Adult Height of Treated Congenital Adrenal Hyperplasia Patients
Noting reports indicating that patients with the 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) often fail to reach their target height, Hoepffner and colleagues reviewed medical charts of 56 patients with 21-hydroxylase deficiency to examine the effects on final height of strictly controlling hydrocortisone and fludrocortisone. Sixty-two patients were followed continuously at a university children’s hospital by the same physician; 6 were excluded from analyses due to receiving additional medications that may effect CAH therapy and/or growth (n=2) or due to bilateral adrenalectomy (n=4).
Participants were divided into 5 subgroups. Patients in the first 3 groups were diagnosed within their first year of life: (1) adult patients born before 1975 (n=13, all salt-wasting, 5 males); (2) adult patients born in or after 1975 (n=26, 21 salt-wasting, 8 males); (3) 7 to 15 years of age and had not yet attained final height (n=9, all salt-wasting, 4 males); (4.1) pre-pubertal bone age, late diagnosed, therapy initiated at 3.5 to 6 years of age (n=5, 3 salt-wasting, 3 males); and (4.2) pubertal bone age, late diagnosed, therapy initiated at 5.5 to 9 years of age (n=3, 1 salt-wasting, 2 males). All patients received therapy monitoring exclusively by the outpatient unit and had regular 3-month measurements of height, weight, blood pressure, and bone age (BA). Hydrocortisone was administered 3x/day, every 8-10 hours. Management was designed so the course of BA followed the course of chronological age (CA), ie, patients received an increased hydrocortisone dose if BA was higher than expected over a 6-month observation period, and vice versa. Fludrocortisone was administered 2-3x/day with the hydrocortisone. Dosage was monitored by blood pressure; to avoid fludrocortisone overdosage, blood pressure values were not allowed to exceed the upper normal range. Change from DOCA to fludrocortisone was gradually introduced to patients in groups 1, 4.1, and 4.2 since the late 1970s when the current therapy regime was initiated. Authors provided specific hydrocortisone and fludrocortisone dosages by age group within group. Beginning in 1992, morning 17-hydroxyprogesterone (17-OHP) in saliva was measured by immunoassay every 3 months and, sometimes more frequently after reaching 5 to 6 years of age. Occasional plasma rennin concentration measurements were added to the monitoring regime. Target height standard deviation scores (htSDS) were based on measured parental height. All values for data analysis were collected via retrospective chart review. Statistical analyses focused mainly on groups 1 and 2. The authors recommended that readers consider results pertaining to groups 4.1 and 4.2 as clinical observations due to the small sample size and to view group 3 results as a demonstration of current corticoid dosage since patients had not reached their final height.
Results showed patients in group 1 had a mean corrected height (ie, measured htSDS minus target htSDS) of approximately –2SDS during their first years of life; this increased to approximately –1 htSDS by age 8 where it remained through adolescence to adulthood (ie, 18-years old) (Figure). In the 1st, 2nd, 4th, and 5th years of life, group 1 growth rates were significantly less than in group 2; in each year (0 to 18 years), the mean group 1 htSDS was significantly lower than that for group 2. With regard to bone age, group 1 experienced significant suppression between ages 1 to 6 years compared with the BA SDS in group 2, followed by a recovery to 1.8 SDS at age 8. Regarding BMI, patients in group 2 showed a continuous and statistically significant increase from ages 2 to 8 years to approximately 1 SD, with no increase after this age. Patients in group 2 reached their target height (0.1 corrected final htSDS). The authors noted that the corrected final mean htSDS of –1.2 of group 1 (those born before 1975) was similar to values reported in the literature and was due to likely excessive corticoid dosages particularly during the first 2 years of life. Use of lower corticoid doses during the following years of life resulted in extremely fast bone maturation up to approximately 1.8 SD, which exceeded growth velocity. In contrast, combined early treatment involving substitution therapy with hydrocortisone and fludrocortisone (ie, group 2) was associated with patients reaching their target height. A similar pattern emerged in groups 3, 4.1, and 4.2. Hoepffner and colleagues credit success with attaining target height to strict medication adherence and monitoring, specifically, by keeping BA the same as CA through combined corticoid administration every 8 hours. For patients with classic CAH who are treated early and following the recommended regimen, they see no need for other forms of therapy (eg, growth hormone (GH), gonadotropin-releasing horomone analogs [GnRHa], antiandrogens, or aromatase blockers).
Hoepffner W, Kaufhold A, Willgerodt H, Keller E. Patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency can achieve their target height: The Leipzig experience. Horm Res 2008;70:42-50.
First Editor’s Comment
At a time when different medications are introduced in an effort to assist children with CAH attain their target heights,1,2 Hoepffner and colleagues findings are quite exciting. Children with CAH can attain their target height with strict monitoring and careful hydrocortisone and fludrocortisone administration. This finding is particularly important as we discover more about the risks of various alternative strategies to increase height. While a full review of all medication side effects is not possible here, I offer the following for thought: GnRHa treatment, in conjunction with GH, is one tool used to arrest pubertal progression in persons with CAH and, thereby, prolong the time over which linear growth can occur. The use of this medication is, however, not without drawbacks. In a study of visuospatial working memory pre- and post-GnRHa treatment in young women, results suggested that hormone withdrawal following GnRHa administration alters the neural circuitry underlying performance of the visual working memory.3 Specifically, although behavioral responses appeared unimpaired, event-related fMRI under GnRHa exposure was found to be associated with attenuated left precuneus and posterior cingulate cortex activation at encoding and cerebellar activation at recognition. These effects were observed at an 8-week assessment. It could be argued that these changes may return to pre-GnRHa-treatment levels following discontinuation; however, alterations to typical brain function during adolescence (the developmental stage at which GnRHa would be administered to youth with CAH) may have organizational effects that extend beyond the point GnRHa is withdrawn. Evidence for this possibility comes from experimental research by Schulz and Sisk4 which demonstrated that pubertal gonadal hormones act in lasting ways on the juvenile brain. For example, the authors showed that male Syrian hamsters deprived of gonadal steroid hormones during their pubertal phase of development failed to demonstrate typical masculine reproductive behavior even when those hormones were later replaced. They found that adolescent exposure to testicular hormones causes male behaviors that communicate moment-to-moment dominance status between animals. Similarly, adolescent exposure to ovarian hormones defeminizes female reproductive behavior in the Syrian hamster. Comparable “organizational” effects of steroid hormone exposure during adolescence are seen in female rats. Species differences notwithstanding, there is as yet no basis to guarantee families of the long-term safety associated with experimental protocols such as GnRHa, antiandrogens, or aromatase blockers to optimize height. It is therefore reassuring to learn that patients with CAH can achieve their target height through vigilant surveillance of hormone replacement alone.
David E. Sandberg, PhD
Second Editor’s Comment
The paper by Hoepffener et al clearly illustrates that CAH patients who receive an appropriate treatment usually attain their target height, whereas those who do not receive the best medications or do not follow a strict adherence and monitoring of the treatment regimen may not reach their genetically determined height. This observation is very important and should raise our awareness of the difficulties that patients face with demanding long-term treatment protocols for chronic conditions like CAH. When such a patient’s growth is faltering additional therapies ie, GnRHa may compound the problem, not withstanding cost, and may lead to other potential concerns. Dr. Sandberg’s commentary focuses on new experimental data that suggested that manipulation of the timing of puberty can affect neuroendocrine function and behavior, at least in animals. These potential effects need be investigated in patients with precocious puberty who are regularly treated with GnRHa. In patients with CAH, as well as in others with chronic conditions, the first challenge is to deal with the adherence and compliance of the patients. This issue was reviewed in GGH5 and despite the importance of medication in treatment, compliance ranged from 11% to 93%.6 Lack of response or inappropriate response to medication may be indicators of poor adherence.7
Fima Lifshitz, MD
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