Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

AIMS: Long acting subcutaneous testosterone pellets are of proved efficacy for the treatment of hypogonadal men, but have not been reported as a treatment modality in adolescent boys. Pharmacodynamic studies of subcutaneous testosterone release have shown prolonged normalisation of testosterone levels for at least four months. Administration of a long acting, safe, effective, and convenient form of treatment is desirable when life-long treatment is indicated. PATIENTS AND METHODS: Eighteen boys (aged 13.9-17.5 years at the start of treatment)-seven with primary hypogonadism, nine with secondary hypogonadism, and two boys being treated with testosterone for tall stature--were given testosterone pellets (8-10 mg/kg) every six months for 18 months. Height, weight, pubertal status, and psychosocial parameters were assessed and follicle stimulating hormone, luteinising hormone, testosterone, prolactin, and lipids were measured at 0, 1, 3, 6, 12, and 18 months. Bone age was measured at 0 and 12 months. RESULTS: In all boys growth velocity continued appropriately for bone age. Puberty continued to progress in all boys and in two boys the amount of virilisation exceeded that seen with previous treatment with intramuscular testosterone. After testosterone administration, follicle stimulating hormone and luteinising hormone suppressed incompletely in the boys with primary hypogonadism. Serum testosterone ranged from 4.3 to 26.7 nmol/l at three months to less than 10 nmol/l at six months after implantation. Prolactin and lipid levels were normal throughout the study. By report, there was an improvement in mood and emotional wellbeing. No pellet extrusions occurred in a total of 156 pellet insertions. CONCLUSIONS: All boys preferred this mode of testosterone administration to intramuscular injections. Long acting subcutaneous testosterone pellets are safe, efficacious, well tolerated, and convenient, and result in normal physical growth and improved psychological outlook in adolescent hypogonadal boys.     

Diagnostic value of testosterone therapy in boys with delayed puberty

A brief course of testosterone injections is known to be an effective treatment for boys with constitutional delayed puberty. In this study, data from seven boys at least 14 years old who received testosterone enanthate (100 mg intramuscularly monthly for four months) were analyzed to see if linear and testicular growth responses could be useful diagnostically in excluding growth hormone deficiency (GHD) and isolated gonadotropin deficiency, two conditions that are often difficult to distinguish from constitutional delayed puberty. During four months of testosterone therapy, growth rate increased from 4.0 +/- 1.0 cm/y to 10.7 +/- 2.3 cm/y, and was greater than 8 cm/y in all patients. Since testosterone-induced stimulation of linear growth is largely GH-mediated, the large increase in growth rate in all boys is considered indicative of GH sufficiency. Testis length, which did not increase during testosterone therapy, increased by 0.6 to 0.8 cm in every patient (from 2.7 +/- 0.3 cm to 3.4 +/- 0.4 cm) over the following four months, indicating normal gonadotropin secretion and normal pubertal progression; in contrast, the increase in serum testosterone concentrations after discontinuation of testosterone treatment was more variable. It is concluded that the growth response to a four-month course of testosterone is helpful in excluding GHD in boys with delayed puberty, and an additional four months of follow-up is sufficient to document the onset of puberty, thereby eliminating the possibility of isolated gonadotropin deficiency.     

Spontaneous and GnRH-provoked gonadotropin secretion and testosterone response to human chorionic gonadotropin in adolescent boys with thalassaemia major and delayed puberty

To elucidate whether the cause of sexual maturation arrest in thalassaemia is of gonadal or pituitary etiology, 10 males with thalassaemia and delayed puberty and 10 with constitutional delay of growth and pubertal maturation (CSS) were extensively studied. Their spontaneous nocturnal gonadotropin secretion and gonadotropin response to intravenous 100 micrograms gonadotropin-releasing hormone (GnRH) were evaluated. Circulating testosterone concentration and clinical response were evaluated after 3 days, 4 weeks and 6 months of intramuscular administration of human chorionic gonadotropin (HCG) (2500 U/m2/dose). Thalassaemic boys had significantly lower circulating concentrations of testosterone compared to those with constitutional delay of growth and sexual maturation (CSS) at the same pubertal stage. Short- and long-term testosterone response to administrations of HCG was markedly decreased in thalassaemic boys. After 6 months of HCG administration 50 per cent (5/10) of the boys did not show significant testicular enlargement or genital changes. Despite the low circulating concentrations of testosterone, none of the patients had high basal or exaggerated gonadotropin response to gonadotropin releasing hormone (GnRH) stimulation. Luteinizing hormone (LH) peak responses to GnRH were significantly lower as compared to controls. Follicle-stimulating hormone (FSH) peak responses to GnRH did not differ among the two study groups. The mean nocturnal LH and FSH secretion was significantly decreased in all thalassaemic boys as compared to boys with CSS at the same pubertal stage (testicular volume). These data proved that hypogonadotropic hypogonadism is the main cause of delayed/failed puberty in adolescents with thalassaemia major. MRI studies revealed complete empty sella (n = 5), marked diminution of the pituitary size (n = 5), thinning of the pituitary stalk (n = 3) with its posterior displacement (n = 2), and evidence of iron deposition in the pituitary gland and midbrain (n = 8) in thalassaemic patients, denoting a high incidence of structural abnormalities (atrophy) of the pituitary gland. Moreover, in many of the thalassaemic boys, the defective testosterone response to long-term (6 months) HCG therapy denoted significant testicular atrophy and/or failure secondary to siderosis. It appears that testosterone replacement might be superior to HCG therapy in these patients. This therapy should be introduced at the proper time in these hypogonadal patients to induce their sexual development and to support their linear growth spurt and bone mineral accretion.     

Nocturnal nasogastric refeeding for hospitalized adolescent boys with anorexia nervosa

Boys with anorexia nervosa have nutritional needs exceeding those of their female counterparts. For many males with anorexia nervosa, oral refeeding alone may result in low discharge weight, a critical risk factor in relapse. This study compared the short-term outcomes of oral refeeding (OR) and a combination of OR with supplemental nocturnal nasogastric refeeding (NNGR) in a sample of hospitalized boys. This was a retrospective chart review with a cohort design. Subjects were partitioned into: The OR group (n = 8, mean age = 14.9, SD = 1.7) and the OR + NNGR group (n = 6, mean age = 13.8, SD = 2.0). The NNGR group had greater increase in weight and Body Mass Index. Their average length of hospitalization was also shorter. Nocturnal nasogastric refeeding, complementing oral refeeding, should be considered as an alternative initial therapy for weight restoration in males with anorexia nervosa.     

Priming with testosterone enhances stimulated growth hormone secretion in boys with delayed puberty

BACKGROUND AND OBJECTIVE: Tests for growth hormone (GH) deficiency are not always helpful in the differential diagnosis of physiological delay of growth and puberty and GH deficiency. PATIENTS AND METHODS: To enhance diagnostic specificity, we used a single dose testosterone priming before repeating the arginine stimulation test in 26 boys with short stature and only early signs of puberty who failed to show an adequate response of serum GH in the first test. RESULTS: 77% (20/26 patients) increased their serum GH peak to more than 10 ng/ml, whereas six patients were still below this concentration. CONCLUSION: We propose that testosterone priming is a useful tool to distinguish between physiological delay of growth and puberty and GH deficiency and should be included in the diagnostic procedure.     

Clinical experience using the Androderm testosterone transdermal system in hypogonadal adolescents and young men with beta-thalassemia major

beta-Thalassemia major is associated with a high prevalence of hypogonadotropic hypogonadism affecting adolescents and young men with this disease. The pharmacokinetics of Androderm, a non-scrotal permeation-enhanced testosterone transdermal system, was previously studied in this population using three application regimens designed to mimic the nocturnal secretion and circadian patterns of testosterone production characteristics of puberty and young adulthood. In regimen I, designed for prepubertal 14 to 16 year-olds, a single Androderm patch (2.5 mg/day nominal delivery rate) is applied at night and removed 12 hours later in the morning. In regimen II, designed for partially virilized 17 to 19 year-olds, a single Androderm patch is applied nightly for 24 hours. In regimen III, intended for virilized men aged 20 years and older, two Androderm patches (total dose of 5 mg/day) are applied nightly for 24 hours. This report presents the results of a 12-month open label study using these three Androderm regimens to treat nine hypogonadal males with beta-thalassemia (ages 16.8 to 31.8 yr). Our data show that Androderm produced physiologically appropriate testosterone levels, lowered SHBG levels, promoted growth and virilization, increased bone mineral density, and was generally well tolerated in this population of hypogonadal adolescents and young men with beta-thalassemia.     

Characterization of interpersonal violence events involving young adolescent girls vs events involving young adolescent boys

BACKGROUND: Multiple studies have demonstrated that girls are engaging in interpersonal violence. However, little is known about the potentially unique aspects of violent events involving girls. OBJECTIVES: To describe characteristics of interpersonal violence events in preadolescents and young adolescents and to determine if events involving any girl are different than those involving only boys. DESIGN: A cross-sectional survey of 8- to 14-year-old patients who were being evaluated at an urban children's hospital emergency department for injuries caused by interpersonal violence was conducted between September 2000 and August 2001. The survey asked the patient to describe details about event circumstances, opponents, weapon use, and injury severity. RESULTS: We enrolled 190 patients into the study; 58 (31%) were girls. Seventy-four events (39%) had a girl involved, 156 (82%) occurred on a weekday, 127 (67%) were classified as fights, 140 (74%) were with a known opponent, and 93 (49%) occurred at school. Events involving girls were more likely than events involving all boys to occur at home (relative risk [RR], 1.6; 95% confidence interval [CI], 1.0-2.5). Both boys and girls reported "being disrespected" and "teasing" as popular reasons for a fight. Events involving girls were more commonly related to a "recurrence of a previous fight" (RR, 6.4; 95% CI, 1.9-21.5), were more likely to end because of adult intervention (RR, 1.7; 95% CI, 1.1-2.6), and have a family member try to physically break up the fight (RR, 3.7; 95% CI, 1.5-9.1). CONCLUSION: Violent events involving preadolescent and early adolescent girls are more likely to be in response to a previous event and to involve the home environment and family member intervention. Health care professionals should screen violently injured girls for safety concerns and retaliation plans and consider engaging the family in efforts to prevent future events.     

A simple estimate of glomerular filtration rate in adolescent boys

We reexamined the relationship between creatinine clearance (Ccr) and body habitus in 212 girls and 356 boys, including 181 boys and 69 girls between 13 and 21 years of age. The use of formula Ccr = k L/Pcr, where k = 0.55 for the calculation of GFR, resulted in a significant underestimation of GFR in adolescent boys but was suitable for girls. In 51 adolescent boys the equation Ccr = 0.7 L/Pcr resulted in an accurate estimate of GFR. Regression analysis in 133 boys aged 3 to 21 years showed that the constant k increased gradually and linearly with age (r = 0.35, P less than 0.01). GFR could be better estimated for boys of any age by the linear bivariate equation Ccr = 1.5 (age) + 0.5 (L/Pcr), where age is given in years (r = 0.82, P less than 0.001). This equation yielded slightly better results than did 0.7 L/Pcr in 91 additional clearance studies performed in adolescent boys with native kidneys or functioning renal transplants. The larger value for the constant k (0.7) and the age correction for GFR reflect the greater rate of urinary creatine excretion (and thus muscle mass) per unit of body mass in adolescent boys.     

Treatment situation of male hypogonadotropic hypogonadism in pediatrics and proposal of testosterone and gonadotropins replacement therapy protocols

Male hypogonadotropic hypogonadism (MHH), a disorder associated with infertility, is treated with testosterone replacement therapy (TRT) and/or gonadotropins replacement therapy (GRT) (TRT and GRT, together with HRT hormone replacement therapy). In Japan, guidelines have been set for treatment during adolescence. Due to the risk of rapid maturation of bone age, low doses of testosterone or gonadotropins have been used. However, the optimal timing and methods of therapeutic intervention have not yet been established. The objective of this study was to investigate the current situation of treatment for children with MHH in Japan and to review a primary survey involving councilors of the Japanese Society for Pediatric Endocrinology and a secondary survey obtained from 26 facilities conducting HRT. The subjects were 55 patients with MHH who reached their adult height after HRT. The breakdown of the patients is as follows: 7 patients with Kallmann syndrome, 6 patients with isolated gonadotropin deficiency, 18 patients with acquired hypopituitarism due to intracranial and pituitary tumor, 22 patients with classical idiopathic hypopituitarism due to breech delivery, and 2 patients with CHARGE syndrome. The mean age at the start of HRT was 15.7 yrs and mean height was 157.2 cm. The mean age at reaching adult height was 19.4 yrs, and the mean adult height was 171.0 cm. The starting age of HRT was later than the normal pubertal age and showed a significant negative correlation with pubertal height gain, but it showed no correlation with adult height. As for spermatogenesis, 76% of the above patients treated with hCG-rFSH combined therapy showed positive results, though ranging in levels; impaired spermatogenesis was observed in some with congenital MHH, and favorable spermatogenesis was observed in all with acquired MHH. From the above, we propose the establishment of a treatment protocol for the start low-dose testosterone or low-dose gonadotropins by dividing subjects into two groups to determine different treatment protocols, acquired and congenital MHH, and to conduct them at a timing closer to the onset of puberty, namely, at a timing near entrance to junior high school. We also propose a new HRT protocol using preemptive FSH therapy prior to GRT aimed at achieving future fertility in patients with congenital MHH.     

The effect of testosterone therapy on spontaneous growth hormone secretion in boys with constitutional delay

Testosterone treatment is known to improve growth hormone (GH) secretion in boys with constitutional delay (CD). To determine whether spontaneous GH secretion is normal after treatment, we assessed GH secretion before and after a four- to five-month course of testosterone enanthate in eight adolescents with CD. Before testosterone therapy, the mean (+/- 1 SD) 24-hour integrated concentration of GH (IC-GH) by constant blood withdrawal technique was 1.7 +/- 1.0 micrograms/L (normal range for age, 3.2 to 11.5 micrograms/L), and the IC-testosterone was 1.8 +/- 2.7 nmol/L. Two patients restudied during treatment had normal IC-GH values. After testosterone treatment, the mean IC-GH of the entire group was 3.3 +/- 2.6 micrograms/L, and the IC-testosterone was 6.5 +/- 5.3 nmol/L. Five of eight patients had IC-GH values that were again subnormal. A subnormal IC-GH associated with CD may persist after testosterone therapy is discontinued. Deficiency of spontaneous GH secretion may contribute to short stature and slower growth rates in this patient group. Whether GH therapy in these patients would have a beneficial effect on final height is unknown.