Ieuan Hughes, MD FRCP FRCPCH FMedSci

Congenital adrenal hyperplasia: optimising cardiometabolic outcomes

The introduction of glucocorticoid replacement for congenital adrenal hyperplasia (CAH) has revolutionised the outlook for patients with this lifelong condition, preventing life-threatening salt-wasting crises. However, accumulating evidence shows persistently increased morbidity, and even mortality, in CAH patients, and links it not only to the disease, but also to the treatment.

Here we review key publications, selected by Ieuan Hughes, Emeritus Professor of Paediatrics from Addenbrooke’s Hospital in Cambridge, UK, which summarise the current knowledge and show how clinicians and the pharmaceutical industry are beginning to respond to this challenge.

Complex disease; challenging treatment

For patients with the salt-wasting (classical) form of CAH, the introduction of glucocorticoid treatment in the 1950s turned the condition into a chronic illness, rather than a guarantee of early death.

And Hughes says that CAH was initially viewed as simple to treat: “Take your hydrocortisone, go away, no problem.”

Yet a 2014 Swedish registry study showed that the problem of salt-wasting crises was reduced, rather than entirely vanquished.1 The mortality rate was 3.9% among 588 CAH patients, compared with 1.6% among nearly 59,000 controls, and 42% of the deaths in CAH patients were due to adrenal crises. Other causes of death were cardiovascular, cancer, accident and suicide, and occurred at a similar rate as in controls. However, study authors Henrik Falhammar (Karolinska University Hospital, Stockholm, Sweden) and colleagues noted that half the cardiovascular deaths in CAH patients occurred concurrently with a severe infection, suggesting that an adrenal crisis could have contributed to these deaths.

The findings imply suboptimal glucocorticoid treatment, a point highlighted in a study of 203 CAH patients treated at specialist endocrine centres in the UK.2 Levels of the androgen precursor andostenedione were suppressed in between 10% and 29% of patients and elevated in around a third. Researcher Wiebke Arlt (University of Birmingham, UK) and colleagues found that, overall, only a third of patients had levels within the target range, and the same was true of renin levels in patients receiving mineralocorticoid replacement.

“Paediatricians have prided themselves – allegedly anyway – including myself, that we’ve done a good job,” says Hughes.

Paediatricians were not only keeping CAH patients alive, he says, but also achieving fairly good growth, helping them attain adult heights that, although lower than expected for their family, were still well within population norms.

“And then of course we hand them over to the adult physicians and they come back to us – quite rightly…”

Storing up trouble

Because the adult physicians, making detailed study of their patients’ health, were becoming aware of increased cardiometabolic morbidity in adult CAH patients. For example, Arlt et al found CAH patients were more often obese relative to the UK population, and frequently had metabolic abnormalities, with 46% having hypercholesterolaemia and 29% having insulin resistance, while around a third had osteopenia.

Similarly, Falhammar et al followed up their mortality study with a look at cardiometabolic morbidities, finding that these were almost fourfold more likely to occur in CAH patients relative to controls from the Swedish population, while cardiovascular disease was nearly threefold more common.3 Specific conditions that were elevated in CAH patients included thyrotoxicosis, venous thromboembolism, atrial fibrillation, obesity and diabetes.

Another study found evidence of cardiovascular morbidity in CAH patients at a worryingly young age.4 Ivani Silva (Universidade Federal de Minas Gerais, Belo Horizonte, Brazil) and team assessed 38 pubertal CAH patients, aged 20 years or younger, and controls matched for age, gender and pubertal status. They showed that, relative to the controls, the CAH patients had significantly increased carotid intima-media thickness – an early sign of atherosclerosis. This was not restricted to overweight patients, but was seen only in females.

So cardiometabolic morbidity is “something that’s now being taken very seriously,” says Hughes.

These studies have not only flagged high cardiometabolic risk in CAH patients, they have also begun to link it directly to CAH treatment. A cross-sectional study of 196 adults with CAH found that patients with more severe disease received higher glucocorticoid doses without achieving better disease control – higher dose was actually associated with higher androgen levels.5 Moreover, the increased glucocorticoid doses were also associated with elevated blood pressure.

Although researcher Richard Ross (Royal Hallamshire Hospital, Sheffield, UK) and team found that dexamethasone – the most potent of the glucocorticoids used in the study patients – was associated with the lowest androgen levels, this came at the expense of greater insulin resistance.

A study from Hughes’ own group took a closer look at insulin resistance in 37 CAH patients and 41 healthy controls.6 The 25 patients with classical CAH, which is diagnosed and treated early in life, had significantly greater fat mass than the controls, which the researchers attributed to the long-term effects of glucocorticoid treatment.

“Add to that the obesity epidemic and you’ve got a pretty powerful cocktail of problems,” observes Hughes.

By contrast, the 12 children with nonclassical CAH, which is usually diagnosed later in childhood, had greater lean body mass and blood pressure than the controls, and significant increases in several measures of insulin resistance. Hughes attributes these changes to the patients’ prolonged exposure to excess androgen levels in early childhood, saying that androgen “in itself is a pretty potent stimulator of insulin resistance.”

Hydrocortisone dose: a balancing act

The most recent guidelines for CAH management, from 2010, acknowledge the difficulty of optimising treatment, calling it “a difficult balance between hyperandrogenism and hypercortisolism”, and noting that efforts to completely normalise androgen levels “typically result in overtreatment”.7

The guidelines also advise against long-acting glucocorticoids in children, because of their growth-suppressing effects, instead recommending hydrocortisone three times daily at the lowest possible dose to avoid compromising growth.

Hughes believes that paediatric endocrinologists “are doing much better now than we used to”, saying that the daily hydrocortisone dose, which “in the past has been too much”, has been brought down. “And that’s being translated into better growth and outcome in the short term.”

However, paediatric CAH patients experience the usual deluge of childhood colds and illnesses, each one placing the body under stress and prompting a temporary increase in hydrocortisone dose. Necessary though this is, Hughes wonders if “collectively, we have been overdosing them.”

Added to that is the highly variable pharmacokinetics of hydrocortisone, not only between different stages of childhood, but also between different children, aptly demonstrated in a paper from Peter Hindmarsh (UCL Institute of Child Health, London, UK) and Evangelia Charmandari (University of Athens Medical School, Greece).8 The researchers gave 48 children the same hydrocortisone bolus, but found that its half-life in the different patients ranged from 40 to 225 minutes. Although all children attained a similar peak plasma cortisol concentration, the speed of absorption varied widely, with time to peak concentration ranging from 20 to 118 minutes and the additional time taken for the concentration to fall below 100 nmol/L ranging from 140 to 540 minutes.

This suggests that hydrocortisone dosing should be highly individualised, and perhaps more frequent, with the study authors moving towards four doses per day on the basis of their findings.

Treatment solutions: something borrowed, something new

But in some cases, clearance of hydrocortisone may be so rapid that even a six-times-daily dosing schedule is insufficient to achieve androgen control. An ingenious solution for this is continuous delivery via an adapted insulin pump, as illustrated in a case study, also by Hindmarsh.9

Pump delivery avoids gaps in hydrocortisone exposure and increased need for hydrocortisone during physiological stress can be managed simply by increasing the infusion rate or using the bolus function. Hindmarsh’s team has implemented this in three children, achieving 24-hour cortisol levels within the normal range, normalised 17-hydroxyprogesterone (17-OHP) levels and large improvements in school attendance and quality of life.

Although an effective means of mimicking physiological hormone production, an insulin pump cannot match the simplicity of oral treatment. And pharmaceutical companies are beginning to develop oral drug formulations that more closely replicate physiological production. Two slow-release formulations are currently undergoing clinical testing: Plenadren (ViroPharma SPRL, Brussels, Belgium) and Chronocort (Diurnal Ltd, Cardiff, UK).

In a phase II study of Chronocort, Ashwini Mallappa (National Institutes of Health Clinical Center, Bethesda, Maryland, USA) and colleagues found that the rates of elevated androstenedione and 17-OHP levels among 16 adult CAH patients decreased significantly with Chronocort treatment relative to conventional therapy (33.7 vs 12.0% and 33.2 vs 12.0%, respectively).10 After 6 months of Chronocort treatment, 73% and 59% had normal androstenedione and 17-OHP levels, respectively.

Hughes highlights that the more physiological replacement appeared to allow further dose reductions, with eight of the 16 patients requiring a dose reduction (although two other patients needed a dose increase).

Chronocort is taken twice daily, and therefore suppresses the overnight rise in adrenocorticotrophic hormone (ACTH) seen with Plenadren, which is taken just once daily.11

Hughes says that combating the overnight ACTH rise “probably is important, but on the other hand, if you want to be a pragmatist you’re more likely to take your medicine if it’s a once-daily thing as opposed to a twice-daily thing.”

Plenadran is a little further down the clinical testing route than Chronocort, being approved and now the subject of a post-authorisation safety registry, which includes CAH patients.12 But both formulations still need to be tested in paediatric patients.

“I hope that perhaps getting these so-called more physiological replacement regimens will in due course improve morbidity in adult life,” says Hughes.

But he adds: “It will take a generation to see that.”


Andrew Dauber, MD, MMSc

The genetic toolbox: dissecting pathways to growth

The role of growth hormone (GH) has been established for many decades, but it is only with the advent of advanced molecular genetic techniques that researchers have started to piece together the precise pathways leading to growth.

Here we review seven key papers, chosen by Professor Andrew Dauber, from Cincinnati Children’s Hospital Medical Center in Ohio, USA, which document the pivotal findings that shed light on the process of signalling through the GH/insulin-like growth factor (IGF)-I axis.

The research largely represents the extreme end of the growth disorder spectrum, with a single mutation having a profound effect on a patient’s height, but Dauber stresses that “they teach us a lot about the underlying physiology and the role that those genes play in normal biology.”

A longstanding theory proved

Laron dwarfism was first described in 1966, as an autosomal recessive syndrome with many clinical similarities to isolated GH deficiency. The characteristic low levels of IGF-I despite increased levels of GH implied a role for the GH receptor, but it was not until 1989 that researchers provided direct evidence of this hypothesis. Michel Goossens (CHU Henri Mondor, Créteil, France) and colleagues identified a likely culprit mutation in the GH receptor gene of a family with consanguineous parents with normal phenotypes who had four children, all affected by Laron dwarfism.1

All of the children were homozygous for a single base-pair substitution resulting in serine being present at a position in the extracellular domain of the GH receptor where phenylalanine is invariably found across multiple species. This, combined with the lack of GH-binding activity in the study patients, led the team to conclude that the mutation was probably causative, providing the first direct evidence for the role of the GH receptor in growth.

Deconstructing signalling pathways

In contrast to this study, which actively sought the genetic basis for a condition, another two landmark reports detail more serendipitous findings; direct evidence for the involvement of STAT5 and the IGF-I receptor in growth signalling both emerged from researchers’ efforts to identify the cause of short stature in an individual child, while the surprising findings of another case study challenged the importance of the acid-labile subunit (ALS) in GH/IGF-I signalling.

In one case, Ron Rosenfeld (Oregon Health and Science University, Portland, USA) and co-researchers studied a girl whose height was 7.5 standard deviations (SD) below the average for her age, of 16.5 years.2 She had elevated GH levels and low IGF-I levels, consistent with GH resistance, yet her GH receptor gene had no mutations.

Administration of GH to the patient’s fibroblasts failed to produce the expected increase in IGF-I, leading the researchers to focus on the signalling pathways between these two molecules. This revealed a homozygous missense mutation in STAT5b, which rendered the protein incapable of activation by GH, despite being stably expressed.

Activated STAT5b in turn starts a signalling cascade that leads to increased transcription of IGF-I, IGF binding protein 3 and ALS. Together these molecules form a ternary complex, in which ALS stabilises the binding of IGF-I to IGF binding protein 3 and extends the half-life of circulating IGF-I. As the majority (80–85%) of IGF-I in the body is in this complex form, it was thought to be the main pathway through which GH exerts its effects.3

However, the case of a boy who entirely lacked ALS challenged this notion. The patient had a frameshift point mutation, which prevented production of ALS; he therefore had no ternary complexes and his plasma level of IGF-I was more than 5 SD below the average.

Yet, although the patient was referred to Horacio Domené (Ricardo Gutiérrez Children’s Hospital, Buenos Aires, Argentina) and colleagues partly for growth restriction, this was less severe than might be expected, at 2.05 SD below average. The team speculated that growth in their patient had been sustained by free or locally produced IGF-I, implying that total circulating IGF-I levels are less critical than previously believed.

An expanding role for IGF

A third case study supplied direct evidence that IGF-I is crucial not just for postnatal growth but also for intrauterine growth. The report featured a 15.8-year-old boy who had a birth length 5.4 SD below average and continued to have severe growth retardation throughout childhood, so that, by the time of the report, his height was 6.9 SD below average.4

This patient had elevated GH levels and undetectable serum IGF-I, and Adrian Clark and colleagues, from St Bartholomew’s Hospital in London, UK, found that this was caused by a mutation of the IGF-I gene itself. Their patient was missing exons 4 and 5, resulting in a truncated IGF-I protein.

Evidence for the role of the IGF-I receptor in pre- and postnatal growth came from Steven Chernausek (Cincinnati Children’s Hospital Medical Center, Ohio, USA) and co-workers, who sequenced the gene in 51 children with heights more than 2 SD below average.5 They identified two children, who both had intrauterine and postnatal growth restriction and both had mutations in the IGF-I receptor gene, one resulting in reduced IGF-I receptor function and the other in a reduced number of IGF-I receptors on the fibroblasts.

Although closely related to IGF-I, and well-recognised as a major influence on intrauterine growth, IGF-II has been considered less important for postnatal growth. However, a very recent paper detailed how a paternally inherited IGF-II nonsense mutation resulted in Silver–Russell syndrome.6

Thomas Eggermann (University Hospital, Aachen, Germany) and co-researchers found their patients lacked mutations known to cause Silver–Russell syndrome, but detected the IGF-II mutation using exome and Sanger sequencing. Two of the three affected children were very small at birth but responded to later growth hormone treatment and achieved an adult height close to the third centile; the third did not respond and had continued poor growth.

Another aspect of these case studies was the finding of other, non-growth symptoms that the researchers attributed to the mutations in the GH/IGF-I axis, implying pleiotropic actions of this pathway. For example, the boy with truncated IGF-I had, among other symptoms, profound sensorineural deafness and mental retardation, the girl with mutated STAT5b had a compromised immune response, and the Silver–Russell patients had symptoms including severe postnatal feeding problems, delayed development, mental retardation and hypotonia.

Beyond the GH/IGF-I axis

Postnatal growth is not regulated only by the GH/IGF-I axis. A notable example outside of this pathway is the SHOX (short stature homeobox-containing) gene, a transcription factor that is expressed in the growth plate.

SHOX was first described in 1997, by Gudrun Rappold (Heidelberg University, Germany) and colleagues.7 The cause of short stature in girls with Turner syndrome had at this time been attributed to monosomy of genes in the sex chromosomes, and narrowed down to the pseudoautosomal region. By studying patients with partial monosomy of this region and adults’ heights ranging from normal to more than 3 SD below average, the team refined this to a 170 kb section, in which they discovered SHOX.

Besides explaining the short stature of Turner syndrome patients, SHOX may also account for a small percentage of idiopathic short stature; the researchers discovered a mutation in one of 91 such patients tested.

Widening the focus

And SHOX is just the tip of the iceberg, according to Dauber. He says that although the reviewed papers have provided “a tremendous amount of insight” into the GH/IGF-I axis, “there’s much more to growth than that one biological pathway.”

Illustrating this, Dauber points out that all reported patients with mutations in the GH/IGF axis number only a few hundred worldwide.

“But if you look at the number of kids who come to be evaluated by an endocrinologist, even with heights below minus 3 standard deviations or so, there are tens of thousands of those and we really only explain a tiny percentage of those with bona fide mutations in the GH/IGF axis.”

This suggests that most patients with idiopathic short stature will prove to have mutations in genes that are not directly involved in this pathway.

Not that Dauber believes the influence of the GH/IGF pathway is fully mapped out; he sees research in that area starting to focus more on mutations in regulatory regions of genes, and in epigenetics.

But he says: “I think that the challenge for endocrinologists in the coming years is going to be how to learn and think about the defects in growth that are outside that classic hormonal pathway.”

A complicating factor is the large grey area between polygenic short stature – caused by the cumulative effect of the thousands of variants with, at most, a millimetre effect on height – and monogenic short stature – caused by a mutation in a specific critical gene.

“The long-term challenge is going to be finding therapies that don’t affect the GH/IGF axis but do affect growth,” says Dauber.

Such therapies are coming into play, however; Dauber gives the example of the NPR2 gene, which encodes a receptor (natriuretic protein receptor B) that acts directly in the growth plate and is essential for endochondral ossification. An NPR2 agonist is currently in development for patients with achondroplasia, he says.

“That’s a totally different type of growth-promoting therapy, in a disorder that’s more commonly handled by geneticists than endocrinologists.”