Management Short Stature

Despite the availability of GH, the primary consideration in the management of growth failure in chronic rheumatic disorders remains aiming for

Table 4 Differential Diagnosis of Amenorrhea Postpubertal Onset

Condition Features/investigations

Primary amenorrhea with puberty onset

Polycystic ovary syndrome History/examination/pelvic ultrasound/androgens Mullerian duct anomalies (adysplasia of Pelvic ultrasound vagina/cervix/uterus) Gonadal dysgenesis Elevated LH/FSH, Karyotype

Hyperprolactinaemia Prolactin levels

Testicular feminization Minimal adrenarche, karyotpye

Secondary amenorrhea Elevated FSH

Milder and partial forms of disorders causing hypergonadotrophic hypogonadism in Table 3 Onset of acquired disorders in Table 3 during puberty for example, SLE treated with systemic steroids FSH not elevated Low estrogen Milder and partial forms of disorders causing hypogonadotrophic hypogonadism in Table 3 Variants of Turner syndrome Virilization Normal estrogen

Extraovarian endocrine conditions Pregnancy, hypothyroidism, under-/overnutrition Disturbance of cyclic LH release Psychogenic stress, hyper-prolactinaemia Hyperandrogenism (polycystic ovary syndrome)

Karyotype

Very high androgen levels/adrenal suppression tests/ultrasound

History/examination/relevant hormones

History/examination/relevant hormones

History/examination/pelvic ultrasound/androgens optimal control of inflammatory activity, minimizing the use of systemic steroids, and maintaining adequate nutrition (see Box 3). It must be emphasized that while systemic steroids reduce height growth, they do not reduce skeletal maturation to the same extent, therefore complete catch-up growth may not be achievable, and every effort must be made to limit the use of systemic steroids to maximize final height potential.

Unfortunately there are some prepubertal young people with chronic rheumatic conditions in whom remission cannot be adequately achieved, or

Box 3 Treatment of Short Stature

■ Primary objective is disease control

■ Catch-up growth potential reduced but greater the earlier disease is controlled before epiphyseal closure

■ Use systemic steroid alternatives where possible

■ If systemic steroids are required, aim for < 0.25mg/kg/day prednisolone equivalent

■ Ensure adequate caloric intake and nutrition

■ Use of growth hormone can prevent further loss in whom disease control only comes at the expense of using growth suppressing doses of systemic steroids. In such situations, height velocities are reduced and loss of height SD scores ensues. Previously it was hoped that the impact on systemic steroids on growth retardation could be minimized with the use of alternate-day steroids or derivatives of Prednisolone such as Deflazacort (38). Unfortunately in practice these alternative regimes usually do not maintain disease control, and are therefore not now commonly used.

The short-term response to GH treatment is generally positive as indicated by the response in the studies discussed earlier. All 14 children treated by Touati et al. (25) with GH (0.46mg/kg/week) had improved height velocities, increasing from a mean height velocity of 1.9 to 5.4 cm per year. This had the net result of preventing further loss of height SDS with no overall catch-up growth. A moderate (r = 0.56) negative correlation was found between baseline IGF-1 levels and height velocity with GH, and is potentially of predictive value for assessing likely response to treatment.

Thirteen of these children went on to have 3 years of GH treatment, following a year without (12). Growth velocity and IGF-1 and IGFBP-3 levels returned to baseline off treatment. Again, even after 3 years of treatment, the net result was prevention of further loss of height SDS with no overall catch-up growth, with height velocities slowing after the first year of treatment. Marked individual variation was seen however, with those with more severe disease (higher inflammatory markers and systemic steroid doses) losing height SDS while those with less disease activity improved their height SDS.

The children treated by Davies et al. (26) also had significant increases in height velocity following a year of GH. Greater height velocities were seen in those with polyarticular rather than systemic disease, mild to moderate disease and in those treated with a higher dose of GH (24 vs. 12 IU/m2). They also found that height velocity correlated negatively with CRP levels. Very similar findings have more recently been reported by Bechtold et al. (39,40) following 2 and 4 years of growth hormone treatment using two dose regimes (determined by growth hormone status) and a control group.

Box 4 Growth Hormone Use in JIA

■ Mostly short-term studies (up to 3 years)

■ No studies through to final height

■ Improved height velocity has been seen for up to 3 years

■ Maintains but does not improve height SDS

■ Highly variable response

■ Best response in those with low disease activity and prednisolone dose < 0.25 mg/kg/day

■ Potential role for prophylactic GH needs further study

Studies have not yet been completed looking at final height outcome in those with JIA treated with GH.

Another more recent initiative has been the use of GH prophylacti-cally. Simon et al. (41) randomly assigned 30 children early in the course of their JIA, having been on Prednisolone for only 12-15 months, to either GH treatment (0.46 mg/kg/week) for 2 years or no GH. Those treated had higher height velocity SD scores with a small (0.2 ± 1.1) overall gain in height SDS at 2 years, while those untreated lost height (height SDS -1.2± 0.8) at 2 years. In addition, those treated gained lean body mass and lost fat mass, with the opposite occurring in those untreated.

These studies do indicate a role for GH in JIA associated growth failure (Box 4). It must be remembered that the response is highly variable, being particularly dependent on disease activity and systemic steroid dose. Young people in whom this treatment is being considered must be appropriately informed and counseled so as not to give false expectations regarding intended benefit and final height outcome. Its use is only appropriate for those young people who are still prepubertal or in early to mid puberty where there is still potential for growth. Potential for further growth may however be difficult to gauge, independent of pubertal status, as damaged growth plates may render bone age interpretation impossible and they may have prematurely fused. For the same reasons it is also difficult to determine how long to continue GH treatment for, especially when there is no final outcome data.

The other prerequisite to treatment is that the young person must be in agreement and prepared to have daily subcutaneous injections, which may be in addition to other injectable treatments such as methotrexate or etanercept.

While there may not be clear, long-term height advantages yet from GH use in those with chronic rheumatic-disease-associated growth failure, the potential for psychological benefits should not be discounted (12,39). GH counteracts the anti-lipolytic effect of glucocorticoids and can improve body composition and reduce cushingnoid appearances. On the other hand, there are potential side effects, including the development of glucose intolerance, which usually reverses on cessation of GH and rarely results in overt diabetes mellitus (12,39).

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