Long-Term Outcome of Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency

CLINICAL INVESTIGATION

Long-Term Outcome of Patients With Congenital Adrenal Hyperplasia Due to 21-hydroxylase Deficiency Mouna Feki Mnif, PhD, Mahdi Kamoun, MD, Fatma Mnif, MD, Nadia Charfi, PhD, Nozha Kallel, MD, Basma Ben Naceur, MD, Nabila Rekik, PhD, Zainab Mnif, PhD, Mohamed Habib Sfar, PhD, Mohamed Tahar Sfar, PhD, Mongia Hachicha, PhD, Leila Ammar Keskes, PhD and Mohamed Abid, PhD

Abstract: Introduction: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid synthesis. In this study, the authors aim to evaluate the impact of CAH due to 21-hydroxylase deficiency on final height (FH), bone health, cardiometabolic risk, fertility, neurocognition and quality of life in a hospitalbased sample from Tunisia. Methods: Twenty-six patients (11 males and 15 females; mean age: 27.4 6 8.2 years) were recruited. Results: Mean FH was 159.5 6 9.7 cm. Twenty-one patients (80.7%) had a FH below the target height. Ten patients (38.4%) exhibited bone demineralization. Eight patients (30.7%) had obesity. Lipid profile alterations and carbohydrate metabolism disorders were detected in 10 (38.4%) and 5 (19.2%) patients, respectively. Seven patients (27%) had insulin resistance. Ambulatory blood pressure monitoring showed abnormalities in 6 patients (23%). Increased carotid intima-media thickness was found in 14 patients (53.8%). Inhibin B level was decreased in 4 male patients. Semen analysis showed abnormalities in 4 of 10 patients. Testicular tumors were detected in 6 of 11 patients. AntiMüllerian hormone level was reduced in 4 female patients. Six patients showed poly-cystic ovary syndrome. Brain magnetic resonance imaging showed abnormalities in 11 patients (42.3%). Quality of life was reduced in 14 of 22 patients (63.6%). Many of the suboptimal outcomes appeared to be related to poor adherence to medication schedules, some to overtreatment. Conclusion: CAH patients have a number of issues due to the disease or its treatment. Regular follow-up, early lifestyle interventions, bone health assessment, testicular ultrasound and psychological management are needed. Key Indexing Terms: Congenital adrenal hyperplasia; Final height; Bone mineral density; Fertility; Cardiometabolic risk; Quality of life. [Am J Med Sci 2012;344(5):363–373.]

C

ongenital adrenal hyperplasia (CAH) describes a group of inherited autosomal recessive disorders that cause a deficiency in an adrenal enzyme resulting in altered cortisol and aldosterone secretion. The most frequent CAH variant, accounting for 95% of all affected patients, is 21-hydroxylase deficiency (21-OHD) and caused by inactivating mutations in the 21-hydroxylase gene (CYP21A2).1 The deficiency of 21-OH causes a decrease in negative feedback to the hypothalamic-pituitary-adrenal axis and subsequent hyperplasia of the adrenal gland.1 There are different clinical forms of

From the Endocrinology Department (MFM, MK, FM, NC, NK, BBN, NR[SCAP], Department of Radiology (ZM) and Pediatric Department (MH), Hedi Chaker Hospital, Sfax; Department of Endocrinology and Internal Medicine (MHS) and Pediatric Department (MTS), Tahar Sfar Hospital, Mahdia; and Laboratory of Histology-Embryology (LAK), Faculty of Medicine, Avenue Magida Boulila, Sfax, Tunisia. Submitted July 27, 2011; accepted in revised form November 22, 2011. Correspondence: Mahdi Kamoun, MD, Endocrinology Department, Hedi Chaker Hospital, Magida Boulila Avenue, 3029 Sfax, Tunisia (E-mail: [email protected]). MA),

The American Journal of the Medical Sciences



CAH associated with 21-OHD: classical CAH, the most severe form comprises both salt-wasting (SW) and simple virilizing (SV) forms, with a worldwide incidence of 1:15,000 live births, and the nonclassical (NC) form which may be asymptomatic or associated with signs of postnatal or even adult onset androgen excess.1 Most patients are compound heterozygotes having different mutations of the CYP21 gene on each allele. The clinical expression of CAH is determined by the remaining enzymatic activity and correlates with the less severely mutated allele.2 Treatment of CAH consists of glucocorticoids and, when necessary, min-eralocorticoids to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex.3 In addition to impaired adrenocortical function, classical CAH is characterized by compromised adrenomedullary function. The latter is owing to developmental defects in the formation of the adrenal medulla, leading to a reduction in epinephrine and metanephrine stores.4 With the availability of glucocorticoid replacement allowing patients to reach adulthood, long-term effect of this disease and its treatment have become an important issue. Data concerning CAH adults have reported conflicting results.3,5 Several reports have verified a decreased final height (FH) in patients with CAH.6 However, factors that could influence growth are controversial.6 Data are conflicting concerning the effect of long-term glucocorticoid replacement therapy on bone mass and bone metabolism in patients with CAH. In adults, bone mineral density (BMD) has been reported to be normal,7 decreased8 or even increased.9 More recently, attention has turned to cardiovascular risk factors in adults with CAH. The chronic, often supraphysiological glucocorticoid dose is potentially harmful and might increase morbidity in cardiovascular disease and diabetes.10,11 Impaired fertility and fecundity were found in female and male patients with CAH.3,5 In females, several hormonal, structural and psychological factors have been suggested to contribute to the disturbed reproductive axis.12 In males, the most obvious cause of subfertility is the presence of testicular adrenal rest tumors (TARTs), but other causes probably contribute.3,5 Some studies suggest that patients with CAH who experienced adrenal crises are at risk for cognitive impairment.13 In addition, white matter abnormalities on brain magnetic resonance imaging (MRI) have been previously reported, possibly due to glucocorticoid therapy and hormonal dysregulation.14 Recent studies,15,16 in contrast to previous observations,17 have demonstrated a reduction in the quality of life in patients with CAH, particularly in its social dimensions. In such context of contradictory results, it is crucial to understand the long-term effect of this disease and its treatment in a setting that is more resource constrained than tertiary care medical centers in Western Europe or North

Volume 344, Number 5, November 2012

363

Mnif et al

TABLE 1. Clinical and hormonal data of the 26 patients at the time of their inclusion in the study Follow-up Morning Morning Patient Height (cm) Treatment duration 17-OHP ACTH No./sex/age (Standard Weight BMI regimen (yr) (ng/mL) (pg/mL) (yr)/phenotype Deviation) (kg) (kg/m2) 1/M/21/SW

155 (23)

48.7

20.3

2/M/18/SW

160 (21.6)

57.3

22.4

3/M/23/SW

186 (+2)

80

23.1

4/M/16.5/SW

158 (22.6)

85.1

34.1

5/M/22.5/SW

166 (21.3)

83

30.1

6/M/22.5/SW

163 (21.8)

72.5

27.3

7/M/31/SV

162 (22)

67.7

25.8

8/M/17.5/SV 9/M/18/SV 10/M/28/SV

178 (+0.6) 164 (21.6) 156 (23)

106.1 68.8 69.8

33.5 25.6 28.7

11/M/47.5/SV 12/F/21/SV

143 (25.1) 163 (0)

57.4 58.4

28.1 22

13/F/26/SV

150 (21.4)

52.8

23.5

14/F/25/SW

168 (+1)

57.8

20.5

15/F/23.5/SW

149 (22.5)

55.7

25.1

16/F/22/SW

166 (+0.5)

72.7

26.4

17/F/27/SW

164 (+0.2)

68

25.3

18/F/33/SV

155 (21.4)

75.4

31.4

19/F/28/NC 20/F/26/NC 21/F/30.5/NC 22/F/48/NC 23/F/36/NC 24/F/36/NC 25/F/34/NC 26/F/32/NC

157 163 150 154 156 141 148 163

55 58.4 52.8 71.6 73.2 69.1 67.9 61.3

22.3 22 23.5 30.2 30.1 34.8 31 23.1

(21) (0) (22.4) (21.6) (21.2) (24) (22.8) (+0)

HC: 13.8 (mg/m2/d) FC: 75 (mg/d) HC: 18.2 (mg/m2/d) FC: 50 (mg/d) HC: 15.6 (mg/m2/d) FC: 50 (mg/d) HC: 16 (mg/m2/d) FC: 100 (mg/d) HC: 15.9 (mg/m2/d) FC: 75 (mg/d) HC: 13.5 (mg/m2/d) FC: 50 (mg/d) HC: 12.8 (mg/m2/d) FC: 50 (mg/d) DEX: 0.5 (mg/d) DEX: 0.5 (mg/d) HC: 18.2 (mg/m2/d) FC: 50 (mg/d) HC: 18.7 (mg/m2/d) HC: 16.2 (mg/m2/d) FC: 100 (mg/d) HC: 23.8 (mg/m2/d) FC: 75 (mg/d) HC: 12.8 (mg/m2/d) FC: 75 (mg/d) HC: 16.4 (mg/m2/d) FC: 75 (mg/d) HC: 13.1 (mg/m2/d) FC: 50 (mg/d) HC: 29.8 (mg/m2/d) FC: 100 (mg/d) HC: 22.3 (mg/m2/d) FC: 50 (mg/d) HC: 13.2 (mg/m2/d) HC: 14.7 (mg/m2/d) DEX: 0.5 (mg/d) HC: 13.7 (mg/m2/d) HC: 21.5 (mg/m2/d) DEX: 0.5 (mg/d) HC: 17.1 (mg/m2/d) DEX: 0.5 (mg/d)

Morning D4-A (ng/mL)

Supine PR (ng/L)

21

50

537

2.3

23

18

60

74

4.6

13

23

21.3

295

3.1

18

16.5

12

77

2.9

18

22.5

60

150.8

14.7

16.5

22.5

9

233

2.9

9

28

25.5

68

6.7

14.7

11.5 11.5 22

18.9 1.64 1.8

57 6.5 368

1.6 2.1 2.7

10 12 14.5

41.5 18

9.8 7

42 59

2.1 1.6

9 12.8

26

23.9

39

2.5

32

25

8.1

25

1.9

12

23.5

9.5

41

4.7

2.7

22

3.3

32

3.9

9.7

15.2

44 12

27

77

320

33

70

166.6

4.7

3 5 9 4 15 13 4 17

14 3.7 6.9 17.6 12.8 53.6 1.1 6.9

13 32.8 235.4 58 78 31 7.6 29.5

24 3.9 5.3 12.6 2.6 1.8 1.7 4.4

— — — — — — — —

SW, salt wasting; SV, simple virilizing; NC, nonclassical; HC, hydrocortisone; FC, fludrocortisone; DEX, dexamethasone; D4-A, D4- androstenedione; PR, plasma rennin; BMI, body mass index; 17-OHP, 17-hydroxyprogesterone; ACTH, adrenocorticotropic hormone.

America. This approach could define the future guidelines of care of children with CAH in order to prevent long-term consequences of CAH.

PATIENTS AND METHODS Patients We included 26 patients (11 males and 15 females; mean age 6 standard deviation (SD) 5 27.4 6 8.2 years; range 5 16.5–48 years) who were followed at the Department of

364

Endocrinology in Mahdia and Sfax, in Tunisia. This sample includes all patients with CAH, aged more than 16 years and regularly followed at these 2 clinics since 1982. Patients or their parents were informed that the purpose of the study was an evaluation of long-term consequences of the CAH and their treatment. Clinical and hormonal data of the 26 patients are presented in Table 1. Data concerning presentation, diagnosis, medical and surgical treatment and other relevant information were reviewed. Volume 344, Number 5, November 2012

Congenital Adrenal Hyperplasia in Adults

All individuals had CAH with 21-OHD. The diagnosis of CAH was based on clinical and biochemical criteria [ie, increased levels of 17-hydroxyprogesterone (17-OHP) and an-drostenedione and adrenocorticotropic hormone (ACTH) stimulation test]. None of the patients was treated in utero with dexamethasone. Karyotype results were concordant with the sex of assignment and rearing in all patients. Ten patients (6 males and 4 females) had the SW form of CAH and they had been diagnosed in their first year of life. Eight patients (5 males and 3 females, age at diagnosis: between birth and 6 years) were diagnosed as classical SV patients. In the other 8 patients (women only in this group), the NC form was diagnosed between the age of 15 and 44 years. All patients had been treated from the time of diagnosis. Twenty-one patients, 16 with the classical form and 5 with the NC form, were started on a regimen of hydrocortisone (HC), given 2 or 3 times daily, while the remaining 5 patients (3 with the NC form and 2 with the classic SV form) were treated with dexamethasone (once daily). Salt wasters were treated with 27.9 6 9.6 mg/m2/d of HC the first 2 years of life, and the doses were decreased to 17.6 6 6.6 mg/m2/d during childhood. Daily doses of HC in patients with classical and NC forms were, respectively, 17.3 6 4.6 mg/m2 and 16.04 6 3.4 mg/m2 during adulthood. For dexamethasone, the prescribed doses ranged from 0.25 to 0.75 mg/d. Fifteen patients (10 with the SW form and 5 with the SV form) additionally received 9a-fludrocortisone (twice daily). A single-stage clitoroplasty, vaginoplasty and labiaplasty was performed in all female patients with classical CAH. Patient age at the time of surgery ranged from 6 months to 6 years. During follow-up, no complications such as fistulas or vaginal strictures were noted, and all patients had a good genital cosmetic appearance. The adequacy of therapy was monitored periodically on the basis of clinical and laboratory data, in accordance with 2002 guidelines.18 Patients were classified as under adequate hormonal control if 50% or more of the total serum androgen levels were within normal limits for age or if 50% or more of the baseline serum 17-OHP concentrations were 2.0 to 10 ng/mL (6–30 nmol/L). Possible overtreatment was defined as suppressed androgen and 17-OHP levels in serum. The mean duration of follow-up period was 18.5 6 9.3 years (range, 3–41.5 years). Seven patients (5 with the SW form and 2 with the SV form) had experienced a SW adrenal crisis in the neonatal period. The onset of puberty (defined by the onset of breast development in females and increased testicular volumes in males) was 10.8 61.4 years for girls and 11.2 6 1.2 years for boys. Menarche occurred spontaneously in all patients, at an average age of 12.8 6 1.1 years. One female patient with the NC form (patient 23) had a history of previously diagnosed congenital hypothyroidism. She was started on L-thyroxine 10 mg/kg/d at the age of 6 months, but she was irregular in follow-up and was not compliant with treatment. One patient with the SW form (patient 4) developed hypertension at the age of 8 years and responded well to Nifedipine. Detailed investigations (renal Doppler ultrasound, adrenal CT scan, urinary metanephrine, 11-deoxycortisol and aldosterone concentrations) failed to detect any cause for secondary hypertension, and a diagnosis of essential hypertension was made. Ó 2012 Lippincott Williams & Wilkins

Methods From January 2009 to November 2010, outcomes data related either to the CAH itself or its treatment were prospectively collected from our patients. Clinical Characteristics All patients underwent physical and neurologic examinations. Physical examination included anthropometry (height, weight and waist circumference), blood pressure and presence of signs of hypo/hypercortisolism. Body mass index (BMI) was calculated as weight/(height)2 (kg/m2). Fat mass (kg), percent body fat and lean mass (kg) were assessed with bioelectrical impedance equipment (TANITA, TBF-300, France). In male patients (n 5 11), testicular palpation was performed to detect any mass. In female patients (n 5 15), Ferriman-Gallwey scoring methods were used to assess hirsutism degree and Prader score to classify abnormalities of the external female genitalia.19,20 Biochemical Investigations Blood samples were collected in the morning after an overnight fast for measurements of serum lipids [total cholesterol, triglycerides, high-density lipoprotein (HDL) and cholesterol], liver enzymes [serum alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transpeptidase], electrolytes, plasma glucose, serum calcium, phosphorus and hormones [insulin, leptin, testosterone, D4-androstenedione (D4-A), 17-OHP, plasma ACTH, renin, osteo-calcin, parathormone (PTH), 25-hydroxy vitamin D (25-OH D), inhibin B and anti-Müllerian hormone (AMH)]. Samples were centrifuged and separated immediately after collection and were stored at 220°C until assayed. Blood samples were collected during the follicular phase in women with regular menstrual cycle and at any time in the amenorrheic patients. Hormone Assays Circulating concentrations of D4-A, testosterone, LH, follicle-stimulating hormone (FSH), ACTH and 17-OHP were measured by commercially available assays. Reference ranges of D4-A, age adjusted, were 0.65 to 2.1 ng/mL for males and 0.8 to 2.4 ng/mL for females. Supine plasma renin concentrations were measured using a commercial radioimmunoassay kit (CIS Bio International, Gif-sur-Yvette, France). Intact PTH was determined by immunoradiometric assay (ELSA-PTH; CIS Bio International). Osteocalcin was measured using an immunoradiometric assay (ELSA-OSTEO; CIS Bio International). Serum 25-OH D was determined by competitive radioimmunoassay after acetonitrile extraction (25-OH D, Diasorin). Serum insulin levels were measured by enzyme-linked immu-nosorbent assay (ELISA). Serum leptin levels (ng/mL) were determined by the ELISA technique using Leptin-EASIA KAP2281 kit (DIA source ImmunoAssays SA, B-1400 Niv-elles, Belgium). Inhibin B concentration was measured in duplicate in serum samples using a solid-phase sandwich ELISA (DSL-10-84100 ACTIVE Inhibin-B ELISA kit). Serum level of AMH was measured by the ELISA technique (DSL-10-14400 ACTIVE MIS/ AMH ELISA kit). The lower limit of detection was 10 pg/mL for inhibin B and 0.1 ng/mL for AMH. Height Outcome For each patient, FH was defined at growth of , 1 cm in the previous year and/or a bone age of . 15 years in a girl or .16 years in a boy.21 FH was then expressed as the SD score (SDS) for chronological age. Target height (TH) was calculated as (maternal height + paternal height 613 cm)/2. Corrected

365

Mnif et al

FH SDS was also calculated by subtracting TH SDS from FH SDS (FH-SDS – TH-SDS). BMD Assessment BMD was measured in all patients with diphotonic x-ray absorptiometry. Results at femoral neck and lumbar spine L2–L4 were calculated and expressed as absolute values in grams per square centimeter and T score. The World Health Organization (WHO) definitions of osteopenia and osteoporosis were applied (ie, T score between 21 and 22.5 SD at any measured site was defined as osteopenia and values below 22.5 SD were defined as osteoporosis).22 Before diphotonic x-ray absorptiometry, plain x-rays of the pelvis and lumbar spine (anteroposterior and lateral view) were examined to search for vertebral compression or spontaneous fractures. Metabolic Profile A 75 g oral glucose tolerance test was also done in all patients and was evaluated using the criteria of the WHO.23 Indeed, insulin resistance (IR) was estimated using the homeo-stasis model assessment (HOMA) method as previously described: IR 5 insulin (mU/mL) 3 glucose (mmol/L)/22.5.24 A HOMA index $2.77 has been suggested to indicate IR.25 The National Cholesterol Education Program Adult Treatment Panel III criteria were used to define the metabolic syndrome.26 Cardiovascular Risk Profile Ambulatory 24-hour blood pressure monitoring was performed in all patients. Mean daytime, nighttime and overall blood pressure values were calculated, and hypertension criteria were those suggested by the European Society of Hypertension.27 In 24-hour measurements, normal blood pressure was defined as #130/80 mm Hg and hypertension as .135/85 mm Hg. Normal daytime blood pressure was defined as #135/85 mm Hg and daytime hypertension as .140/90 mm Hg. Normal nocturnal blood pressure was defined as , 120/70 mm Hg and nocturnal hypertension as .125/75 mm Hg. Patients were defined as dippers when nighttime systolic BP fall was $10% and nondippers when nighttime systolic BP fall was ,10%.28 Carotid intima-media thickness (CIMT) was assessed in all patients using high-resolution B-mode ultrasound with a 10-MHz linear transducer. Measurements were performed in the posterior wall of both common carotid arteries (CCA) at 3 angles. The average of the mean CIMT values of the 3 segments was calculated to determine the mean right and left CIMT per patient.29 In this study, the mean CIMT was compared with reference values from the MultiEthnic Study of Atherosclerosis.30 Patients were thereby stratified as having normal CIMT (CIMT ,75th percentile) or increased CIMT (CIMT $75th percentile in at least 1 CCA).30 Fertility All male patients underwent a testicular ultrasonogram. Images were obtained using both B-mode and color Doppler mode. Indeed, seminal fluid was collected by 10 patients after 2 to 3 days of ejaculatory abstinence. The analysis included estimation of semen volume, sperm concentration, total sperm count, motility and morphology. Semen was evaluated according to the WHO standard.31 For female patients, pelvic ultrasonography was performed for the diagnosis of polycystic ovary syndrome (PCOS), as proposed by the Rotterdam consensus.32 Neurocognitive Outcome Brain MRI was performed in all patients using a 1.5-T scanner (Gryoscan ACS NT; Philips Medical Systems, Best,

366

The Netherlands). Sagittal Tl-weighted sections, axial proton density T2-weighted sections and coronal turbo spin-echo T2-weighted and fluid-attenuated inversion recovery (FLAIR) sections were used. White matter changes were defined as areas of increased signal intensity on intermediate and T2-weighted sequences. MR scans were also evaluated for morphological abnormalities involving the temporal lobe and the amygdalo-hippocampal area. Thin coronal MRI slices, perpendicular to the axis of the hippocampus, were used for determining hippocampal dysplasia (distorted anatomy and/or increased signal). Amygdala was regarded as dysplastic if it was smaller than the contralateral side, if increased signal on T2 and FLAIR sequences was observed or both. Quality of Life Evaluation Quality of life was assessed in 22 patients using the Arabic version of the “36 item Short Form Health Survey.”33,34 This is a short, 36-item questionnaire that measures 8 multiitem general health scales, ranging from 0 (worst possible health status) to 100 (best possible health status). The scores on the 8 subscales can be aggregated in 2 distinct summary scores: physical component summary (physical functioning, role physical, bodily pain and general health) and mental component summary (vitality, social functioning, role emotional and mental health). Participants who had overall mean score of ,66.7 were considered as having reduced quality of life.33,34

RESULTS Hormonal Control At the time of inclusion in the study, mean morning baseline 17-OHP in serum for the whole cohort was 22.51 ng/mL (range, 1.1–77 ng/mL); mean morning androstenedione levels were 5.25 ng/mL (range, 1.6–24 ng/mL) and mean morning plasma ACTH levels were 118.31 pg/mL (range, 6.5–537 pg/mL). During the treatment period, 9 patients (34.6%) showed well-controlled CAH. Poor hormonal control, with elevation of 50% or more of D4-A and 17-OHP serum measurements, was present in 16 patients (61.5%). These were chronically noncompliant patients, mainly because of ignorance and lack of understanding. The remaining patient (patient 8) had suppressed androgen and 17-OHP levels indicating possible overtreatment. Height Outcome Mean FH was 159.15 6 9.8 cm (range, 141–186 cm) corresponding to a 21.38 6 1.6 SDS (range, 25.1 to +2 SDS). Mean female height was 156.4 6 7.8 cm (range, 141-168 cm) and mean male height was 162.8 6 11.4 cm (range, 143–186 cm). Corrected FH was 20.9 6 1.2 SDS in females and 21.7 6 1.4 SDS in males. Twenty-one patients (9 males and 12 females, 80.7%) had an FH below the TH. Short stature, as defined by height less than 22 SDS, was noted in 8 patients (4 males and 4 females): 2 patients (patient 11 and 15) had adequate hormonal control and the remainder were noncompli-ant with elevation of androgen and 17-OHP levels during follow-up. Bone Metabolism and BMD Hypocalcemia (1.9–2.1 mmol/L) was found in 3 patients (patients 11, 24 and 25). Low serum concentrations of 25-OH D (4–28 ng/mL; normal range, .30 ng/mL) were detected in 21 patients (11 males and 10 females, 80.7%). Low serum concentrations of osteocalcin (8.3–22.6 ng/mL; normal range, Volume 344, Number 5, November 2012

Congenital Adrenal Hyperplasia in Adults

TABLE 2. Bone turnover parameters and BMD results in our patients according to clinical phenotype of CAH (mean 6 standard deviation) SW Patients (n 5 10) SV Patients (n 5 8) NC Patients (n 5 8) All Patients (n 526) S-Ca2+ (mmol/L) S-phosphate (mmol/L) S-alkaline phosphatase (IU/L) S-PTH (pg/mL) 25-Hydroxyvitamin D (ng/mL) Osteocalcin (ng/mL) Lumbar spine BMD (g/cm2) Lumbar spine (T score) Femoral neck BMD (g/cm2) Femoral neck (T score) Osteopenia or osteoporosis

2.35 6 0.14 1.09 6 0.25 174.5 6 51.3 31 6 25.46 20.23 6 7.6 27.64 6 9.4 1.18 6 0.09 20.08 6 0.92 1.05 6 0.1 20.14 6 0.85 3 patients

2.33 6 0.23 1.10 6 0.11 182.3 6 69.4 26.95 611.5 18.5 6 7.86 17.6 6 3.4 1.11 6 0.1 20.67 6 0.86 0.96 6 0.07 20.5 6 0.33 3 patients

2.28 6 0.15 1.07 6 0.12 121.2 6 40.6 92.5 6 48.78 7.42 6 4.02 15.8 6 6.3 1.2 6 0.09 0.37 6 0.96 0.94 6 0.09 20.52 6 0.88 4 patients

2.32 6 0.16 1.08 6 0.15 160.6 6 53.8 89.8 6 29.4 15.8 6 8.6 20.98 6 6.4 1.16 6 0.09 20.12 6 0.9 0.98 6 0.08 20.37 6 0.7 10 patients

BMD, bone mineral density; S-PTH, parathormone; SW, salt wasting; SV, Simple virilizing; NC, nonclassical; CAH, congenital adrenal hyperplasia.

24–70 ng/mL) were noted in 15 patients (6 males and 9 females, 65.2%). Elevation of PTH concentration (62.8–141 pg/mL; normal range, 11–62 pg/mL) was noted in 9 patients (3 males and 6 females, 39.1%). X-rays of 1 patient (patient 15) showed a compression deformity of the LI vertebra with narrowing of the L1-L2 interspace. According to the WHO definitions, 10 patients (4 males and 6 females, 38.4%) had bone demineralization: 1 patient had lumbar spine osteoporosis (patient 11) and the remainder had osteopenia (lumbar spine: 4 patients; femoral neck: 5 patients). Eight patients with bone loss showed poor hormonal disease with elevation in androgen and 17-OHP levels during follow-up period, 1 patient (patient 15) had adequate hormonal control and 1 patient (patient 8) was overtreated. Obesity and vitamin D deficiency were noted in 1 and 9 patients, respectively. Bone turnover parameters and BMD results in our patients according to clinical phenotype of CAH are showed in Table 2. Metabolic Profile Obesity (BMI ranging from 30 to 34.8 kg/m2) was noted in 8 patients (3 males and 5 females, 30.7%): 1 patient was overtreated (patient 8) and the remainder were noncompliant to their medication with elevation of androgen and 17-OHP concentrations. Bioelectrical impedance showed increased body fat mass in 12 patients (6 males and 6 females, 46.1%): 10 patients were noncompliant, 1 patient had adequate disease control (patient 16) and 1 patient was overtreated (patient 8). Lipid profile alterations were detected in 10 patients (1 male and 9 females, 38.4%): 1 patient had well-controlled disease (patient 17), 1 patient was overtreated (patient 8) and 8 patients were noncompliant. An isolated hypercholesterolemia (2.6–2.7 g/L) was noticed in 2 patients (patients 22 and 25). An isolated hypertriglyceridemia (1.7–1.9 g/L) was detected in 3 patients (patients 19, 23 and 24), and 5 patients (1 male and 4 females) had decreased HDL cholesterol (,1.0 and ,1.2 mmol/L in men and women, respectively). Insulin resistance (HOMA-IR ranging from 2.79 to 4.27) was documented in 7 patients (3 males and 4 females, 27%), all were noncompliant with their treatment. Hyperleptinemia was present in 3 patients (patients 2, 15 and 19, 11.5%). Moderate hepatic cytolysis was Ó 2012 Lippincott Williams & Wilkins

found in patient 8 (ASAT: 103 IU/L, ALAT: 223 IU/L). This patient had suppressed androgen and 17-OHP levels during follow-up, indicating possible overtreatment. During oral glucose tolerance test, 21 patients (80.7%) had normal glucose tolerance. Carbohydrate metabolism disorders were detected in 5 patients (19.2%): 4 patients were noncompliant and 1 patient was overtreated (patient 8). Four patients (patient 8, 22, 24 and 25) were identified as having glucose intolerance and 1 patient (patient 23) had diabetes (blood glucose 120 minutes: 11.05 mmol/L). The metabolic syndrome as defined by the National Cholesterol Education Program Adult Treatment Panel III criteria was documented in patient 23, who had diabetes, obesity, low HDL-C and hypertriglyceridemia. Table 3 shows metabolic parameters according to clinical phenotype of CAH. Cardiovascular Risk Profile Ambulatory 24-hour blood pressure monitoring showed mild daytime systolic hypertension (150 mm Hg) in 1 patient (patient 5). Indeed, 5 patients (2 males and 3 females, 19.2%) were classified as nondippers, 1 patient was overtreated (patient 8) and 4 patients were poorly controlled due to noncom-pliance with their medication. Comparison with reference values revealed normal CIMT in 12 patients (46.1%). An increase in CIMT (up to 1.1 mm) in at least 1 CCA was observed in 14 patients (5 males and 9 females, 53.8%): 1 patient was overtreated (patient 8) and the remainder were noncompliant, with subsequent androgen and 17-OHP elevation. Table 4 illustrates cardiovascular parameters according to clinical phenotype of CAH. Male Fertility Palpation of the testes revealed bilateral testicular atrophy and a 2-cm bilateral, firm and irregular nodule in patient 1. This patient had also a low level of testosterone (1.3 ng/mL), FSH (0.72 U/L) and LH (0.27 U/L). All these parameters were within the reference range in the 10 remaining patients. The mean serum inhibin B level was 117.74 6 75.25 pg/mL (range, 15.36–222.91 pg/mL). Inhibin B levels were below the reference range in 4 of 11 patients. Testicular sonography detected TARTs in 6 of 11 patients, all showed poor hormonal control and noncompliance to steroid therapy. The maximal diameter of these tumors ranged from 0.8 to 2.6 cm. In all cases, these tumors were bilateral and seemed to originate from the medi-astinum testis. Indeed, sperm abnormalities were found

367

Mnif et al

TABLE 3. Metabolic profile of patients according to clinical phenotype of CAH SW Patients (n 5 10) SV Patients (n 5 8) (kg/m2)

BMI Body fat percentage Fasting blood glucose (mmol/L) 75-g OGTT 120 min glucose (mmol/L) Total cholesterol (g/L) HDL cholesterol (g/L) TG (g/L) Fasting insulin (mIU/mL) HOMA-IR Serum leptin (ng/mL)

25.4 21.6 4.49 5.94 1.54 0.47 0.89 8.8 1.77 6.34

6 6 6 6 6 6 6 6 6 6

4.3 10.3 0.3 0.9 0.08 0.06 0.28 0.9 0.6 5.4

27.3 25.7 4.62 6.22 1.64 0.43 0.93 11.2 2.43 8.57

6 6 6 6 6 6 6 6 6 6

3.8 8.3 0.6 1.56 0.15 0.06 0.24 7.2 1.6 2.2

NC Patients (n 5 8) 27.1 27.9 5.46 7.14 1.87 0.47 0.98 9.05 2.29 7.41

6 6 6 6 6 6 6 6 6 6

4.9 12.5 2.5 1.56 0.38 0.07 0.3 3.2 1.2 5.6

All Patients (n 5 26) 26.5 24.8 4.82 6.39 1.66 0.46 0.91 9.6 2.1 7.51

6 6 6 6 6 6 6 6 6 6

4.3 10.6 0.52 1.41 0.26 0.06 0.27 4.3 1.1 4.7

SW, salt wasting; SV, simple virilizing; NC, nonclassical; CAH, congenital adrenal hyperplasia; HOMA-IR, homeostasis model assessmentinsulin resistance; TG, triglycerides; HDL, high-density lipoprotein; BMI, body mass index; OGTT, oral glucose tolerance test.

in 4 of 10 patients: azoospermia in 2 patients (patients 1 and 5), oligo-asthenospermia in 1 patient (patient 2) and oligo-asthenoteratospermia in 1 patient (patient 10). Female Fertility Hirsutism was present in 9 of 15 female patients (60%), and the median Ferriman-Gallwey score was 15.8 (range, 10–20). In addition, 3 female patients (2 with the NC form and 1 with the SV form) presented with mild clitoromegaly (Prader score stage 1). Irregular menses (oligomenorrhea or spaniom-enorrhea) were noted in 4 patients (2 with the NC form, 1 with the SW form and 1 with the SV form). Serum estradiol concentration was reduced in 1 patient (patient 18, ,9 pg/mL). This patient was noncompliant with her treatment and had also low serum FSH and LH levels (1.26 and 1.66 U/L, respectively). Mean AMH serum level was 2.92 62.1 ng/mL (range, 0.1–6.06 ng/mL) and was reduced in 4 patients. Mean serum testosterone level was 1.95 6 2.21 ng/mL (range, 0.26– 6.4 ng/mL). Pelvic ultrasound showed polycystic ovaries in 5 patients. According to the Rotterdam criteria, 6 patients (40%) had PCOS. All female patients with either PCOS or reduced AMH levels were noncompliant with their medication and showed poor hormonal control. Four female patients were married and wished to get pregnant. Three of them became pregnant spontaneously: 1 (patient 17) had a spontaneous miscarriage and 2 (patients 16 and 21) had 1 healthy child, born by cesarean delivery. The remaining patient (patient 19) was sterile. This patient was very

noncompliant with her daily glucocorticoid treatment. She complained of spaniomenorrhea and presented with moderate hirsutism associated with bilaterally enlarged, cystic ovaries. Absolute causes of sterility, such as bilateral tubal obstruction and azoospermia of the male partner, were previously excluded. Neurocognitive Findings On neurological examination, mental retardation was evident in 3 patients (patients 4, 6 and 23). On intellectual quotient test,35 it was moderate in patients 4 and 6 (both had developed salt-losing crisis during the neonatal period) and profound in patient 23 (having poor control of congenital hypothyroidism). Other neurological signs included postural and action tremor in 2 patients (patients 4 and 23), tendon reflexes asymmetry in 1 patient (patient 1) and static and kinetic cerebellar syndrome in 1 patient (patient 4). Fifteen patients (57.7%) had normal brain MRI. Eleven patients (5 males and 6 females, 42.3%) showed MRI abnormalities: 1 patient was overtreated (patient 8), 2 patients had good hormonal control (patients 13 and 15) and 8 patients were poorly controlled due to noncompliance with their medication. Eight patients (7 with the classical form and 1 with the NC form) evidenced white matter hyperintensities on T2-weighted and FLAIR images. These hyperintensities were located in periventricular regions in 7 patients (Figure 1) and in cerebellar white matter in the remaining patient (patient 1, Figure 2). One patient (patient 11) with the classical SV form showed moderate

TABLE 4. Prevalence of cardiovascular risk factors in our patients according to clinical phenotype of CAH SW Patients (n 5 10) SV Patients (n 5 8) NC Patients (n 5 8) All Patients (n 5 26) 24-Hour systolic blood pressure (mm Hg) 24-Hour diastolic blood pressure (mm Hg) Daytime systolic blood pressure (mm Hg) Daytime diastolic blood pressure (mm Hg) Nighttime systolic blood pressure (mm Hg) Nighttime diastolic blood pressure (mm Hg) Right-CIMT (mm) Left-CIMT (mm)

115.8 71 119 73.12 107.75 62.75 0.49 0.51

6 6 6 6 6 6 6 6

9.7 7.4 12 7.6 8.1 5.8 0.07 0.08

114.6 72.4 118.4 72.8 108.8 67.8 0.51 0.48

6 6 6 6 6 6 6 6

7.2 1.1 9 2.1 10.3 4.7 0.03 0.1

114.1 70.5 116 73.5 106.5 64.8 0.6 0.65

6 6 6 6 6 6 6 6

9.4 4.5 8.8 5.3 7.4 5.7 0.24 0.23

114.9 71.2 117.9 73.15 107.6 64.7 0.55 0.53

6 8.9 6 4.8 6 10.2 6 5.4 6 8.45 65.4 6 0.2 6 0.2

SW, salt wasting; SV, simple virilizing; NC, nonclassical; CAH, congenital adrenal hyperplasia; CIMT, carotid intima-media thickness.

368

Volume 344, Number 5, November 2012

Congenital Adrenal Hyperplasia in Adults

FIGURE 2. Axial fluid-attenuated inversion recovery and T2 MRI showing bilateral cerebellar white matter hyperintensities in a 21year-old man affected by salt-wasting congenital adrenal hyperplasia (patient 1). MRI, magnetic resonance imaging.

FIGURE 1. T2-weighted axial MRI sequence showing bilateral periventricular white matter hyperintensities and cortico-subcortical atrophy in a 16.5-year-old man affected by salt-wasting congenital adrenal hyperplasia (patient 4). MRI, magnetic resonance imaging.

right temporal lobe atrophy. Indeed, 2 patients with the NC form showed right hippocampal dysgenesis: patient 23 had small right hippocampus, whereas in patient 21, hippocampus was globular in shape and its internal structures were not identified (Figure 3). Other MRI findings included partially empty sella in 1 patient (patient 25) and cortico-subcortical atrophy associated with complete agenesis of the corpus callo-sum in another patient (patient 4). No cases of amygdala atrophy were identified.

cognitive outcome and quality of life. These issues were discussed in the literature with inconsistent results.3 It should be noted, however, that our study population included mainly patients with poor hormonal control and a high rate of noncompliance with glucocorticoid treatment, and this may explain the high prevalence of complications. In CAH, patients often fail to reach their TH.6 Our study showed a mean FH of 21.35 SD, similar to a recent metaanalysis,6 and short stature was noted in 30.7% of our patients. Height predictors are controversial and may include the clinical form of CAH, age at diagnosis, adequacy and compliance with therapy and degree of hormonal control.6,36 Obesity in patients

Quality of Life Analysis The assessment of quality of life (excluding patients with mental retardation) revealed a global average score of 64.14 6 11.56 (range, 43.75–78.75). Quality of life was altered in 14 of 22 patients (4 males and 10 females, 63.6%): 2 patients had adequate hormonal control (patients 7 and 15), 1 patient was overtreated (patient 8) and 11 patients were noncompliant with their treatment. Mean item scores on physical and mental dimensions were 72.72 6 9.4 (range, 56.25–85) and 55.5 6 15.2 (range, 28.75-76.25), respectively. Quality of life scales according to clinical phenotype of CAH are shown in Table 5.

DISCUSSION This study establishes that the objective and subjective health status of the adult patients with CAH in our sample is poor. Our main focus was on FH, cardiovascular and metabolic risk profiles, bone health, male and female fertility, neuroÓ 2012 Lippincott Williams & Wilkins

FIGURE 3. Coronal T2-weighted MRI in a 30.5-year-old woman affected by nonclassical congenital adrenal hyperplasia. The right hippocampus is moderately round shaped and its internal structures are not identified (patient 21). MRI, magnetic resonance imaging.

369

Mnif et al

TABLE 5. Mean of quality of life scales according to clinical phenotype of CAH (22 patients) SW Patients SV Patients NC Patients All Patients (n 5 9) (n 5 7) (n 5 6) (n 5 22) PF RP BP GH VT SF RE MH

80.55 78.89 74.45 63.89 62.78 54.44 50 62.22

79.28 77.14 72.85 67.85 59.28 61.42 57.14 64.28

71.66 75 70 56.66 43.33 46.66 48.33 50

77.72 77.27 72.72 63.17 59.54 54.53 51.81 59.54

Subjective health status Short Form-36. Data are given as mean scores. The lower the score, the worse is the perceived impairment. SW, salt wasting; SV, simple virilizing; NC, nonclassical; CAH, congenital adrenal hyperplasia; PF, physical functioning; RP, role limitations due to physical problems; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role limitations due to emotional problems; MH, mental health.

with CAH also seems to be correlated with reduced height potential.36 In our patients, noncompliance seems to be an important factor influencing the height outcome. Noncompliant patients have diminished FH as a result of premature epiphyseal fusion caused by chronic hyperandrogenaemia. Thus, with strict compliance to medical therapy and close clinical and laboratory monitoring, patients with CAH can attain a normal FH which is close to their TH. Critical periods of growth when overtreatment with glucocorticoids should especially be avoided are during infancy and puberty. Mineralocorticoid replacement and, in infants, salt supplementation are also important in optimizing height.37,38 Our study demonstrates a high prevalence (38.4%) of bone demineralization according to the WHO criteria. In fact, data are conflicting concerning the effect of long-term glucocorticoid replacement therapy on bone mass in patients with CAH. BMD in these patients has been reported to be normal,7 decreased8 or even increased.9 Nevertheless, the overall conclusion is in favor of preservation of bone integrity in patients on standard glucocorticoid therapy (10–20 mg/m2).3,37 It is suggestive that low BMD is associated with glucocorticoid overtreatment, especially during infancy and childhood.39 However, increased BMI, common in CAH, may be protective for bone, and episodes of androgen excess may have an anabolic effect on bone.9,36 Thus, unless there is a clinical suspicion of previous overtreatment with glucocorticoids, routine bone density measurements are unnecessary in the young adult with CAH. However, if there is evidence of overtreatment with glucocorticoids, BMD measurement is justified, and osteoporosis prophylaxis such as physical activities, calcium and vitamin D intake could be considered.3,37 Glucocorticoid excess may be not the main cause of bone loss in our patients, most of whom were noncompliant and, as consequence, exposed to chronic hyperandrogenism. It is possible that vitamin D deficiency, a common problem in many populations, plays a determining role, as it was present in almost all of our patients with bone demineralization. Therefore,

370

vitamin D status should systematically be determined in patients with CAH.37,40 Similarly, markers of bone formation, especially osteocalcin, are reported to be low in adult CAH.7 In this study, we observed low osteocalcin levels in 65.2% of our patients. Although these markers are not recommended for use in diagnosis of osteoporosis, they seem to be useful for predicting future bone loss.41 One of our patients, with the SW form, had a nontraumatic vertebral compression fracture. This observation agrees with recent data suggesting increased tendency for osteoporotic fractures (spine, femoral neck and wrist fractures) in patients with CAH managed with high doses of glucocorticoids.42 Few data on the cardiometabolic consequences of CAH in adult life are available. Overall, studies demonstrate an increased prevalence of obesity, body composition alterations, hypertension, dyslipidemia, carbohydrate metabolism disorders and IR.10,11,43 More interestingly, in accordance with our study, markers of subclinical atherosclerosis, such as nondipper status and increased intima-media thickness, were described in this population.44,45 Nondipper status has been shown to be an additional risk factor for the development of adverse cardiovascular events.44 CIMT could be a surrogate marker for cerebral and coronary events and imparts prognostic information independent of traditional cardiovascular risk factors.45 It has been suggested that patients with CAH develop an unfavorable cardiovascular risk profile either because of the existence of hyperandrogenism in untreated or undertreated patients or because of the supraphysiological doses of glucocorticoids used to suppress androgen levels to normal values. Other factors, such as adrenomedullary dysfunction and alteration in leptin axis, may promote metabolic disorders and cardiovascular risk factors.10,11 In our patients, hyperandrogenism may play a crucial role in favoring metabolic and cardiovascular abnormalities. Androgen excess may itself lead to hyperinsulinism and may be an independent contributor to the development of the metabolic syndrome components.10,11 Further studies are required to better evaluate the risk of atherosclerotic vascular disease in patients with CAH. Early lifestyle intervention, consisting mainly of appropriate diet and exercise, may prevent deleterious metabolic effects of this disease.11,37 Targeted pharmacologic therapy should also be considered in patients with CAH who have major cardiovascular risk factors.11 In this study, markers of gonadal function including LH, FSH, testosterone and inhibin B were reduced in 4 of 11 patients and abnormalities in semen analysis were noted in 4 of 10 patients. Furthermore, testicular sonograms revealed testicular adrenal rests in 6 of 11 subjects, all of whom were noncompliant with their glucocorticoid replacement, with subsequent chronic elevation of ACTH. Our findings confirm and extend previous studies showing reduced fertility in men with CAH.46 Although some males with CAH may develop hypogonadotropic hypogonadism due to high levels of steroids which suppress the hypothalamicpituitary-gonadal axis, the most common reason for reduced fertility in men with CAH is the presence of TARTs.46 Most authors now agree that TARTs develop from ectopic remnants of intratesticular adrenal tissue stimulated by ACTH hypersecretion.47 These tumors may be prevalent in up to 94% of CAH adults and may already appear during childhood.47 TARTs can affect testicular function directly through mechanical compression of adjacent seminiferous tubules and Volume 344, Number 5, November 2012

Congenital Adrenal Hyperplasia in Adults

obstruction of the vascular supply. Such tumors may also have a paracrine effect via local steroid production which may be toxic to the Leydig cells and/or germ cells. Indeed, longstanding TARTs can lead to peritubular fibrosis and tubular hyalinization, which confirms irreversible testicular damage. Thus, these tumors should be periodically screened from adolescence by ultrasound. Early intensifying glucocorticoid therapy may lead to tumor regression and prevent fertility problems in CAH males.37,47 Similarly, fertility in women with 21-OHD seems to be reduced, especially those with salt-losing CAH.48 Several factors have been suggested to contribute to the impaired fertility in CAH females: adrenal overproduction of androgens and progestins (17-OHP and progesterone), ovarian hyperandrogenism, PCOS, neuroendocrine factors, genital surgery and psychological factors such as delayed psychosexual development, reduced sexual activity and low maternal feelings.12,48 In our cohort of 15 female patients, 1 had sterility, 1 presented with hypogonadotropic hypogonadism and 6 showed POCS. Indeed, 4 women had low level of AMH, which is considered now as an important clinical marker of ovarian functioning and a useful predictor of fertility outcomes.49 The main causes of fertility issues in our female patients seem to be medication noncompliance and subsequent hyperandrogenism. Thus, better compliance with therapy and careful monitoring of androgen levels could contribute to improving fertility rates among women with CAH. Studies of cognitive function have reported discrepant findings. Some studies suggest those patients with the most severe form of CAH and who have experienced SW adrenal crises with abnormal electrolytes as neonates are at risk for cognitive impairment.13 In this study, 3 patients showed mental retardation, 2 of them with the classical SW form and 1 with the NC form. The latter had an uncontrolled congenital hypothyroidism which can explain her profound mental retardation. Our participants provide evidence of an increased frequency of white matter hyperintensities and hippocampal dysgenesis. In the past, only a few studies described brain MRI abnormalities in CAH. Overall, these studies documented abnormalities affecting white matter signal, temporal lobe and amygdala structure and function.14,50,51 White matter hyperintensities related to CAH are most often subclinical or, less frequently, associated with unremarkable neurological signs.14,50 In this study, 3 of 26 patients revealed an abnormal neurological examination. These white matter changes involve typically periventricular regions or, less frequently, cerebellar area as seen in one of our patients.14,50,51 The mechanisms that could explain MRI lesions in CAH remain poorly understood. Hormonal imbalance related to a deficiency of cortisol and aldosterone and an overproduction of 17-OHP and androgen would cause a destabilization of the myelin molecule leading to its degeneration. In addition, exogenous glucocorticoids may interfere with the process of neuronal maturation and myelination by inhibiting the proliferation of oligodendrocyte precursors.14,50,51 In our patients, chronic hyperandrogenism, a result of noncompliance with treatment, may be the main mechanism involved in the genesis of brain MRI abnormalities. Two structures are particularly susceptible to the effects of excess glucocorticoids: the hippocampus, a central neural substrate of declarative memory, and the amygdala, a key to emotional coding. In this context, Merke et al. 4 recently reported irregularities in the structure and function of the Ó 2012 Lippincott Williams & Wilkins

amygdala in children with CAH. Specifically, they documented reduced volume in both male and female patients and enhanced response to negative facial emotions in female patients.51 Studies of adult patients with chronic hypercortisolemia have shown that prolonged exposure to glucocorticoid excess results in hippocampal atrophy and memory dysfunction.52 This study is the first one demonstrating hippocampal abnormalities in patients with CAH, and it showed, also for the first time, brain MRI abnormalities in patients with the NC form of CAH. Recent studies,15,16 in contrast to previous observations,17 have demonstrated a reduction in the quality of life in patients with CAH, particularly in its social dimensions. Patients with CAH were more often single, were less sexually active, displayed more negative body image and had more negative self-image with regard to self-confidence, sociability and social acceptance.3,17 Indeed, CAH females had higher depression and anxiety scores than controls.17 There are many factors that influence quality of life in patients with CAH, such as genital surgery procedure, mutation severity, short stature, increased weight and hirsutism.37,53 In this study, impairment of quality of life, affecting 63.6% of patients, could be underestimated as we have excluded from this analysis 3 patients with mental retardation. This reduction in quality of life was related mainly to the emotional and social problems. Thus, our findings corroborate those reported in the recent literature. With the aim of reducing the degree of social and psychological problems and improving patients’ quality of life, it is important to consider the psychological care and support of both the patients with CAH and their parents all through childhood, adolescence and adult life.54 The major limitations of this study are small sample size and involvement of few individuals older than 30 years. Despite these limitations, this study was able to address simultaneously several issues related to long-term consequences of CAH and its treatment. Our study specifically addresses the outcome of patients with poor disease control and highlights the need for providing education and support to patients with CAH and their families. The outcome in well-controlled patients with CAH may be different. Thus, more data from large and systematic clinical studies are needed to better understand adult consequences of CAH and to define optimal management of this population. In conclusion, health outcomes in CAH adults with poor hormonal control are generally unsatisfactory. Most of the problems relate to FH, fertility, cardiometabolic risk, bone metabolism and psychoneurological issues. Patients with CAH should be regularly followed up from childhood to adulthood by multidisciplinary teams who have knowledge of CAH. Monitoring of anthropometric and biochemical measurements, dose adjustments of corticoids, especially during infancy and puberty, early lifestyle interventions, bone health assessment, regular testicular ultrasound and psychological management are needed. ACKNOWLEDGMENTS The authors are grateful to Dr. Henda Ketata, Dr. Ilyes Siala, Dr. Walid Ayedi, Dr. Nabil Sfar, Dr. Mohamed Attia, Dr. Nader Hammami and Dr. Kamel Haddouk for their excellent technical assistance. REFERENCES 1. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev 2000;21:245–91.

371

Mnif et al

2. Forest MG, Tardy V, Nicolino M, et al. 21-Hydroxylase deficiency: an exemplary model of the contribution of molecular biology in the understanding and management of the disease. Ann Endocrinol 2005;66:225–32.

22. Bates DW, Black DM, Cummings SR. Clinical use of bone densitometry: clinical applications. JAMA 2002;288:1898–900.

3. Ogilvie CM, Crouch NS, Rumsby G, et al. Congenital adrenal hyperplasia in adults: a review of medical, surgical and psychological issues. Clin Endocrinol 2006;64:2–11.

23. Gabir MM, Hanson RL, Dabelea D, et al. The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care 2000;23:1108–12.

4. Merke DP, Chrousos GP, Eisenhofer G, et al. Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 2000;343:1362–8.

24. Matthews DR, Hosker JP, Rudenski AS, et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–9.

5. Ambroziak U, Bednarczuk T, Ginalska-Malinowska M, et al. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency—management in adults. Endokrynol Pol 2010;61:142–55.

25. Radikova Z, Koska J, Huckova M, et al. Insulin sensitivity indices: a proposal of cut-off points for simple identification of insulin-resistant subjects. Exp Clin Endocrinol Diabetes 2006;114:249–56.

6. Eugster EA, Dimeglio LA, Wright JC, et al. Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr 2001;138:26–32.

26. Stone NJ, Bilek S, Rosenbaum S. Recent National Cholesterol Education Program Adult Treatment Panel III update: adjustments and options. Am J Cardiol 2005;96:53E–59E.

7. Guo CY, Weetman AP, Eastell R. Bone turnover and bone mineral density in patients with congenital adrenal hyperplasia. Clin Endocrinol 1996;45:535–41.

27. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87.

8. Falhammar H, Filipsson H, Holmdahl G, et al. Fractures and bone mineral density in adult women with 21-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92:4643–9. 9. Arisaka O, Hoshi M, Kanazawa S, et al. Preliminary report: effect of adrenal androgen and estrogen on bone maturation and bone mineral density. Metabolism 2001;50:377–9. 10. Mooij CF, Kroese JM, Claahsen-van der Grinten HL, et al. Unfavourable trends in cardiovascular and metabolic risk in paediatric and adult patients with congenital adrenal hyperplasia? Clin Endocrinol 2010;73:137–46. 11. Kim MS, Merke DP. Cardiovascular disease risk in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Semin Reprod Med 2009;27:316–21. 12. Gastaud F, Bouvattier C, Duranteau L, et al. Impaired sexual and reproductive outcomes in women with classical forms of congenital adrenal hyperplasia. J Clin Endocrinol Metab 2007;92:1391–6. 13. Johannsen TH, Ripa CP, Reinisch JM, et al. Impaired cognitive function in women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2006;91:1376–81. 14. Bergamaschi R, Livieri C, Uggetti C, et al. Brain white matter impairment in congenital adrenal hyperplasia. Arch Neurol 2006;63:413–6. 15. Arlt W, Willis DS, Wild SH, et al. Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab 2010;95:5110–21. 16. Nermoen I, Husebye ES, Svartberg J, et al. Subjective health status in men and women with congenital adrenal hyperplasia: a populationbased survey in Norway. Eur J Endocrinol 2010;163:453–9. 17. Jääskeläinen Voutilainen R. Long-term outcome of classical 21hydroxylase deficiency: diagnosis, complications and quality of life. Acta Paediatr 2000;89:183–7. 18. Joint LWPES/ESPE CAH Working Group. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 2002;87:4048–53. 19. Hatch R, Rosenfield RL, Kim MH, et al. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol 1981;140:815–30. 20. Prader A, Gurtner HP. Das Syndrom des Pseudohermaphrotismus masculinus bei kongenitaler Nebennierenindenhyperplasie ohne androgenubë rproduktion (adrenaler Pseudohermaphroditismus masculinus). Helv Paediatr Acta 1955;10:397–412. 21. Muirhead S, Sellers EA, Guyda H; Canadian Pediatric Endocrine Group. Indicators of adult height outcome in classical 21-hydroxylase deficiency congenital adrenal hyperplasia. J Pediatr 2002;141:247–52.

372

28. Liivak K, Tillmann V. 24-hour blood pressure profiles in children with congenital adrenal hyperplasia on two different hydrocortisone treatment regimens. J Pediatr Endocrinol Metab 2009;22:511–7. 29. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 2008;21:93–111. 30. Denarié N, Gariepy J, Chironi G, et al. Distribution of ultrasonographically-assessed dimensions of common carotid arteries in healthy adults of both sexes. Atherosclerosis 2000;148:297–302. 31. Kliesch S, Cooper TG. [Semen analysis: spermiogram according to WHO criteria]. Urologe A 2008;47:1550–4. 32. Trivax B, Azziz R. Diagnosis of polycystic ovary syndrome. Clin Obstet Gynecol 2007;50:168–77. 33. Gandek B, Ware JE Jr. Methods for validating and norming translations of health status questionnaires: the IQOLA Project approach. International Quality of Life Assessment. J Clin Epidemiol 1998;51:953–9. 34. Coons SJ, Alabdulmohsin SA, Draugalis JR, et al. Reliability of an Arabic version of the RAND-36 Health Survey and its equivalence to the US-English version. Med Care 1998;36:428–32. 35. Atkinson L. Mental retardation and WAIS-R difference scores. J Ment Defic Res 1991;35:537–42. 36. Nguyen AT, Brown JJ, Warne GL. Growth in congenital adrenal hyperplasia. Indian J Pediatr 2006;73:89–93. 37. Speiser PW, Azziz R, Baskin LS, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010;95:4133–60. 38. Hoepffner W, Kaufhold A, Willgerodt H, et al. Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency can achieve their target height: the Leipzig experience. Horm Res 2008; 70:42–50. 39. Chakhtoura Z, Bachelot A, Samara-Boustani D, et al. Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency. Eur J Endocrinol 2008;158:879–87. 40. Bachelot A, Chakthoura Z, Rouxel A, et al. Classical forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in adults. Horm Res 2008;69:203–11. 41. Ivaska KK, Gerdhem P, Väänänen HK, et al. Bone turnover markers and prediction of fracture: a prospective follow-up study of 1040

Volume 344, Number 5, November 2012

Congenital Adrenal Hyperplasia in Adults

elderly woman for a mean of 9 years. J Bone Miner Res 2010;25: 393–403. 42. Loechner KJ, Patel S, Fordham L, et al. Decreased bone mineral density and vertebral compression fractures in a young adult male with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH): is CAH an unrecognized population at risk for glucocorticoid-induced osteoporosis? J Pediatr Endocrinol Metab. 2010;23:179–87. 43. Charmandari E, Chrousos GP. Metabolic syndrome manifestations in classic congenital adrenal hyperplasia: do they predispose to atherosclerotic cardiovascular disease and secondary polycystic ovary syndrome? Ann N Y Acad Sci 2006;1083:37–53. 44. Völkl TM, Simm D, Dötsch J, et al. Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006;91:4888–95.

47. Claahsen-van der Grinten HL, Otten BJ, Stikkelbroeck MM, et al. Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab 2009;23:209–20. 48. Casteràs A, De Silva P, Rumsby G, et al. Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. Clin Endocrinol 2009;70:833–7. 49. Fanchin R, Schonäuer LM, Righini C, et al. Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003;18:323–7. 50. Nass R, Heier L, Moshang T, et al. Magnetic resonance imaging in the congenital adrenal hyperplasia population: increased frequency of white-matter abnormalities and temporal lobe atrophy. J Child Neurol 1997;12:181–6. 51. Ernst M, Maheu FS, Schroth E, et al. Amygdala function in adolescents with congenital adrenal hyperplasia: a model for the study of early steroid abnormalities. Neuropsychologia 2007;45:2104–13.

45. Sartorato P, Zulian E, Benedini S, et al. Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2007;92:1015–8.

52. Sapolsky RM. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatry 2000;57:925–35.

46. Reisch N, Flade L, Scherr M, et al. High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2009;94:1665–70.

54. Johannsen TH, Ripa CP, Mortensen EL, et al. Quality of life in 70 women with disorders of sex development. Eur J Endocrinol 2006;155: 877–85.

Ó 2012 Lippincott Williams & Wilkins

53. Nordenskjöld A, Holmdahl G, Frisén L, et al. Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2008;93:380–6.

373