Congenital Adrenal Hyperplasia in Adults: A Review of Medical, Surgical and Psychological Issues

Cara Megan Ogilvie; Naomi S. Crouch; Gill Rumsby; Sarah M. Creighton; Lih-Mei Liao; Gerard S. Conway

Disclosures

Clin Endocrinol. 2006;64(1):2-11. 

In This Article

General Adult Issues

Glucocorticoid treatment in adults has to be adjusted according to individual goals; there is no 'perfect regimen'. For instance, in the Middlesex series, of those with salt-wasting CAH 37% use hydrocortisone (median 30 mg, range 15–40), 53% use prednisolone (median 7 mg, range 4–10), 4% dexamethasone and 5% a mix of glucocorticoid replacement. All use fludrocortisone (median 175 µg, range 50–400). Of those with simple virilizing CAH, 12% receive no treatment, 42% use hydrocortisone (median 20 mg, range 15–30), 31% use prednisolone (median 5 mg, range 3–75), 3% use dexamethasone, 12% use a mix of glucocorticoid replacement and 38% also use fludrocortisone (median 100 µg,range 0–200). Sixteen women also use the oral contraceptive pill and three receive antiandrogen therapy.

In contrast to the paediatric agenda of optimizing final height, the adult concerns relate to long-term consequences of glucocorticoid use. Therefore, one common strategy is to find the minimum effective dose of glucocorticoid for adult maintenance determined by a combination of clinical and biochemical markers. By analogy to the management of type I diabetes, 17-hydroxyprogesterone is often considered equivalent to random glucose measurements and so is not a perfect biochemical marker. Moreover, complete suppression often results in side-effects of glucocorticoid excess so the usefulness of this parameter is to signal the need for dose reduction. Serum testosterone and androstenedione concentrations behave similarly to glycated haemoglobin in type I diabetes, moving on a longer time-scale and indicating too low a dose of glucocorticoid when raised. Thus, we have found the optimal dose of glucocorticoid is that which fails to fully suppress 17-hydroxyprogesterone and maintains androgens in the mid-normal range. In transition from paediatric care, compliance can be very variable but often improves in the third decade of life, allowing reduction of 'prescribed' doses in early adult life.

Mineralocorticoid treatment requires precise monitoring in adulthood. The childhood sensitivity to salt loss diminishes over the teenage years, and in adults, salt-wasting disorders are far less precarious.[4] In addition, the tendency to acquire hypertension with age means that many adults are better off on progressively lower doses of fludrocortisone. Balanced against this strategy is the notion that angiotensin II might mediate end-organ damage[5] so that markedly raised renin activity should be avoided. The clinical markers of hypertension and hypokalaemia are late events in the natural history of mineralocorticoid excess compared to suppression of plasma renin activity or total renin concentrations. This sensitivity of renin as a guide to the adjustment of the dose of fludrocortisone is essential if hypertension is to be avoided and our clinic protocol aims to maintain plasma renin activity in the upper normal range or to be slightly raised (up to twofold).

Osteoporosis has been an understandable concern for adults with CAH who are glucocorticoid dependent.[6] Corticosteroid therapy inhibits osteoblastic activity, which potentially leads to decreased bone density. Similarly, markers of bone formation,[6] especially osteocalcin, are reported to be low in adult CAH.[7]

There are no data regarding fracture risk in subjects with CAH. Table 1 summarizes eight papers measuring surrogate markers of bone integrity in subjects with CAH. Five studies show normal bone mineral density (BMD) with the expected decline with age. Several studies suggested that low BMD in CAH reflects overtreatment with glucocorticoid, resulting in an increased steroid effect on bone and, to a lesser degree, to an oversuppression of androgens, which can be bone protective. However, other studies[7,8] found no association between BMD and duration of steroid treatment. In the 36 individuals attending the Middlesex Clinic who have had BMD measurements, we found mean t-scores for the lumbar spine and hip (–0·55 and –0·48, respectively) were not significantly lower than a normal comparison group and that BMI and glucocorticoid dose were not significantly associated with the measurement.

The overall conclusion is that, despite lower serum concentrations of bone turnover markers, bone density is normal in most individuals with CAH. Preservation of bone integrity despite glucocorticoid use may have several explanations. The raised BMI common in CAH may be protective for bone.[9,10] Furthermore, episodes of androgen excess may have an anabolic effect on bone.[11] However, it is important to note that, when measured,[7] androgen levels were generally lower in both men and women with CAH than that found in control groups. It is likely that current treatment strategies provide close to physiological replacement of glucocorticoid, therefore avoiding the effects of supraphysiological doses of these medications on bone.[6]

In summary, unless there is a clinical suspicion of previous over-treatment with glucocorticoids, routine bone density measurements are not necessary in the young adult with CAH. If there is evidence of significant glucocorticoid overtreatment, one baseline BMD measurement is probably justified. Currently there is insufficient information on older subjects with CAH; one study included three older female subjects[7] and another two,[12] while none included older male subjects. Until we have more data in this age group, it seems prudent to consider bone density measurements in those subjects over the age of 40.

Glucocorticoid treatment has only been used clinically since the 1950s. Therefore, people with CAH are only now reaching an age where risk of cardiovascular disease generally becomes more of a concern. Theoretically, individuals with CAH may be at an increased risk of cardiovascular disease and so far only a few preliminary studies have addressed this specific health issue.

Hyperandrogenism in women has been associated with insulin resistance and, in turn, increased cardiovascular risk in other more common conditions such as polycystic ovarian syndrome.[13] People with CAH are known to have higher body fat percentage for BMI.[12,14] In addition, glucocorticoid therapy has been linked with dyslipidaemia[15] and decreased insulin sensitivity in other conditions.[16]

A search of the literature reveals one adult study in this area. Speiser et al.[17] found a lower than expected insulin sensitivity for BMI in six nonclassical CAH women compared with a control group assessed by tolbutamide infusion and frequent glucose sampling. However, baseline insulin was not reported, the sample was small, and the degree to which this relates to classical CAH is unclear.

In children with CAH receiving prednisone, a significant elevation in triglyceride levels has been reported.[18] The authors attribute this result to glucocorticoid replacement, although the degree to which this finding might be related to difficulties in matching the control group is unclear. Daytime systolic blood pressure is higher in children with CAH and absence of the nocturnal blood pressure dip has also been noted.[19] Elevated leptin and insulin levels have been found in prepubertal children with classical CAH,[20] and it was hypothesized that low serum adrenaline levels secondary to chronic adrenomedullary hypofunction leads to loss of inhibition of leptin and insulin secretion through β-adrenergic receptors. The resulting hyperinsulinaemia may constitute an increased long-term cardiovascular risk.

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