Treatment of hypogonadal adolescent boys with long acting subcutaneous testosterone pellets

Accepted 26 February
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 18months. 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 12months.
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 10nmol/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.

• Continued normal progress of growth and pubertal status occurs with subcutaneous testosterone • Prolonged stable physiological levels of testosterone are maintained for four to six months • Bone age advance is commensurate with change in chronological age • Psychological outlook and self image are reported to be improved • Subcutaneous testosterone is safe, well tolerated, efficacious, and convenient     

A double blind, placebo controlled study of the effects of low dose testosterone undecanoate on the growth of small for age, prepubertal boys

OBJECTIVE--To assess whether very low doses of testosterone can accelerate growth without an undue advance in bone age in prepubertal boys with constitutional delay of growth. SUBJECTS--23 prepubertal boys aged 11-14 years with height at or below the third centile for chronological age. DESIGN--Randomised, double blind trial comparing oral testosterone undecanoate 20 mg once daily versus placebo for six months. The 18 months' observation period of each subject comprised a six month pretreatment period, followed by a six month treatment (testosterone undecanoate or placebo) period, and a six month period after termination of treatment. OUTCOME MEASURES--At intervals of six months standing and sitting height were measured. Bone age, pubertal stage, weight, and lean body mass were also determined. Growth hormone, luteinising hormone, and follicle stimulating hormone secretion and testosterone concentration were measured before, after, and six months after treatment. RESULTS--Boys taking testosterone undecanoate (n = 11) showed a significantly greater height velocity (mean (SEM) 5.84 (0.53) cm/year) and sitting height velocity (3.54 (0.57) cm/year) during treatment than the placebo treated boys (n = 12, height velocity = 3.38 (0.22) cm/year, sitting height velocity = 1.58 (0.19) cm/year. There were no significant differences between the groups regarding changes in growth hormone, gonadotrophins, testosterone, or dihydrotestosterone concentrations. Bone age was not advanced significantly more rapidly in either group. CONCLUSIONS--There is accelerated gain in height during six months of treatment with low dose testosterone undecanoate, without a significantly greater rise in bone age compared with controls. Testosterone undecanoate is a safe, well tolerated, and effective treatment in the management of constitutional delay of growth.     

A double blind,placebo controlled study of the effects of low dose testosterone undecanoate on the growth of small for age,prepubertal boys.

OBJECTIVE--To assess whether very low doses of testosterone can accelerate growth without an undue advance in bone age in prepubertal boys with constitutional delay of growth. SUBJECTS--23 prepubertal boys aged 11-14 years with height at or below the third centile for chronological age. DESIGN--Randomised, double blind trial comparing oral testosterone undecanoate 20 mg once daily versus placebo for six months. The 18 months'' observation period of each subject comprised a six month pretreatment period, followed by a six month treatment (testosterone undecanoate or placebo) period, and a six month period after termination of treatment. OUTCOME MEASURES--At intervals of six months standing and sitting height were measured. Bone age, pubertal stage, weight, and lean body mass were also determined. Growth hormone, luteinising hormone, and follicle stimulating hormone secretion and testosterone concentration were measured before, after, and six months after treatment. RESULTS--Boys taking testosterone undecanoate (n = 11) showed a significantly greater height velocity (mean (SEM) 5.84 (0.53) cm/year) and sitting height velocity (3.54 (0.57) cm/year) during treatment than the placebo treated boys (n = 12, height velocity = 3.38 (0.22) cm/year, sitting height velocity = 1.58 (0.19) cm/year. There were no significant differences between the groups regarding changes in growth hormone, gonadotrophins, testosterone, or dihydrotestosterone concentrations. Bone age was not advanced significantly more rapidly in either group. CONCLUSIONS--There is accelerated gain in height during six months of treatment with low dose testosterone undecanoate, without a significantly greater rise in bone age compared with controls. Testosterone undecanoate is a safe, well tolerated, and effective treatment in the management of constitutional delay of growth.     

The effect of testicular irradiation on Leydig cell function in prepubertal boys with acute lymphoblastic leukaemia.

Testicular function was investigated by the luteinising hormone releasing hormone (LHRH) test and a three day human chorionic gonadotrophin (HCG) test in 11 prepubertal boys with acute lymphoblastic leukaemia (ALL) who had received 2400 rads of fractionated radiation to their testes after relapse at this site. The results were compared with an unirradiated control group. Basal and peak testosterone values after 1000 units of HCG were significantly lower in the irradiated patients than in the control group. Peak follicle stimulating hormone (FSH) values after 100 micrograms LHRH were significantly higher in irradiated boys, but there was no difference in either basal FSH or basal and peak luteinising hormone values. The findings suggest that the ability of the Leydig cell to produce testosterone--as detected by the HCG test--is appreciably reduced after irradiation and that tubular dysfunction in prepubertal boys may sometimes be predicted by a raised FSH response.     

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.     

Hypogonadism in adolescent females: new insights and rationale supporting the use of physiologic regimens to induce puberty

Puberty in girls begins with nocturnal pulsatile gonadotropin releasing hormone (GnRH) secretion which increases gradually over a 4 year period and occurs throughout the day. Pulsatile GnRH secretion stimulates pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) which induces gonadal steroid secretion, ovulation and oogenesis. Over the past decade, naturally occurring genetic mutations have been identified in a number of genes that impact the onset and progression of puberty and continued progress in this area will lead to earlier diagnosis of hypogonadotropic hypogonadism (HypoH) and potentially improved therapeutic options. Data are accumulating to support the use of more physiological hormone regimens to induce puberty. In addition, our better understanding of how estrogen interacts with the growth hormone - insulin-like growth factor-1 (GH-IGF-1) axis and of differential effects of oral versus non-oral estrogen on various biological parameters have important therapeutic implications for the management of hypogonadal adolescent girls. These implications will be addressed.     

Hormonal profile of puberty in South Australian children I

Serum follicle stimulating hormone (FSH), luteinising hormone (LH) and testosterone (T) concentrations in 118 boys aged 8 to 17.9 years were related to chronological age (CA), bone age (BA), genital development (G1–5+), pubic hair development (PH1–5 +) and mean testicular volume (MTV). A progressive rise in serum FSH, LH and T was noted in relation to CA, BA and all pubertal parameters studied. FSH showed an approximate twofold increase, LH an eight to tenfold increase and T a fourfold increase from pre-puberty through to full adult maturity. The FSH/LH ratio decreased with advancing CA, BA and pubertal development.     

Preclinical diagnosis of testotoxicosis in a boy with an activating mutation of the luteinizing hormone receptor

BACKGROUND: Testotoxicosis is an autosomal dominant disorder usually recognized by progressive virilization, linear growth acceleration, skeletal maturation and pubertal testosterone levels in boys before 4 years of age. OBJECTIVE: To describe the clinical and hormonal follow-up of a male infant with testotoxicosis who was initially diagnosed by molecular analysis. PATIENT: A healthy asymptomatic 10 month-old boy was referred to the endocrinologist because his older brother had diagnosis of familial testotoxicosis due to the activating mutation Thr577Ile of the luteinizing hormone (LH) receptor. RESULTS: Automatic sequencing of exon 11 of the LH receptor gene revealed the same heterozygous Thr577Ile mutation in the asymptomatic boy. He had no signs of virilization or accelerated growth. His bone age was delayed. Serum LH and follicle stimulating hormone (FSH) concentrations were in the prepubertal range, testosterone levels were slightly elevated (31 ng/dl [1.07 nmol/l]). In the following 6 months, his testosterone levels progressively increased, achieving higher levels (146 ng/dl [5 nmol/l]) without testicular enlargement or pubic hair development. Despite the lack of virilization signs, an anti-androgen was started due to the increase in testosterone levels and growth velocity at the age of 1.3 years. CONCLUSION: We describe the preclinical diagnosis of testotoxicosis in a boy by DNA analysis. Very early diagnosis in affected families can result in prompt treatment, and reduce the deleterious consequences of premature puberty in boys with this rare monogenic disorder.     

Gender and hormonal regulation of growth

Puberty is the transitional period between childhood and adulthood when substantial growth, sexual maturation, and reproductive capacity is attained. The onset of puberty is triggered by the combined action of the somatotropic (GH-IGF-I) and gonadotropic (GnRH-LH/FSH-sex steroid) hormone axes, the latter of which stimulates the former to produce the pubertal growth spurt. Studies of GH secretion in boys and girls, in Turner's syndrome, in hypogonadal girls, and in androgen-deficient boys have revealed estrogen-dependent mechanisms controlling GH production, age-dependent response to and control of GH, and gender-dependent differences in response to GH therapy. The interplay between the somatotropic and gonadotropic hormone axes during puberty has profound implications on the treatment of adolescent patients in need of hormone replacement therapy for growth deficiency or hypogonadism.     

Gonadal function after allogenic bone marrow transplantation for thalassaemia.

Thirty prepubertal patients with thalassaemia major (15 boys and 15 girls) aged from 9.3 to 17.2 years (mean 12.9) who had successfully undergone allogenic bone marrow transplantation were studied. Before the transplant all patients were given short courses of high doses of busulphan (total dose 14 mg/kg) followed by cyclophosphamide (total dose 200 mg/kg). Pituitary gonadal function was assessed between 0.7 and 5.1 years (mean 2.3) after bone marrow transplantation. Increased gonadotrophin concentrations indicating gonadal damage were found in 80% of the girls, probably as a result of the chemotherapy. In all the prepubertal boys the basal follicle stimulating hormone and luteinising hormone concentrations were normal. Most of the boys had reduced gonadotrophin and testosterone responses after gonadotrophin releasing hormone and human chorionic gonadotrophin tests. This could have been the result of iron overload but the effect of cytotoxic agents cannot be excluded. These findings emphasise the need for vigilant long term follow up of thalassaemic patients treated with cytotoxic chemotherapy for bone marrow transplantation so that those requiring hormone replacement can be identified and treated.     

Diagnosis of X-recessive Kallmann syndrome in early infancy

A 3-month-old infant presented with hypogonadism, a small penis and bilateral cryptorchidism. He showed an insufficient response of luteotropic hormone (LH) and follicle stimulating hormone (FSH) to luteotropic hormone releasing hormone (LHRH) and of testosterone to human chorionic gonadotrophin. The maternal uncle had hypogonadism and anosmia and also showed an impaired LH and FSH response to LHRH. MRI examination showed hypoplasia of the rhinencephalon in both cases. These findings in the son and brother of the clinically unaffected mother suggest X-linked recessive inheritance.     

Developmental processes in early adolescence: relationships between adolescent adjustment problems and chronologic age, pubertal stage, and puberty-related serum hormone levels

Relations between adolescent psychosocial adjustment problems and markers of biologic development, including chronologic age, pubertal status, and serum hormone levels, were examined in 56 normal boys and 52 normal girls, ages 9 to 14 years. Adolescent psychosocial adjustment was assessed by adolescent self-ratings of various aspects of self-image (Offer Self-Image Questionnaire for Adolescents) and parent ratings of adolescent behavior problems (Child Behavior Checklist). The pubertal status measure used in the analyses was Tanner genital stage for boys and Tanner breast stage for girls. The hormone measures, determined by radioimmunoassay, were serum levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), sex steroids (testosterone and estradiol), and adrenal androgens (dehydroepiandrosterone and its sulfate, and androstenedione). The testosterone/estradiol ratio also was computed. Overall, findings were stronger, more consistent, and more generalized for boys than for girls. For boys, adjustment problems typically were associated with a multivariate profile that may be characteristic for later maturers: relatively low sex steroid levels, or lower pubertal stage, and relatively high adrenal androgen (androstenedione) levels, frequently in conjunction with higher chronologic age. Univariate relations predominated for girls; that is, associated with adjustment problems for girls were relatively high levels of gonadotropins, relatively low levels of dehydroepiandrosterone sulfate, and relatively high levels of androstenedione on their own or in conjunction with lower pubertal stage. Higher levels of androstenedione, a steroid particularly responsive to stress, were associated with adjustment problems in both boys and girls. This relation may reflect the stress of later maturation, which could result from environmental factors, such as adolescent self-comparisons with same-age peers, or endogenous effects of hormones.     

Oxandrolone induces a sustained rise in physiological growth hormone secretion in boys with constitutional delay of growth and puberty

We describe the treatment of 3 boys, mean age 14.9 years (range 13.8-16.1 years) with constitutional delay of growth and puberty using oxandrolone in two dose regimens, 2.5 or 1.25 mg/day for 3 months. Treatment induced an increase in mean height velocity from 5.1 to 8.5 cm/year; this was sustained at 8.8 cm/year in the period following treatment. Growth hormone (GH), luteinising hormone and testosterone secretion were assessed by overnight or 24-hour venous sampling at 15-min intervals before, during treatment and after cessation of treatment. A computer programme was used to analyse GH secretory dynamics. The 3 boys had a mean sustained increase in total GH secretion of 190%. The increase in GH secretion was associated with an increase in amplitude of GH pulses rather than an alteration in pulse frequency.     

Low-dose testosterone effect on somatic growth

Low-dose testosterone has been found to preserve the growth potential of hypogonadal children requiring anabolic or androgenic therapy. Five girls with Turner syndrome were treated when their chronologic ages were 13 to 14 years and their bone ages were 10.6 to 12.75 years; six hypogonadal boys were treated when their chronologic ages were 11 to 15 years and their bone ages were 10.9 to 14.2 years. Depot testosterone was given as an anabolic agent in an average dose of 28 mg/m2/mo for 6 months to the patients with Turner syndrome and was given to initiate puberty in an average dose of 44 mg/m2/mo for 6 months to the hypogonadal boys. Growth rate doubled on these doses of testosterone, and bone age did not advance disproportionately. Consequently, height potential was preserved. Pubic hair advanced one Tanner stage during the 6-month treatment. Clitoral hypertrophy was observed in only one of the five girls with Turner syndrome and regressed when testosterone therapy was discontinued. Four hypogonadal boys were continued on low-dose testosterone until their bone ages passed 14 years of age and their growth rate waned. Then, the testosterone dosage was increased in increments to 100 to 200 mg/m2/mo. This group reached a height of 100.3 +/- 0.8% of the height initially predicted. In addition, all attained an adult height at least 15 percentiles greater than that before therapy. These studies indicate that testosterone in very low doses resembles "anabolic steroids" in that growth is stimulated without an inordinate androgenic effect. Furthermore, these studies show that institution of low-dose therapy in the early teenage years stimulates pubertal growth normally without loss of height potential.     

Testicular function following combination chemotherapy with cis-platin, vinblastine, and bleomycin

Recovery of the pituitary-gonadal axis following treatment with vinblastine, bleomycin, cis-platin +/- doxorubicin (VBP +/- A) is assessed retrospectively in 18 men with germinal neoplasms. One patient also received VP-16-213. In the first year after completing treatment all men demonstrated elevated follicle stimulating hormone (FSH) and luteinizing hormone (LH) values with concomitant azoospermia. Of the 11 men evaluated at least 24 months from completion of therapy, seven (64%) had recovery of both FSH and LH to normal or near normal levels. Spermatogenesis was present in five of six (83%) men providing semen samples and who were at least 2 years from stopping VBP. Five of seven (71%) men who were within 24 months of therapy were azoospermic. Regardless of the time of evaluation, most men (94%) had normal serum testosterone. Patients receiving maintenance vinblastine had more prolonged elevation of serum gonadotropins. We conclude that some men have evidence of recovery of fertility beginning two years after VBP +/- A. In addition to germinal epithelium destruction, transient Leydig cell dysfunction occurs but is not accompanied by clinical findings of hypogonadism.     

Effect of human chorionic gonadotropin on growth velocity and biological growth parameters in adolescents with thalassaemia major

The effect of long-term human chorionic gonadotropin (HCG) therapy on the linear growth and biological growth parameters was studied in six thalassaemic boys aged 14.5–15.5 years old with hypogonadotropic hypogonadism. A significant (P<0.001) increase in growth velocity (from 3.3±0.3 to 7.6±0.6 cm/year) was found after 6–12 months of therapy, without acceleration of bone age. A striking improvement in pubertal development was observed. The treatment significantly increased growth hormone (GH) response to l-dopa administration (P<0.025) as well as sleep GH secretion (P<0.025). Serum growth factors, evaluated as thymidine activity during deep sleep, increased (P<0.001), but somatomedin C (Sm-C) levels did not. Prior to treatment, baseline and peak values of plasma growth hormone releasing hormone (GH-RH) following l-dopa were low. After HCG therapy, GH-RH response to l-dopa increased significantly (from 9.2±5.6 to 20.2±6.2 pg/ml; P<0.05), but remained (P<0.001) lower than in normal prepubertal children. This study suggests that in thalassaemia major an impaired GH-RH release can be observed, in addition to the described alteration in Sm-C generation.Abbreviations LH luteinising hormone - FSH follicle stimulating hormone - HCG human chorionic gonadotropin - GH growth hormone - GH-RH growth hormone releasing hormone - GnRH gonadotropin releasing hormone - TA thymidine activity - Sm-C somatomedin C     

Pituitary-gonadal axis in male undermasculinisation.

AIMS: To study the value of assessing serum concentrations of luteinising hormone (LH), follicle stimulating hormone (FSH), testosterone, and dihydrotestosterone (DHT) in patients with male undermasculinisation not caused by androgen insensitivity. METHODS: A retrospective study of a register of cases of male undermasculinisation (20 with abnormal testes, eight with 5alpha-reductase deficiency, three with testosterone biosynthetic defects, seven with Drash syndrome, and 210 undiagnosed). RESULTS: A human chorionic gonadotropin (hCG) stimulation test was performed in 66 of 185 children with male undermasculinisation. In 41 of 66 patients the dose of hCG was either 1000 U or 1500 U on three consecutive days. The rise in testosterone was related to basal serum testosterone and was not significantly different between the two groups. Testosterone:DHT ratio in patients with 5alpha-reductase deficiency was 12.5-72.8. During early infancy, baseline concentrations of LH and FSH were often within normal reference ranges. In patients with abnormal testes, median pre-LHRH (luteinising hormone releasing hormone) concentrations of LH and FSH were 2 and 6.4 U/l, respectively, and post-LHRH concentrations were 21 and 28 U/l. An exaggerated response to LHRH stimulation was observed during mid-childhood in children where the diagnosis was not clear and in all children with abnormal testes. CONCLUSIONS: The testosterone:DHT ratio following hCG stimulation is more reliable than the basal testosterone:DHT ratio in identifying 5alpha-reductase deficiency. During infancy, the LHRH stimulation test may be more reliable in identifying cases of male undermasculinisation due to abnormal testes than basal gonadotrophin concentrations.     

GONADOTROPIN-RELEASING HORMONE (LH-RH) AND HUMAN CHORIONIC GONADOTROPIN IN THE TREATMENT OF TWO BOYS WITH HYPOGONADOTROPHIC HYPOGONADISM

Abstract. Two brothers, 16 and 14 years of age, with hypogonadotrophic hypogonadism and anosmia were treated with subcutaneous injections of 200μg gonadotropin-releasing hormone at 8-hour intervals for 4 weeks. Serum FSH increased to the range of normal adult men, but serum LH and serum testosterone showed little change and no clinical signs of pubertal development occurred. Thereafter the 2 patients were given HCG for 11 months and a combination of HCG and HMG for a further 3 months. In response to this treatment, the serum testosterone levels increased to the range of normal adult men and a marked development of the secondary sex characteristics was seen.     

Treatment of persistent pubertal gynecomastia with dihydrotestosterone heptanoate

Four boys with persistent pubertal gynecomastia were given intramuscular dihydrotestosterone heptanoate (DHT-hp) at 2 to 4-week intervals for 16 weeks. By the end of treatment, breast size in all four boys had decreased 67% to 78%. Initial plasma levels of gonadotropins, estradiol, testosterone, and dihydrotestosterone (DHT) were normal. Mean plasma DHT concentration rose with the injections of DHT-hp, and remained elevated throughout the treatment period. Estradiol, LH, FSH, and testosterone decreased during treatment, as did 24-hour urinary LH and FSH. No regrowth of breast tissue was observed 6 to 15 months after treatment, although hormone concentrations had returned to near pretreatment values by 2 months after the last injection. DHT-hp has potential to be an effective medical therapy for persistent pubertal gynecomastia.     

A workshop on pubertal hormone replacement options in the United States

BACKGROUND: The optimal pubertal hormone replacement therapy in females and males is unclear. OBJECTIVE: To review hormone replacement options for hypogonadal teenagers and to determine the relevant attitudes and practices of pediatric endocrinologists in the United States. DESIGN/METHODS: A workshop on pubertal hormone replacement options was held during the Lawson Wilkins Pediatric Endocrine Society meeting in 2004. A questionnaire was distributed to investigate the audience's attitudes and practices in inducing puberty. RESULTS: The majority of respondents used conjugated estrogens to treat hypogonadal girls with the primary aim of treatment being attainment of maximal adult height. The majority of respondents used depot testosterone to treat hypogonadal boys with the primary aim of treatment being pubertal development and virilization. CONCLUSIONS: The use of physiological sex hormone replacement to optimize the induction of puberty in hypogonadal adolescents was recommended. The workshop revealed striking differences between US and European pediatric endocrinologists regarding their practices and attitudes regarding the induction of puberty in hypogonadal females. Detailed studies are necessary to develop more uniform guidelines.