not shown). Hirsutism scores, evaluation of pigmentation, acne, cushingoid appearance, and striae did not differ between patients and controls (data not shown).
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Discussion |
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In the younger patients, BMI, waist circumference, waist to hip ratio, body fat, and lean body mass were not different from age-matched controls. This is in accordance with the results from Cameron et al. (21), who studied a mixed group of 21 males and females aged 18–23 yr and found similar BMI and fat to lean ratios measured by DXA in patients and controls. In contrast, Stikkelbroeck et al. (8) found higher BMI and fat mass and lower lean body mass in young adult female patients, compared with controls. Similar results have also been reported from our group (7). However, in the present study, there was a wide range in BMI from 18 to 48 kg/m2 in the patients and from 17.5 to 40 kg/m2 in the controls.
In contrast, CAH women older than 30 yr had higher BMI and waist to hip ratios than both age-matched controls and younger patients. Despite a higher waist to hip ratio, total or regional fat measured by DXA was not elevated, compared with controls, but higher than in the younger patients who also had lower BMI and waist to hip ratios. This may reflect an improvement of therapy over time, which has been beneficial, especially for the younger patients, despite the fact that there was no difference in height. Encouragement of physical activities, healthy food, and more optimal glucocorticoid therapy, as part of today’s management of CAH patients, may explain lower fat mass and BMI in the younger patients because there was no difference in fat mass and BMI between older and younger controls.
Furthermore, the older patients had higher lean body mass adjusted for height than both controls and younger patients. The reason is not known. Increased lean body mass as the only explanation for a higher BMI is unlikely in view of a higher waist to hip ratio. In the whole group of patients and controls, the strongest correlation with lean mass was fat mass. The higher fat mass in older than younger patients may have contributed to the maintenance of lean mass. Overexposure to androgens in the past is possible, but at the time of the present study, most patients had suppressed androgens. Whether the older patients were more physically active than the younger ones is not known.
The prevalence of hypertension in adult women with 21-hydoxylase deficiency has not been reported. In children and adolescents, Roche et al. (22) found that 58% had systolic and 24% had diastolic hypertension when measuring 24-h ambulatory blood pressure. In the present study, three patients (9%) had antihypertensive therapy, compared with none in the control group. Moderate elevation of blood pressure measured in the morning was found in three more patients and four controls in the older groups.
Hyperlipidemia is a recognized risk factor for cardiovascular disease (23). In the present study, there was no indication that patients had a more harmful lipid profile than controls. In contrast, the older patients had somewhat higher levels of HDL cholesterol and HDL to LDL ratio than controls, which are considered to be protective factors.
Glucocorticoid excess can lead to insulin resistance and diabetes (24). One of the older patients had previously known type 2 diabetes, and in one patient a slightly elevated plasma glucose concentration was detected. Insulin levels were similar in younger patients and controls, whereas patients in the older group had a modest elevation, compared with controls. This is in contrast to previous reports in children with classic CAH and adult women with NC CAH showing higher insulin levels as well as higher testosterone concentrations than controls (24, 25). Elevated androgens may lead to insulin resistance (26). If suppressed androgens in our patients may have modified insulin sensitivity remains speculative. The very modest increase in insulin concentrations despite higher BMI and waist to hip ratio in the older patients might be explained by a larger lean body mass. Insulin is regarded as the principal regulator of hepatic production of IGFBP-1 and hyperinsulinemia leads to decreased levels of IGFBP-1 (27). Normal IGFBP-1 concentrations indicate that there was no major aberration in insulin sensitivity at group level.
The high frequency of gestational diabetes among the patients indicates, however, high risk of future diabetes (28). Certainly there is a need for long-term follow-up and further studies of insulin sensitivity in CAH. Fasting blood glucose was lower in the patients, most likely reflecting cortisol deficiency before the morning glucocorticoid medication.
Monitoring glucocorticoid treatment in CAH may be complicated. The ultimate aim to normalize androgens and steroid precursors without causing signs and symptoms of glucocorticoid excess or deficiency may not always be accomplished. In the present study of patients taking moderate doses of corticosteroids, there were signs of overtreatment with low androgens, in particular DHEAS, being the steroid most sensitive to the suppressive effect of glucocorticoids. Furthermore, urinary pregnanetriol was suppressed in many patients, suggesting that the glucocorticoid doses may be further reduced if it can be done without causing cortisol deficiency. It should be remembered that patients with classic CAH in addition to impaired adrenocortical function also have developmental defects in adrenomedullary function, leading to decreased production of catecholamines, which can increase the severity of an adrenal crisis (29).
To monitor the dose of glucocorticoids, measurements of morning levels of 17-OH-P did not seem to be useful due to wide variation unrelated to 24-h urinary pregnanetriol. The value of diurnal measurements of 17-OH-P in adult CAH patients is presently being evaluated.
Mineralocorticoids are often recommended to patients without SW to minimize the dose of glucocorticoids. In the authors’ experience, lower doses of fludrocortisone must be given to older compared with younger patients to avoid edema and hypertension. A lower mineralocorticoid dose was most likely the reason for higher renin and potassium concentrations in the older patients.
In conclusion, the present study addressed the prevalence of some of the established risk factors for cardiovascular disease in CAH adult females on long-term glucocorticoid therapy. Although suppressed androgens indicated overtreatment, there was no clear evidence of unfavorable cardiovascular risk factors. Older patients, however, had higher BMI and waist to hip ratio than controls. Few patients had hypertension, manifest cardiovascular disease, or diabetes. Older patients had also higher lean mass adjusted for their shorter height than controls. Lean mass was correlated to fat mass. The occurrence of gestational diabetes was significantly elevated, indicating an increased risk for type 2 diabetes in the future. Few of the patients were, however, above the age of 50 yr, and we have little knowledge of the future course through menopause and old age. Regular follow-up with lifestyle intervention and monitoring of glucocorticoid doses is important. Suppressed adrenal androgens indicate that the doses may be reduced. Long-term consequences of low androgens are largely unknown.
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Acknowledgments |
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Footnotes |
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Disclosure Summary: The authors have nothing to declare.
First Published Online October 10, 2006
Abbreviations: BMI, Body mass index; CAH, congenital adrenal hyperplasia; DHEAS, dehydroepiandrostendione sulfate; DXA, dual-energy x-ray absorptiometry; HDL, high-density lipoprotein; IGFBP, IGF-binding protein; LDL, low-density lipoprotein; NC, nonclassic; 17-OH-P, 17-hydroxyprogesterone; SV, simple virilizing; SW, salt wasting.
Received June 22, 2006.
Accepted October 4, 2006.
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, CAH women 30 yr old or older; 
, CAH women younger than 30 yr; •, controls 30 yr old or older; and 
, controls younger than 30 yr.