M Mercè Fernández-Balsells, Kalpana Muthusamy, Galina Smushkin, Julianna F Lampropulos, Mohamed B Elamin, Nisrin O Abu Elnour, Khalid B Elamin, Neera Agrwal, Juan F Gallegos-Orozco, Melanie A Lane, Patricia J Erwin, Victor M Montori, M Hassan Murad
Prenatal dexamethasone use for the prevention of virilization in pregnancies at risk for classical congenital adrenal hyperplasia because of 21-hydroxylase (CYP21A2) deficiency: a systematic review and meta-analyses.
Clin Endocrinol (Oxf). 2010 Oct;73(4):436-44. doi: 10.1111/j.1365-2265.2010.03826.x.
Abstract/Text
CONTEXT: Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial.
OBJECTIVE: To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2).
DATA SOURCES: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies.
STUDY SELECTION: Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment.
DATA EXTRACTION: Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes.
DATA SYNTHESIS: We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Meta-analysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, -2.33, 95% CI, -3.38, -1.27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsychological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone.
CONCLUSIONS: The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients' values and preferences and requires fully informed and consenting parents.
© 2010 Blackwell Publishing Ltd.
Kalpana Muthusamy, Mohamed B Elamin, Galina Smushkin, Mohammad Hassan Murad, Julianna F Lampropulos, Khalid B Elamin, Nisrin O Abu Elnour, Juan F Gallegos-Orozco, Mitra M Fatourechi, Neera Agrwal, Melanie A Lane, Felipe N Albuquerque, Patricia J Erwin, Victor M Montori
Clinical review: Adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis.
J Clin Endocrinol Metab. 2010 Sep;95(9):4161-72. doi: 10.1210/jc.2009-2616.
Abstract/Text
CONTEXT: Treatment for patients with congenital adrenal hyperplasia (CAH) may affect the final height of these patients.
OBJECTIVE: Our objective was to determine the distribution of achieved height in patients with classic CAH diagnosed at infancy or early childhood and treated with glucocorticoids.
DATA SOURCES: We searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, and Scopus through September 2008; the reference sections of included studies; and expert files.
STUDY SELECTION: Eligible studies included patients diagnosed with CAH before age 5 and followed to final height.
DATA EXTRACTION: Reviewers working in duplicate independently extracted data on study characteristics and outcomes and determined each study's risk of bias.
DATA SYNTHESIS: The sd score (SDS) for final height and corrected height (defined as final height SDS - midparental height SDS) were estimated from each study and pooled using random-effects metaanalysis. The I(2) statistic was used to assess inconsistency in results across studies.
RESULTS: We found 35 eligible studies, most of which were retrospective single-cohort studies. The final height SDS achieved by CAH patients was -1.38 (-1.56 to -1.20; I(2) = 90.2%), and the corrected height SDS was -1.03 (-1.20 to -0.86; I(2) = 63.1%). This was not significantly associated with age at diagnosis, gender, type and dose of steroid, and age of onset of puberty. Mineralocorticoid users had a better height outcome in comparison with the nonusers (P = 0.02).
CONCLUSION: Evidence derived from observational studies suggests that the final height of CAH patients treated with glucocorticoids is lower than the population norm and is lower than expected given parental height.
Nicole Reisch, Michael Scherr, Linda Flade, Martin Bidlingmaier, Hans-Peter Schwarz, Ullrich Müller-Lisse, Martin Reincke, Marcus Quinkler, Felix Beuschlein
Total adrenal volume but not testicular adrenal rest tumor volume is associated with hormonal control in patients with 21-hydroxylase deficiency.
J Clin Endocrinol Metab. 2010 May;95(5):2065-72. doi: 10.1210/jc.2009-1929. Epub 2010 Feb 26.
Abstract/Text
CONTEXT: Patients with 21-hydroxylase deficiency (21-OHD) have been shown to develop adrenal adenomas and, in males, testicular adrenal rest tumors (TARTs) at a high percentage.
OBJECTIVE: The aim of this study was to evaluate the interrelation of adrenal masses and TARTs as well as factors stimulating tumor growth of orthotopic and ectopic adrenal tissue in 21-OHD.
DESIGN: In a cross-sectional study, 26 adult male patients with classic 21-OHD (15 salt wasting, 11 simple virilizing; age range, 18-48 yr) were clinically assessed according to their hormonal control. Magnetic resonance imaging of the adrenals (26 of 26) and of the testes (18 of 26) was performed. Adrenal size and morphology was compared to 26 age-matched controls.
RESULTS: Combined adrenal volume of 21-OHD patients was significantly higher (median, 9.3 ml; range, 3.2-124.5 ml) in comparison to controls (median, 7.4 ml; range, 5.5-10.8 ml; P = 0.005). Morphologically, adrenals were classified as normal without nodules in 27% of 21-OHD patients compared to 69% of controls. None of the controls, but 42% of 21-OHD patients had an overall adrenal volume higher than 11 ml. Ten of 18 patients had TARTs with a median volume of 3.3 ml (range, 0.4-21.6 ml). Total adrenal volume and tumor size but not TART volume correlated positively with current parameters of hormonal control (androstenedione, morning 17-OHP in serum, pregnanetriol in 24-h urine; P < 0.001 for each). Baseline ACTH was independent of adrenal and TART volume. There was no correlation of total adrenal or adrenal tumor size with TART volume.
CONCLUSION: These data provide indirect evidence that different factors regulate the growth of orthotopic adrenal tissue and ectopic adrenal remnants in TARTs.
Wiebke Arlt, Debbie S Willis, Sarah H Wild, Nils Krone, Emma J Doherty, Stefanie Hahner, Thang S Han, Paul V Carroll, Gerry S Conway, D Aled Rees, Roland H Stimson, Brian R Walker, John M C Connell, Richard J Ross, United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE)
Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients.
J Clin Endocrinol Metab. 2010 Nov;95(11):5110-21. doi: 10.1210/jc.2010-0917. Epub 2010 Aug 18.
Abstract/Text
CONTEXT: No consensus exists for management of adults with congenital adrenal hyperplasia (CAH) due to a paucity of data from cohorts of meaningful size.
OBJECTIVE: Our objective was to establish the health status of adults with CAH.
DESIGN AND SETTING: We conducted a prospective cross-sectional study of adults with CAH attending specialized endocrine centers across the United Kingdom.
PATIENTS: Participants included 203 CAH patients (199 with 21-hydroxylase deficiency): 138 women, 65 men, median age 34 (range 18-69) years.
MAIN OUTCOME MEASURES: Anthropometric, metabolic, and subjective health status was evaluated. Anthropometric measurements were compared with Health Survey for England data, and psychometric data were compared with appropriate reference cohorts.
RESULTS: Glucocorticoid treatment consisted of hydrocortisone (26%), prednisolone (43%), dexamethasone (19%), or a combination (10%), with reverse circadian administration in 41% of patients. Control of androgens was highly variable with a normal serum androstenedione found in only 36% of patients, whereas 38% had suppressed levels suggesting glucocorticoid overtreatment. In comparison with Health Survey for England participants, CAH patients were significantly shorter and had a higher body mass index, and women with classic CAH had increased diastolic blood pressure. Metabolic abnormalities were common, including obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.
CONCLUSIONS: Currently, a minority of adult United Kingdom CAH patients appear to be under endocrine specialist care. In the patients studied, glucocorticoid replacement was generally nonphysiological, and androgen levels were poorly controlled. This was associated with an adverse metabolic profile and impaired fertility and quality of life. Improvements in the clinical management of adults with CAH are required.
Thang S Han, Nils Krone, Debbie S Willis, Gerard S Conway, Stefanie Hahner, D Aled Rees, Roland H Stimson, Brian R Walker, Wiebke Arlt, Richard J Ross, United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE)
Quality of life in adults with congenital adrenal hyperplasia relates to glucocorticoid treatment, adiposity and insulin resistance: United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE).
Eur J Endocrinol. 2013 Jun;168(6):887-93. doi: 10.1530/EJE-13-0128. Epub 2013 May 3.
Abstract/Text
CONTEXT: Quality of life (QoL) has been variously reported as normal or impaired in adults with congenital adrenal hyperplasia (CAH). To explore the reasons for this discrepancy we investigated the relationship between QoL, glucocorticoid treatment and other health outcomes in CAH adults.
METHODS: Cross-sectional analysis of 151 adults with 21-hydroxylase deficiency aged 18-69 years in whom QoL (assessed using the Short Form Health Survey), glucocorticoid regimen, anthropometric and metabolic measures were recorded. Relationships were examined between QoL, type of glucocorticoid (hydrocortisone, prednisolone and dexamethasone) and dose of glucocorticoid expressed as prednisolone dose equivalent (PreDEq). QoL was expressed as z-scores calculated from matched controls (14,430 subjects from UK population). Principal components analysis (PCA) was undertaken to identify clusters of associated clinical and biochemical features and the principal component (PC) scores used in regression analysis as predictor of QoL.
RESULTS: QoL scores were associated with type of glucocorticoid treatment for vitality (P=0.002) and mental health (P=0.011), with higher z-scores indicating better QoL in patients on hydrocortisone monotherapy (P<0.05). QoL did not relate to PreDEq or mutation severity. PCA identified three PCs (PC1, disease control; PC2, adiposity and insulin resistance and PC3, blood pressure and mutations) that explained 61% of the variance in observed variables. Stepwise multiple regression analysis demonstrated that PC2, reflecting adiposity and insulin resistance (waist circumference, serum triglycerides, homeostasis model assessment of insulin resistance and HDL-cholesterol), related to QoL scores, specifically impaired physical functioning, bodily pain, general health, Physical Component Summary Score (P<0.001) and vitality (P=0.002).
CONCLUSIONS: Increased adiposity, insulin resistance and use of prednisolone or dexamethasone are associated with impaired QoL in adults with CAH. Intervention trials are required to establish whether choice of glucocorticoid treatment and/or weight loss can improve QoL in CAH adults.
Mass Screening Committee, Japanese Society for Pediatric Endocrinology, Japanese Society for Mass Screening, Tomohiro Ishii, Makoto Anzo, Masanori Adachi, Kazumichi Onigata, Satoshi Kusuda, Keisuke Nagasaki, Shohei Harada, Reiko Horikawa, Masanori Minagawa, Kanshi Minamitani, Haruo Mizuno, Yuji Yamakami, Masaru Fukushi, Toshihiro Tajima
Guidelines for diagnosis and treatment of 21-hydroxylase deficiency (2014 revision).
Clin Pediatr Endocrinol. 2015 Jul;24(3):77-105. doi: 10.1297/cpe.24.77. Epub 2015 Jul 18.
Abstract/Text
Purpose of developing the guidelines: The first guidelines for diagnosis and treatment of 21-hydroxylase deficiency (21-OHD) were published as a diagnostic handbook in Japan in 1989, with a focus on patients with severe disease. The "Guidelines for Treatment of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency) Found in Neonatal Mass Screening (1999 revision)" published in 1999 were revised to include 21-OHD patients with very mild or no clinical symptoms. Accumulation of cases and experience has subsequently improved diagnosis and treatment of the disease. Based on these findings, the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology further revised the guidelines for diagnosis and treatment. Target disease/conditions: 21-hydroxylase deficiency. Users of the guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, referring pediatric practitioners, general physicians; and patients.
Walter Bonfig, Susanne Bechtold Dalla Pozza, Heinrich Schmidt, Philipp Pagel, Dietrich Knorr, Hans Peter Schwarz
Hydrocortisone dosing during puberty in patients with classical congenital adrenal hyperplasia: an evidence-based recommendation.
J Clin Endocrinol Metab. 2009 Oct;94(10):3882-8. doi: 10.1210/jc.2009-0942. Epub 2009 Jul 21.
Abstract/Text
CONTEXT: Patients with congenital adrenal hyperplasia (CAH) are at risk for early pubertal development and diminished pubertal growth. Liberal treatment with glucocorticoids will prevent early puberty but may inhibit growth outright.
OBJECTIVE: The aim of the study was to determine an optimal range for hydrocortisone dosing during puberty in children with classical CAH who were exclusively treated with hydrocortisone.
METHODS: The effects of glucocorticoid treatment for classical CAH were retrospectively analyzed in 92 patients (57 females). Growth pattern, final height (FH), and mean daily hydrocortisone dose were recorded.
RESULTS: Pubertal growth was significantly reduced in all patients: salt-wasting (SW) females, 13.8 +/- 7.4 cm; simple virilizing (SV) females, 13.1 +/- 6.2 cm; vs. reference, 20.3 +/- 6.8 cm (P < 0.05); and SW males, 17.7 +/- 6.7 cm; SV males, 16.2 +/- 5.7 cm; vs. reference, 28.2 +/- 8.2 cm (P < 0.05). Decreased pubertal growth resulted in FH at the lower limit of genetic potential (corrected FH in SW females, -0.6 +/- 0.9; SV females, -0.3 +/- 0.9; SW males, -0.8 +/- 0.8; and SV males, -1.0 +/- 1.0). During puberty, mean daily hydrocortisone dose was 17.2 +/- 3.4 mg/m(2) in females (SW, 17.0 +/- 3.3; SV, 17.4 +/- 3.5) and 17.9 +/- 2.5 mg/m(2) in males (SW, 17.4 +/- 2.0; SV, 18.7 +/- 3.1). In a logistic regression model, a significant correlation between hydrocortisone dose and FH was found (P < 0.01), and the positive predictive value for short stature rose from below 30% to above 60% when hydrocortisone dose exceeded 17 mg/m(2).
CONCLUSION: With conventional hydrocortisone treatment, pubertal growth is significantly reduced in both sexes, resulting in a FH at the lower limit of genetic potential. These deleterious effects on pubertal growth can be reduced if hydrocortisone does not exceed 17 mg/m(2).
Gau M, Konishi K, Takasawa K, Nakagawa R, Tsuji‐Hosokawa A, Hashimoto A, Sutani A, Tajima T, Hasegawa T, Morio T, Kashimada K. The progression of salt wasting and the body weight change during the first two weeks of life in classical 21‐hydroxylase deficiency patients. Clin Endocrinol (Oxf) [Internet]. Wiley; 2020 Oct [cited 2020 Oct 22]; Available from: https://pubmed.ncbi.nlm.nih.gov/33001476/
T S Han, R H Stimson, D A Rees, N Krone, D S Willis, G S Conway, W Arlt, B R Walker, R J Ross, United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE)
Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia.
Clin Endocrinol (Oxf). 2013 Feb;78(2):197-203. doi: 10.1111/cen.12045.
Abstract/Text
BACKGROUND: Adults with congenital adrenal hyperplasia (CAH) are treated with a wide variety of glucocorticoid treatment regimens.
OBJECTIVE, DESIGN AND METHODS: To test whether drug dose and timing of glucocorticoid treatment regimen impacts on health outcomes. This was a cross-sectional study of 196 adult CAH patients in whom treatment and health outcomes were measured. Glucocorticoid dose was converted to prednisolone dose equivalent (PreDEq) using three published formulae. Associations between the type of glucocorticoid regimen and PreDEq with specific health outcome variables were tested using partial correlation and principal components analysis (PCA).
RESULTS: Patients on dexamethasone had lower androgens and ACTH but greater insulin resistance compared with those receiving hydrocortisone or prednisolone. Dexamethasone dose and once daily administration were associated with insulin resistance. Partial correlation analysis adjusted for age and sex showed PreDEq weakly correlated (r < 0·2) with blood pressure and androstenedione. Mutation severity was associated with increased PreDEq (F(3,141) = 4·4, P < 0·01). In PCA, 3 PCs were identified that explained 62% of the total variance (r(2) ) in observed variables. Regression analysis (age and sex adjusted) confirmed that PC2, reflecting disease control (androstenedione, 17-hydroxypregesterone and testosterone), and PC3, reflecting blood pressure and mutations (systolic and diastolic blood pressure and mutation severity), related directly to PreDEq (r(2) = 23%, P < 0·001).
CONCLUSIONS: In adults with congenital adrenal hyperplasia, dexamethasone use was associated with lower androgens but greater insulin resistance, and increasing glucocorticoid dose associated with increased blood pressure, poor disease control and mutation severity.
© 2012 Blackwell Publishing Ltd.
Glucocorticoid Regimens in the Treatment of Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis - PubMed [Internet]. [cited 2021 Dec 13]. Available from: https://pubmed.ncbi.nlm.nih.gov/31187081/
Ori Eyal, Irit Ayalon-Dangur, Anat Segev-Becker, Anita Schachter-Davidov, Shoshana Israel, Naomi Weintrob
Pregnancy in women with nonclassic congenital adrenal hyperplasia: Time to conceive and outcome.
Clin Endocrinol (Oxf). 2017 Nov;87(5):552-556. doi: 10.1111/cen.13429. Epub 2017 Aug 16.
Abstract/Text
OBJECTIVE: Nonclassic congenital adrenal hyperplasia (NCAH) is common among Ashkenazi Jews (1:400). It is associated with various degrees of postnatal virilization, irregular menses and infertility. Therapy of symptomatic subjects consists of physiologic doses of glucocorticoids. The objective of this study was to evaluate the effect of glucocorticoid treatment on fertility and on pregnancy outcome in women with NCAH.
DESIGN, SETTING AND PATIENTS: This retrospective study included 75 women diagnosed with NCAH who were followed in our clinic and sought fertility between 2008 and 2015.
RESULTS: Seventy-two women succeeded in conceiving (187 pregnancies). Time to conception was 4.0 ± 7 months without and 3.3 ± 3 months with glucocorticoid therapy (P = .43). Seventeen pregnancies were achieved by glucocorticoid therapy after failure to conceive spontaneously. Time to conception before therapy initiation was 10.2 ± 11.4 months compared to 3.3 ± 3.4 months after therapy initiation (P = .02). Of 187 pregnancies, 135 (72%) resulted in live births, 38 (20.3%) ended in spontaneous miscarriages during the first trimester, seven (3.7%) were electively terminated, three (1.6%) were ectopic and four (2.1%) were ongoing during the study with similar rate in glucocorticoid treated and untreated pregnancies.
CONCLUSIONS: The 96% pregnancy rate among our cohort of NCAH females was similar to the 95% rate reported for the normal population. Glucocorticoid therapy may shorten the time to conceive in a subgroup of women with NCAH. Glucocorticoid therapy did not affect the rate of first trimester miscarriage. Our 77% live birth rate was similar to the 72% live birth rate in the current healthy US population.
© 2017 John Wiley & Sons Ltd.
