REVIEWS Treatment and health outcomes in adults with congenital adrenal hyperplasia Thang S. Han, Brian R. Walker, Wiebke Arlt and Richard J. Ross Abstract | Congenital adrenal hyperplasia (CAH) is a genetic disorder caused by defective steroidogenesis that results in glucocorticoid deficiency; the most common underlying mutation is in the gene that encodes 21-hydroxylase. Life-saving glucocorticoid treatment was introduced in the 1950s, and the number of adult patients is now growing; however, no consensus has been reached on the management of CAH beyond childhood. Adult patients are prescribed a variety of glucocorticoids, including hydrocortisone, prednisone, prednisolone, dexamethasone and combinations of these drugs taken in either a circadian or reverse circadian regimen. Despite these personalized treatments, biochemical control of CAH is only achieved in approximately one-third of patients. Some patients have a poor health status, with an increased incidence of obesity and osteoporosis, and impaired fertility and quality of life. The majority of poor health outcomes seem to relate to inadequate treatment rather than the genotype of the patient. Patients receiving high doses of glucocorticoids and the more potent synthetic long-acting glucocorticoids are at an increased risk of obesity, insulin resistance and a reduced quality of life. Further research is required to optimize the treatment of adult patients with CAH and improve health outcomes. Han, T. S. et al. Nat. Rev. Endocrinol. 10, 115–124 (2014); published online 17 December 2013; doi:10.1038/nrendo.2013.239
Introduction
Department of Diabetes and Endocrinology, St Peter’s NHS Foundation Trust, Guildford Road, Chertsey, Surrey KT16 0PZ, UK (T. S. Han). BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK (B. R. Walker). Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK (W. Arlt). Academic Unit of Diabetes, Endocrinology & Metabolism, The Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK (R. J. Ross). Correspondence to: R. J. Ross [email protected]
Congenital adrenal hyperplasia (CAH) is the most common genetic endocrine disorder.1 Mutations in the CYP21A2 gene, which encodes the enzyme 21‑hydroxylase, account for 95% of cases.2,3 In 21‑hydroxylase deficiency, disrupted cortisol synthesis results in reduced cortisol feedback that increases the release of adrenocortico‑ tropic hormone (ACTH) from the pituitary gland, which promotes overproduction of 17‑hydroxyprogesterone (17OHP), progesterone and adrenal androgens. Thus, patients with CAH due to 21‑hydroxylase deficiency have two major problems: cortisol deficiency and androgen excess. Many patients also have mineralocorticoid defi‑ ciency, as 21‑hydroxylase also mediates a key step in the synthesis of aldosterone. Glucocorticoid replacement therapy in patients with CAH aims to replace cortisol and prevent the ACTH-driven androgen excess.4,5 Achieving this aim is challenging, as therapy to normalize androgen levels frequently results in excess glucocorticoid exposure with its associated complications, including short stature, obesity, hypertension, osteoporosis and an adverse meta‑ bolic profile. The foremost conundrum facing the physi cian is striking a balance between too much and too little glucocorticoid treatment to avoid the complications of glucocorticoid excess and a life-threatening adrenal crisis (Figure 1). Competing interests R. J. Ross and W. Arlt declare associations with the following company: Diurnal Ltd. See the article online for full details of the relationships. The other authors declare no competing interests.
CAH is a lifelong chronic disorder. In childhood, treatment focuses on issues of gender assignment, genital surgery and optimization of growth and puber‑ tal development. The priorities change as the patient gets older, focusing on fertility in early adult life and prevention of the metabolic syndrome and osteoporosis in middle and older age. Guidelines have been agreed for the management of children with CAH.4,6 However, no consensus exists on the optimal management of adult patients because of a paucity of data from cohorts of a meaningful size. To address this issue, the congenital adrenal hyper‑ plasia adult study executive (CaHASE) was formed in 2003 to study the health status of patients with CAH in adulthood.7 Around the UK, 17 specialist endocrinology centres recruited a cohort of 203 adult patients under their care (median age [range]: men 32 years [18–56 years] and women 34 years [18–69 years]) and gathered infor‑ mation on medical treatment, fertility, genetic analysis and quality of life (QoL). The CaHASE cohort study is the largest published study of adults with CAH to date, but caution is required when interpreting the findings because of its cross-sectional nature and the fairly low response rate, with the 203 patients representing only 54% of all patients invited to participate.7 However, similar results have been reported from other cohort studies in Europe8–10 and the USA.11 Taken together, these studies highlight that adult patients with CAH have a higher morbidity than the general population. The CaHASE findings also showed that only ~10% of adult patients with CAH in the UK receive specialist endocrine care.
NATURE REVIEWS | ENDOCRINOLOGY
VOLUME 10 | FEBRUARY 2014 | 115 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ The health status in adults with congenital adrenal hyperplasia (CAH) is impaired, with an increased incidence of obesity, hypertension, osteoporosis and reduced quality of life and fertility ■■ The poor health status of adults with CAH seems to be a result of their treatment; therefore, patient care needs to be improved and hormone replacement therapy optimized ■■ Potent synthetic and long-acting glucocorticoids should only be used in patients with a clinical indication, and the dose should be maintained at the lowest level for the shortest time possible ■■ Increasing the dose of glucocorticoids does not necessarily result in improved disease control, but will probably have adverse health consequences ■■ Hypertension is common, so mineralocorticoid replacement therapy should avoid suppressing plasma levels of renin below the normal range, and blood pressure should be monitored regularly in adults with CAH Excess cortisol Psychological effects Short stature
Excess androgens Psychological effects
Insulin resistance
Osteoporosis
Hirsutism, amenorrhoea
Short Abnormal and/or Infertility stature early puberty
Obesity
Hypothalamus
Pituitary gland Cortisol
ACTH
Adrenal gland
Androgens
Figure 1 | Treating congenital adrenal hyperplasia. The challenge in treating congenital adrenal hyperplasia is balancing therapy to provide optimal control of androgens whilst avoiding over-replacement with glucocorticoids. Excess glucocorticoid and excess androgens both have consequences for the patient. Abbreviation: ACTH, adrenocorticotropic hormone.
This Review describes the pathophysiology of CAH attributable to 21‑hydroxylase deficiency, classifica‑ tion and current treatment approaches. The latest data on the health status of adult patients are also discussed. The perspectives of the CaHASE study investigators are presented here.
Pathophysiology and classification Adrenal steroidogenesis involves a pathway of precursor hormones that require specific enzymatic steps (Figure 2). Defects in the genes that encode the enzymes involved in the control of steroid biosynthesis give rise to the various forms of CAH. The most common form is caused by 21‑hydroxylase deficiency, whilst the rare forms arise from mutations affecting other enzymes involved in adrenal steroidogenesis, including 11β‑hydroxylase, 116 | FEBRUARY 2014 | VOLUME 10
17α‑hydroxylase, 3β‑hydroxysteroid dehydrogenase or the electron donor enzyme P450 oxidoreductase, which is crucial for the function of the 21‑hydroxylase and 17α‑hydroxylase enzymes. 12 CAH as a result of 21‑hydroxylase deficiency is inherited as an autosomal recessive trait. Inactivating mutations in the CYP21A2 gene account for ~95% of CAH cases,2,3,12 and many of these mutant alleles are deletions in the CYP21A2 gene or CYP21A1P/CYP21A2 chimeric genes caused by unequal crossing-over events within the RCCX locus (a common multiallelic copy number variation locus).13 The clinical classification of 21‑hydroxylase deficiency is based on the severity of the disease, which in turn cor‑ relates with the severity of mutations. For example, major loss-of-function mutations disrupt the patient’s ability to produce both glucocorticoids and mineralocorticoids, whereas the mildest mutations cause androgen excess only. The most severe form of CAH occurs in about 1 in 10,000 to 1 in 20,000 of the general population, and the mildest nonclassic form occurs more frequently in about 1 in 1,000 of the general population of white people, with higher rates in some other populations.2,12 The classic form is made up of ‘salt-wasting’ and ‘simple virilizing’ subgroups based on whether the severity of aldosterone deficiency causes a salt-wasting hypotensive crisis in the neonate. Patients with classic CAH, especially those with salt-wasting, are usually diagnosed before they are 1 year old. By contrast, patients with the nonclassic form are often diagnosed later, frequently during adolescence when the clinical features of androgen excess become apparent in female patients.10 Many boys with nonclassic CAH remain undiagnosed and are not seen by special‑ ists, as there are usually no clinical features.10 Neonatal screening has improved detection of the salt-wasting form of CAH in girls as well as boys, saving lives in both sexes.1,10,14 However, neonatal screening for CAH still does not form part of the routine practice in a number of countries, including the UK. The traditional clinical classification of CAH is based on the phenotype of children; however, terms such as simple virilizing make less sense when describing adults with CAH.15 It has been suggested that adults with classic CAH with 21‑hydroxylase deficiency should be classified under the same subgroup as those who have cortisol defi‑ ciency only and those with deficiency of both cortisol and aldosterone (Box 1). 15 The diagnosis of aldosterone deficiency is based on the measurement of renin, with levels above the reference range suggesting aldosterone deficiency in the absence of other causes. Adults with nonclassic CAH as a result of 21‑hydroxylase deficiency should be classified as ‘normal cortisol reserve’ or ‘partial cortisol deficiency’, depending on whether the cortisol response after stimulation with 250 μg ACTH is normal or borderline impaired using the established cut-off levels for adrenal insufficiency. Patients with a border‑ line blunted cortisol response (peak cortisol levels
Introduction
Department of Diabetes and Endocrinology, St Peter’s NHS Foundation Trust, Guildford Road, Chertsey, Surrey KT16 0PZ, UK (T. S. Han). BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK (B. R. Walker). Centre for Endocrinology, Diabetes and Metabolism, School of Clinical & Experimental Medicine, University of Birmingham, Birmingham B15 2TT, UK (W. Arlt). Academic Unit of Diabetes, Endocrinology & Metabolism, The Medical School, University of Sheffield, Beech Hill Road, Sheffield, South Yorkshire S10 2RX, UK (R. J. Ross). Correspondence to: R. J. Ross [email protected]
Congenital adrenal hyperplasia (CAH) is the most common genetic endocrine disorder.1 Mutations in the CYP21A2 gene, which encodes the enzyme 21‑hydroxylase, account for 95% of cases.2,3 In 21‑hydroxylase deficiency, disrupted cortisol synthesis results in reduced cortisol feedback that increases the release of adrenocortico‑ tropic hormone (ACTH) from the pituitary gland, which promotes overproduction of 17‑hydroxyprogesterone (17OHP), progesterone and adrenal androgens. Thus, patients with CAH due to 21‑hydroxylase deficiency have two major problems: cortisol deficiency and androgen excess. Many patients also have mineralocorticoid defi‑ ciency, as 21‑hydroxylase also mediates a key step in the synthesis of aldosterone. Glucocorticoid replacement therapy in patients with CAH aims to replace cortisol and prevent the ACTH-driven androgen excess.4,5 Achieving this aim is challenging, as therapy to normalize androgen levels frequently results in excess glucocorticoid exposure with its associated complications, including short stature, obesity, hypertension, osteoporosis and an adverse meta‑ bolic profile. The foremost conundrum facing the physi cian is striking a balance between too much and too little glucocorticoid treatment to avoid the complications of glucocorticoid excess and a life-threatening adrenal crisis (Figure 1). Competing interests R. J. Ross and W. Arlt declare associations with the following company: Diurnal Ltd. See the article online for full details of the relationships. The other authors declare no competing interests.
CAH is a lifelong chronic disorder. In childhood, treatment focuses on issues of gender assignment, genital surgery and optimization of growth and puber‑ tal development. The priorities change as the patient gets older, focusing on fertility in early adult life and prevention of the metabolic syndrome and osteoporosis in middle and older age. Guidelines have been agreed for the management of children with CAH.4,6 However, no consensus exists on the optimal management of adult patients because of a paucity of data from cohorts of a meaningful size. To address this issue, the congenital adrenal hyper‑ plasia adult study executive (CaHASE) was formed in 2003 to study the health status of patients with CAH in adulthood.7 Around the UK, 17 specialist endocrinology centres recruited a cohort of 203 adult patients under their care (median age [range]: men 32 years [18–56 years] and women 34 years [18–69 years]) and gathered infor‑ mation on medical treatment, fertility, genetic analysis and quality of life (QoL). The CaHASE cohort study is the largest published study of adults with CAH to date, but caution is required when interpreting the findings because of its cross-sectional nature and the fairly low response rate, with the 203 patients representing only 54% of all patients invited to participate.7 However, similar results have been reported from other cohort studies in Europe8–10 and the USA.11 Taken together, these studies highlight that adult patients with CAH have a higher morbidity than the general population. The CaHASE findings also showed that only ~10% of adult patients with CAH in the UK receive specialist endocrine care.
NATURE REVIEWS | ENDOCRINOLOGY
VOLUME 10 | FEBRUARY 2014 | 115 © 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS Key points ■■ The health status in adults with congenital adrenal hyperplasia (CAH) is impaired, with an increased incidence of obesity, hypertension, osteoporosis and reduced quality of life and fertility ■■ The poor health status of adults with CAH seems to be a result of their treatment; therefore, patient care needs to be improved and hormone replacement therapy optimized ■■ Potent synthetic and long-acting glucocorticoids should only be used in patients with a clinical indication, and the dose should be maintained at the lowest level for the shortest time possible ■■ Increasing the dose of glucocorticoids does not necessarily result in improved disease control, but will probably have adverse health consequences ■■ Hypertension is common, so mineralocorticoid replacement therapy should avoid suppressing plasma levels of renin below the normal range, and blood pressure should be monitored regularly in adults with CAH Excess cortisol Psychological effects Short stature
Excess androgens Psychological effects
Insulin resistance
Osteoporosis
Hirsutism, amenorrhoea
Short Abnormal and/or Infertility stature early puberty
Obesity
Hypothalamus
Pituitary gland Cortisol
ACTH
Adrenal gland
Androgens
Figure 1 | Treating congenital adrenal hyperplasia. The challenge in treating congenital adrenal hyperplasia is balancing therapy to provide optimal control of androgens whilst avoiding over-replacement with glucocorticoids. Excess glucocorticoid and excess androgens both have consequences for the patient. Abbreviation: ACTH, adrenocorticotropic hormone.
This Review describes the pathophysiology of CAH attributable to 21‑hydroxylase deficiency, classifica‑ tion and current treatment approaches. The latest data on the health status of adult patients are also discussed. The perspectives of the CaHASE study investigators are presented here.
Pathophysiology and classification Adrenal steroidogenesis involves a pathway of precursor hormones that require specific enzymatic steps (Figure 2). Defects in the genes that encode the enzymes involved in the control of steroid biosynthesis give rise to the various forms of CAH. The most common form is caused by 21‑hydroxylase deficiency, whilst the rare forms arise from mutations affecting other enzymes involved in adrenal steroidogenesis, including 11β‑hydroxylase, 116 | FEBRUARY 2014 | VOLUME 10
17α‑hydroxylase, 3β‑hydroxysteroid dehydrogenase or the electron donor enzyme P450 oxidoreductase, which is crucial for the function of the 21‑hydroxylase and 17α‑hydroxylase enzymes. 12 CAH as a result of 21‑hydroxylase deficiency is inherited as an autosomal recessive trait. Inactivating mutations in the CYP21A2 gene account for ~95% of CAH cases,2,3,12 and many of these mutant alleles are deletions in the CYP21A2 gene or CYP21A1P/CYP21A2 chimeric genes caused by unequal crossing-over events within the RCCX locus (a common multiallelic copy number variation locus).13 The clinical classification of 21‑hydroxylase deficiency is based on the severity of the disease, which in turn cor‑ relates with the severity of mutations. For example, major loss-of-function mutations disrupt the patient’s ability to produce both glucocorticoids and mineralocorticoids, whereas the mildest mutations cause androgen excess only. The most severe form of CAH occurs in about 1 in 10,000 to 1 in 20,000 of the general population, and the mildest nonclassic form occurs more frequently in about 1 in 1,000 of the general population of white people, with higher rates in some other populations.2,12 The classic form is made up of ‘salt-wasting’ and ‘simple virilizing’ subgroups based on whether the severity of aldosterone deficiency causes a salt-wasting hypotensive crisis in the neonate. Patients with classic CAH, especially those with salt-wasting, are usually diagnosed before they are 1 year old. By contrast, patients with the nonclassic form are often diagnosed later, frequently during adolescence when the clinical features of androgen excess become apparent in female patients.10 Many boys with nonclassic CAH remain undiagnosed and are not seen by special‑ ists, as there are usually no clinical features.10 Neonatal screening has improved detection of the salt-wasting form of CAH in girls as well as boys, saving lives in both sexes.1,10,14 However, neonatal screening for CAH still does not form part of the routine practice in a number of countries, including the UK. The traditional clinical classification of CAH is based on the phenotype of children; however, terms such as simple virilizing make less sense when describing adults with CAH.15 It has been suggested that adults with classic CAH with 21‑hydroxylase deficiency should be classified under the same subgroup as those who have cortisol defi‑ ciency only and those with deficiency of both cortisol and aldosterone (Box 1). 15 The diagnosis of aldosterone deficiency is based on the measurement of renin, with levels above the reference range suggesting aldosterone deficiency in the absence of other causes. Adults with nonclassic CAH as a result of 21‑hydroxylase deficiency should be classified as ‘normal cortisol reserve’ or ‘partial cortisol deficiency’, depending on whether the cortisol response after stimulation with 250 μg ACTH is normal or borderline impaired using the established cut-off levels for adrenal insufficiency. Patients with a border‑ line blunted cortisol response (peak cortisol levels
