Congenital adrenal hyperplasia (CAH) refers to a group of genetic disorders characterized by defective steroidogenesis due to enzyme deficiency. The most common form of CAH, 21-hydroxylase deficiency, affects approximately 1:15,000 live births (1, 2). A 21-hydroxylase deficiency results in glucocorticoid deficiency and an increase in pituitary adrenocorticotropin (ACTH) secretion, leading to adrenal androgen excess and adrenal hyperplasia. Depending on disease severity, CAH due to 21-hydroxylase deficiency is classified into classic (salt-wasting and simple virilizing) and non-classic forms (1). The early diagnosis of 21-hydroxylase deficiency through newborn screening test using 17-hydroxyprogesterone (17-OHP) has decreased mortality and morbidity rates, leading to increased interest in improving long-term health outcomes in adulthood (1, 2).

Several studies have reported adverse outcomes in adults with CAH. In the United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE), 203 adults with CAH were significantly shorter and had a higher body mass index (BMI) compared to the health survey data (3). In a Swedish study, based on disease codes, 360 adults with CAH had an approximately four-fold higher risk of having any cardiovascular and metabolic disorders than matched controls (4). In a cross-sectional study of the National Institutes of Health (NIH) and French cohort, the prevalence of obesity was common, ranging from 35% to 44% (5, 6), although the latter two studies did not compare the patients’ metabolic risk with that of healthy controls. In a European multicenter study, 226 adults with CAH were a higher risk for hypertension, dyslipidemia, and cardiovascular disease but not type 2 diabetes (7). A recent meta-analysis including children and adults with CAH demonstrated that these patients had a high prevalence of cardiovascular and metabolic risk factors (8).

The two main goals for CAH management are to replace the deficient hormones for adrenal insufficiency and control androgen excess. However, it is challenging to balance glucocorticoid doses because supraphysiologic doses of glucocorticoids are usually required to suppress androgen excess. It remains controversial whether over- or undertreatment is more harmful to the metabolic and cardiovascular health of patients with CAH (3, 5, 6, 9–11). Moreover, the relationship between testicular adrenal rest tumors (TARTs) and disease control remains unclear (5, 6, 12).

Most related studies have not performed a sex-stratified analysis and rarely evaluated adrenal morphology such as hyperplasia or thinning (6, 13). In Asia, few studies have examined the determining factors for adverse outcomes in adults with CAH. In this context, we hypothesized that adults with CAH are at a higher risk of metabolic morbidity than their age- and sex-matched controls in the Asian general population. Furthermore, we aimed to investigate sex-specific indicators related to adverse health outcomes by focusing on metabolic morbidity, TARTs, and menstrual irregularity in adults with CAH.

The present study suggested that waist circumference and blood pressure were higher in adults with CAH compared with age- and BMI-matched controls from the KNHANES database. Moreover, there was an increased risk of hypertension in men and obesity in women with CAH than controls. Obese men with CAH showed higher adrenal limb thicknesses than non-obese ones, while obese women had higher 17-OHP and DHEAS levels than non-obese ones. In addition, more than half of the adults with CAH exhibited TARTs or menstrual irregularities. The presence of TARTs in men with CAH was not related to disease control, while women with CAH who had irregular periods were shorter and had higher DHEAS levels than those with regular periods.

The prevalence of obesity or central obesity in adults with classic CAH is reportedly 20–50%, higher than that in healthy controls (3–6). In the present study, obesity was more prevalent in women with CAH, and waist circumference was obviously higher in both sexes than in healthy controls, consistent with the increased abdominal obesity and higher visceral to subcutaneous fat ratio linked to insulin resistance and inflammation, suggesting an unhealthy metabolic phenotype among adults with CAH (18).

It remains controversial whether hypertension, dyslipidemia, and hyperglycemia are more prevalent in adults with CAH than in healthy controls. The prevalence of hypertension was higher in the NIH and Swedish nationwide CAH cohorts (4, 5, 8) and similar or lower in the CaHASE and French cohorts (3, 19). In our study, men with CAH but not women with CAH showed a higher prevalence of hypertension than the controls, which can be related to the relatively high proportion of fludrocortisone use and central obesity among men with CAH and the protective effect of estrogen on blood pressure among women with CAH. The prevalence of dyslipidemia and hyperglycemia was similar between adults with CAH and controls in this study. However, fasting glucose and HDL cholesterol levels in men with CAH and total cholesterol, triglyceride, and HDL cholesterol levels in women with CAH were higher than the values in controls, although a recent meta-analysis including 300 pediatric and 137 adults showed no difference in glucose and lipid levels (8). The result of higher HDL-cholesterol levels in our patients with CAH remains to be reproduced in further studies, and the underlying mechanism also remains to be determined. However, Falhammar et al. suggested that older women with CAH had also higher lean mass which may explain the favorable lipid profile (20). Our study population mainly consisted of young adult patients who showed elevated androgen levels, suggesting poor disease control. Inconsistency in reporting the prevalence of metabolic comorbidities may have resulted from differences in patient age, glucocorticoid and mineralocorticoid doses, treatment target goals, disease control status, and 21-hydroxylase activity.

We further analyzed factors that differed according to whether patients with CAH had more metabolic risk factors. Previous studies identified that adults with CAH are at risk for hyperandrogenism and iatrogenic hypercortisolism, both of which lead to obesity, insulin resistance, and cardiometabolic comorbidities (5, 6, 9, 10). In addition to glucocorticoid overtreatment, suppressed 17-OHP levels were related to obesity or metabolic morbidity (3, 11) as well as androgen excess, suggesting that poor disease control contributed to higher metabolic risk factors as shown in our study.

Intriguingly, obese men with CAH presented with thick adrenal limbs, while obese women had high 17-OHP and DHEAS levels. Few studies have examined the adrenal morphology of adults with CAH (6, 21). Adrenal nodules were more frequently detected in poorly controlled patients with CAH, and regressed in size after high-dose steroids (13). Adrenal hyperplasia and/or nodules have been reported in 29.3– 45% of patients with CAH (22), with significant correlation with high levels of ACTH, 17-OHP, and plasma renin activity (6). Adrenal tumors were detected in 15% (14/93) among our adult patients evaluated by CT. Despite the limitation of a single hormonal measurement in the morning due to the cross-sectional nature of this study, adrenal limb thickness or the presence of adrenal tumors could be a long-term disease control marker in adults with CAH.

Obese women with CAH showed higher 17-OHP levels than non-obese ones, suggesting the contribution of androgen excess. A similar phenomenon was demonstrated in polycystic ovary syndrome in postmenopausal women (23–25). Androgen excess drives visceral fat accumulation and induces the android phenotype in women with CAH (26, 27). Even with continued treatment, patients may respond poorly to glucocorticoid treatment (6, 28) related to glucocorticoid receptor gene polymorphism in addition to low adherence to glucocorticoid therapy regimens (29). Further studies are warranted to determine optimal targets and androgen metabolites that reflect adequate hormonal control and ideal glucocorticoid regimens to minimize cardiometabolic comorbidities.

The presence of TART is the main factor of male infertility since it blocks the seminiferous tubules and leads to Leydig cell failure, which has a reported prevalence of around 37% (14–86%) depending on age and genotype (5, 6, 19, 30). In our study, TARTs were found in 57.1% of men with CAH who underwent testicular sonography. Since TARTs express adrenal-specific enzymes and ACTH and angiotensin II receptors (31), poor disease control and high ACTH or renin activity can lead to adrenocortical hyperplasia and TARTs (5, 32, 33), although the lack of a correlation between 17-OHP levels and TARTs has been reported (6, 12, 34). Although the present study failed to demonstrate a relationship between disease control and the presence of TARTs, in our previous study, TART size was related to the undertreatment percentage (35).

The prevalence of menstrual irregularity was up to 58.1% in the women with CAH in our study, which is consistent with that of a previous report of 30–75% depending on genotype (3). Women with CAH and irregular periods exhibited shorter stature and higher DHEAS levels, reflecting hyperandrogenism. Patients with CAH exposed to high androgens in childhood can experience earlier epiphyseal closure and short stature. Hyperandrogenism suppresses serum progesterone, which reduces luteinizing hormone pulsatility during the follicular phase and induces endometrial thinning, leading to oligo- or anovulation and oligo- or amenorrhea (36–38).

This cross-sectional study had several limitations. There were several missing values due to the retrospective study design. We could not assess the total cumulative doses of glucocorticoid or perform a longitudinal hormone assessment to determine disease control due to a lack of childhood data before the electronic medical record era. Since most patients were diagnosed before the genetic testing era, we could not analyze the patients’ clinical or hormone characteristics according to genotype. When we assessed single hormone measurements in the morning at the last visit, only 7.3% of patients had well-controlled disease based on the early-morning 17-OHP levels. Since undertreatment still affected most of our patients compared to those in previous reports (3), we could not compare the effect of undertreatment versus overtreatment on long-term outcomes. Androstenedione, which was known to be the reliable marker for disease control (1), was not checked due to the cost and unavailability. Although this cross-sectional design could not prove the causal relationship of disease itself or treatment effect with metabolic complications, our study had several strengths. First, it is the largest single-center Asian study of adults with CAH. We also compared age-, sex-, and ethnicity-matched controls to assess metabolic risk. We separately analyzed sex-specific indicators according to health outcomes and obtained different findings by sex. Adrenal thickness assessed by CT was incorporated into the variables to reflect long-term glucocorticoid exposure. Most patients had taken the same dosage of prednisolone in adulthood, thereby allowing us to compare their hormonal effects in patients with CAH without glucocorticoid dose interference.

The present study confirmed the higher prevalence of metabolic morbidities in young adults with CAH than in healthy controls. Moreover, adverse metabolic outcomes and menstrual irregularity were associated with poor disease control in our study subjects. Considering the harmful effects of poor disease control on long-term outcomes, compliance should be guaranteed. Early attention should be paid to identifying at-risk patients and regular follow-up provided to minimize cardiovascular risk in patients with CAH. Further studies are needed to elucidate the mechanisms leading to metabolic morbidity and the respective roles of androgen excess and glucocorticoid exposure.

The original contributions presented in the study are included in the article/supplementary files. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Seoul National University Hospital Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

SL and JK contributed in the conception of the work, participated in the study design, and wrote the manuscript. YL contributed in the conception of the work, participated in the study design, and critically revised the manuscript. HJ, SK, CA, SK, and CS contributed in the conception of the work, performed statistical analyses, and critically revised the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by a donation from one CAH patient.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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