Two-year recombinant human growth hormone (rhGH) treatment is more effective in pre-pubertal compared to pubertal short children with X-linked hypophosphatemic rickets (XLHR).

CONTEXT: Twenty-five to 40% of patients with well-controlled X-linked hypophosphatemic rickets (XLHR) have a final height under -2 SDS. Previous studies have shown that recombinant human growth hormone (rhGH) treatment improves linear growth in short children with XLHR. OBJECTIVE: We studied the effectiveness of rhGH treatment in children with XLHR in a larger cohort. DESIGN: Monocentric, prospective, non-randomized trial. SETTING: University hospital in France. PATIENTS: 19 patients with XLHR and a mutation in the PHEX gene. Six male and 6 female Tanner stage 1 patients (age 6.1±2.4years) and 4 male and 3 female Tanner stage 2 patients (age 13.1±1years). At inclusion, height SDS was -2.35±0.8 SDS and growth velocity was -1.12±1.2 SDS. INTERVENTION: 2years of treatment with 67mcg/kg/day of rhGH at initiation. Every three months rhGH dosage was adjusted using an IGF-1 dosing protocol. MAIN OUTCOME MEASURES: Comparison in change from baseline to year 2 in height and growth velocity. RESULTS: Height SDS improved from -2.35±0.8 SDS at baseline, to -1.62±0.8 SDS (p=0.01) after one and to -1.2±1 SDS (p=0.04) after two years of rhGH treatment. There was a strong correlation (r2=0.6104, p<0.0001) between the age of onset of rhGH treatment and the number of cm gained over the study period. Pre-pubertal patients height SDS improved compared to baseline height SDS after one (-1.5±0.7, p<0.03) and two (-0.96±1, p<0.03) years of rhGH treatment. In pubertal patients there was no significant improvement in height SDS after one year (-1.75±1) and after two years (-1.7±0.8) of rhGH treatment. CONCLUSION: Two-year rhGH treatment is effective to treat short stature in XLHR children. Pre-pubertal children responded better to rhGH. CLINICAL TRIAL REGISTRATION NUMBER: NCT02720770.

Validation and ease of use of a new pen device for self-administration of recombinant human growth hormone: results from a two-center usability study.

Close adherence to the recommended treatment regimen is important for the success of recombinant human growth hormone therapy, although nonadherence can be common. Ease of use and safety during use/storage are among several important factors in the design of a growth hormone injection device intended for long-term use. This study was performed to validate the usability and assess the ease of use of a new pen device (SurePal™) that has been developed to support daily administration of the recombinant human growth hormone product, Omnitrope® (somatropin). The primary objectives of the study were to assess if study participants, representing intended users of the pen in clinical practice, were able to perform an injection procedure into an injection pad effectively and safely and disassemble the pen without receiving a needlestick injury. A total of 106 participants (61 adults and 45 children/adolescents) were enrolled at two study centers (one in the US, one in Germany). Results for both primary usability tasks met the predefined acceptance criteria, with >85% of participants successfully performing each task. All of the other tasks/handling steps assessed were also successfully performed by most participants, with high success rates reflected in the high proportion of participants who classified each task as "very easy" or "easy". After a second use of the device, 87%-97% of participants rated it as "very easy" or "easy" to use. In summary, the new pen device is safe and easy to use for both adults and children, and will help to support effective, long-term daily administration of the recombinant human growth hormone product, Omnitrope®.

Impaired puberty, fertility, and final stature in 45,X/46,XY mixed gonadal dysgenetic patients raised as boys.

CONTEXT: Gender assignment followed by surgery and hormonal therapy is a difficult decision in the management of 45,X/46,XY patients with abnormal external genitalia at birth considering the paucity of studies evaluating pubertal development and fertility outcome, most notably for patients raised as boys. OBJECTIVE: The purpose of this study was to describe the pubertal course of 20 45,X/46,XY patients born with ambiguous genitalia and raised as boys. METHODS: This is a multicenter retrospective study. RESULTS: Mean age at study was 25.6±2.4 years. Eighty-five percent of the patients presented a 'classical' mixed gonadal dysgenetic phenotype at birth. Puberty was initially spontaneous in all but three boys, although in six other patients, testosterone therapy was subsequently necessary for completion of puberty. Sixty-seven percent of the remaining patients presented signs of declined testicular function at the end of puberty (increased levels of FSH and low levels of testosterone and/or inhibin B). Moreover, an abnormal structure of the Y chromosome, known to alter fertility, was found in 10 out of 16 (63%) patients. Two patients developed testicular cancer. Half of the patients have adult penile length of <80 mm. Mean adult height is 156.9±2 cm, regardless of GH treatment. CONCLUSIONS: In summary, 45,X/46,XY children born with ambiguous genitalia and raised as boys have an altered pubertal course and impaired fertility associated with adult short stature, which should, therefore, be taken into consideration for the management of these patients.

Treatment adherence with the easypod™ growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents.

BACKGROUND: Accurately monitoring adherence to treatment with recombinant human growth hormone (r-hGH) enables appropriate intervention in cases of poor adherence. The electronic r-hGH auto-injector, easypod™, automatically records the patient's adherence to treatment. This study evaluated adherence to treatment of children who started using the auto-injector and assessed opinions about the device. METHODS: A multicentre, multinational, observational 3-month survey in which children received r-hGH as part of their normal care. Physicians reviewed the recorded dose history and children (with or without parental assistance) completed a questionnaire-based survey. Children missing ≤2 injections per month (92% of injections given) were considered adherent to treatment. Adherence was compared between GH treatment-naïve and treatment-experienced children. RESULTS: Of 834 recruited participants, 824 were evaluated. The median (range) age was 11 (1-18) years. From the recorded dose history, 87.5% of children were adherent to treatment over the 3-month period. Recorded adherence was higher in treatment-naïve (89.7%, n = 445/496) than in treatment-experienced children (81.7%, n = 152/186) [Fisher's exact test FI(X) = 7.577; p = 0.0062]. According to self-reported data, 90.2% (607/673) of children were adherent over 3 months; 51.5% (421/817) missed ≥1 injection over this period (mainly due to forgetfulness). Concordance between reported and recorded adherence was 84.3%, with a trend towards self-reported adherence being higher than recorded adherence. Most children liked the auto-injector: over 80% gave the top two responses from five options for ease of use (720/779), speed (684/805) and comfort (716/804). Although 38.5% (300/780) of children reported pain on injection, over half of children (210/363) considered the pain to be less or much less than expected. Given the choice, 91.8% (732/797) of children/parents would continue using the device. CONCLUSIONS: easypod™ provides an accurate method of monitoring adherence to treatment with r-hGH. In children who received treatment with r-hGH using easypod™, short-term adherence is good, and significantly higher in treatment-naïve children compared with experienced children. Children/parents rate the device highly. The high level of acceptability of the device is reflected by a desire to continue using it by over 90% of the children in the survey.

Comparison of oral versus transdermal testosterone supplementation in hypogonadal men.

OBJECTIVE: To compare mean serum total testosterone, bioavailable-testosterone, and dihydrotestosterone levels between transdermal testosterone and oral testosterone undecanoate treatment. METHODS: Multicentre, randomized, cross-over study; 44 men >18 years, testosterone ≤2.5 ng/mL. Two patches (Testopatch®) every other day in the morning or two capsules Pantestone® 40 mg bid in each 22-day period. Hormone serum levels of four blood samples over the first and last 48 h of each treatment period. RESULTS: Mean age 49 years. Mean testosterone before inclusion 1.99 ng/mL. Mean testosterone serum levels over the last 48 h of Testopatch treatment were superior to Pantestone (4.64 vs. 2.58 ng/mL, p<0.001). Testosterone trough levels at the end of each treatment period were significantly higher for Testopatch (3.15 vs. 2.45 ng/mL, p<0.01). Bioavailable-testosterone levels over the first and last 48 h of treatment were significantly greater with Testopatch than with Pantestone (p=0.001 and p<0.01). Dihydrotestosterone levels over the first and last 48 h of treatment (0.71 vs. 1.05 ng/mL and 0.68 vs. 0.89 ng/mL) as well as at trough (0.59 vs. 0.96 ng/mL) were significantly lower with Testopatch than with Pantestone (p<0.001, p<0.05, and p<0.001). SHBG levels decreased by Pantestone but not by Testopatch (p<0.001). CONCLUSIONS: Testopatch was superior to Pantestone to increase testosterone and bioavailable-testosterone levels in hypogonadal men from the first days and throughout the three weeks of treatment. Pantestone increased dihydrotestosterone to a larger extent and decreased SHBG.

Treatment of central precocious puberty by subcutaneous injections of leuprorelin 3-month depot (11.25 mg).

Depot GnRH agonists are widely used for the treatment of precocious puberty. Leuprorelin 3-month depot is currently used in adults but has not been evaluated in children. We evaluated the efficacy of this new formulation (11.25 mg every 3 months), for the suppression of gonadotropic activation and pubertal signs in children with central precocious puberty. We included 44 children (40 girls) with early-onset pubertal development in a 6-month open trial. The inclusion criteria were clinical pubertal development before the age of 8 (girls) or 10 (boys), advanced bone age, enlarged uterus (>36 mm), testosterone more than 1.7 nmol/liter (boys), and pubertal response of LH to GnRH (peak >5 IU/liter). The principal criterion for efficacy assessment, GnRH-stimulated LH peak less than 3 IU/liter, was met in 81 of 85 (95%) of the tests performed at months 3 and 6. The remaining four values were slightly above the threshold. The levels of sex steroids were also significantly reduced and clinical pubertal development was arrested. Plasma leuprorelin levels, measured every 30 d, were essentially stable after d 60. Local intolerance was noted after 10 of 86 injections (12%), and was mild in four cases, moderate in five cases, and severe in one. Among these 10 events, 4 consisted in local pain at injection's site. In conclusion, leuprorelin 3-month depot efficiently inhibits the gonadotropic axis in 95% of children with central precocious puberty studied for a 6-month period. This regimen allows the reduction of the number of yearly injections from 12 to 4.