A 4-Year, Open-Label, Multicenter, Randomized Trial of Genotropin® Growth Hormone in Patients with Idiopathic Short Stature: Analysis of 4-Year Data Comparing Efficacy, Efficiency, and Safety between an Individualized, Target-Driven Regimen and Standard Dosing.

BACKGROUND/AIMS: Growth hormone (GH) treatment regimens for children with non-GH-deficient, idiopathic short stature (ISS) have not been optimized. To compare the efficacy, efficiency, and safety of an individualized, target-driven GH regimen with standard weight-based dosing after 4 years of treatment. METHODS: This is a 4-year, open-label, multicenter, randomized trial comparing individualized, formula-based dosing of Genotropin® versus a widely used ISS dose of Genotropin®. Subjects were prepubertal, had a bone age of 3-10 years for males and 3-9 years for females, were naive to GH treatment, and had a height standard deviation score (Ht SDS) of -3 to -2.25, a height velocity <25th percentile for their bone age, and peak stimulated GH >10 ng/ml. After the first 2 years, the individualized-dosing group was further randomized to either 0.18 or 0.24 mg/kg/week. RESULTS: At 4 years, subjects in all treatment regimens achieved similar average height gains of +1.3 SDS; however, the individualized dosing regimen utilized less GH to achieve an equivalent height gain. CONCLUSION: Individualized, formula-based GH dosing, followed by a dose reduction after 2 years, provides a more cost-effective growth improvement in patients with ISS than currently employed weight-based regimens.

Duration of suppression of adrenal steroids after glucocorticoid administration.

Hydrocortisone has long been the treatment of choice for congenital adrenal hyperplasia (CAH). However, treatment with this medication remains problematic. Patients with 21-hydroxylase deficiency CAH have significant diurnal variation in the secretion of 17-hydroxyprogesterone (17OHP). When considering treatment strategies, this variation must be considered along with the pharmacokinetic and pharmacodynamic properties of exogenous glucocorticoids. Orally administered hydrocortisone is highly bioavailable, but it has a short time to maximum concentration (T(max)) and half life (T(1/2)). While prednisone has a somewhat longer T(max) and T(1/2), they remain relatively short. There have been several studies of the pharmacodynamics of hydrocortisone. We present data indicating that the maximum effect of hydrocortisone in CAH patients is seen 3 hours after a morning dose. After an evening dose, suppression of adrenal hormones continues until approximately 0500 the next day. In both situations, however, there is a large degree of intersubject variability. These data are consistent with earlier published studies. Use of alternate specimen types, possibly in conjunction with delayed release hydrocortisone preparations under development, may allow the practitioner to design a medication regimen that provides improved control of androgen secretion. Whatever dosing strategy is used, clinical judgment is required to ensure the best outcome.

Differences in endocrine parameters and psychopathology in girls with premature adrenarche versus on-time adrenarche.

Girls with premature adrenarche (PA) are at risk for multiple problems related to exaggerated androgen synthesis. Whether PA carries a risk of psychopathology remains unknown. This study examined group differences in: (a) anthropometric and endocrine parameters, and (b) mood and behavior problems, in 6-8 year-old girls with PA (n = 40) compared to on-time adrenarche girls (n = 36). PA girls were taller (p < or =0.05) and heavier (p < or =0.01) than the on-time adrenarche girls but body mass index showed no difference. PA girls had significantly (p <0.05) higher adrenal androgen and testosterone concentrations but not cortisol or leptin. PA girls also had significantly more oppositional defiant disorder, and higher symptom counts reflecting anxiety, mood or disruptive behavior disorders. PA girls may be more vulnerable to psychopathology than on-time adrenarche girls. The challenge of future studies is to determine which PA girls are at risk for psychopathology and which are more resilient.

Congenital neonatal hyperthyroidism caused by germline mutations in the TSH receptor gene.

Neonatal hyperthyroidism, a rare and serious disorder, occurs in two forms. An autoimmune form associated with maternal Graves' disease, resulting from transplacental passage of maternal thyroid-stimulating antibodies, and a non-autoimmune form, resulting from mutations in the stimulatory G protein or the thyrotropin receptor (TSHR) causing constitutive activation of intracellular signaling cascades. To date, 29 separate cases of thyrotoxicosis caused by germline mutations of the TSHR have been documented. These cases have expressed themselves in a range of clinical consequences. This report describes a new case of a newborn with non-autoimmune hyperthyroidism secondary to a constitutively active TSHR mutation (S281N) whose clinical course was complicated by severe respiratory compromise. Typical clinical findings in this disorder are discussed by a review of all previously published cases.

Treatment of precocious puberty in a female with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, hyperphagia, childhood obesity at an early age, short stature, varying degrees of mental deficiency, and hypogonadism. In PWS, puberty is usually delayed and fails to complete, with most females never having regular menstrual cycles. We report a female patient with uniparental disomy, who experienced precocious puberty with menarche at age 8 years. The patient was treated with luteinizing hormone releasing hormone (LHRH) analog, which suppressed pubertal development. From our search of the literature this is the first application of LHRH analog to a female PWS patient for precocious puberty. Use of LHRH analog along with recombinant human growth hormone (rhGH) permitted stature closer to target height. The clinical course of this patient with PWS underscores the need for individualized treatment.

Treatment of precocious puberty in two patients with Turner mosaicism.

Turner's syndrome (TS) is clinically characterized by reduced growth, ovarian dysgenesis and infertility. The majority of patients with TS do not undergo spontaneous pubertal development. We report two patients with mosaic Turner karyotype who experienced precocious pubertal development. The first patient responded well to LHRH analog treatment and now has regular menses and has nearly achieved her target height. The second patient was treated with both LHRH analog and recombinant growth hormone. LHRH analog delayed puberty for the patient and the recombinant growth hormone increased the patient's predicted height from 145 cm to 158 cm. This report emphasizes that the treatment goals and modalities of patients must be tailored to the individual to optimize pubertal and growth outcomes.

Early puberty in girls: the case of premature adrenarche.

In this article we examine the issue of early puberty in girls. First, a brief overview of normal pubertal development is provided, including the two endocrine components of puberty: gonadarche and adrenarche. Second, we critically discuss the controversy regarding whether puberty truly is occurring earlier in girls. Third, we emphasize one type of early puberty, the case of premature adrenarche (PA). PA is used to illustrate the importance of identifying types of early puberty, evaluating the types to determine causality, determining whether follow-up of early puberty is necessary, and showing the potential ramifications of ignoring this variation in pubertal development. Findings from a pilot study comparing PA and on-time puberty children are used to show the importance of determining whether early puberty is normal in all cases.