Testosterone Use in Adolescent Males

Current Practice and Unmet Needs

Maria Vogiatzi; James P. Tursi; Jonathan S. Jaffe; Sue Hobson; Alan D. Rogol

Disclosures

J Endo Soc. 2021;5(1) 

In This Article

Current Options for Testosterone Therapy in Adolescents and Evidence From Pediatric Studies

The current TRT options for adolescent males with CDGP and hypogonadism, and information on dosing, or lack thereof, are summarized in Table 1.[1,15,22,25,32,36,59,60,62–82]

Injectable Testosterone Esters

IM TE is the most frequently used formulation for induction and progression of puberty in adolescent males. The practice is supported by limited numbers of studies, primarily in those with CDGP. Two prospective controlled trials, published in 1995 or earlier, evaluated 2 regimens for pubertal induction in adolescents with CDGP.[11,83] The first involved TE administration at the dose of 200 mg every 3 weeks for 4 times in 8 boys, while 8 boys served as controls.[83] The second trial used TE 100 mg IM monthly for 6 months in 148 treated boys and 50 controls.[11] Both reported increases in height velocity compared to controls, with no adverse bone age advancement. Testicular size and serum T concentrations were greater in boys treated with TE vs their respective controls 1 year after initiation of therapy.[11] Greater satisfaction with growth and increased muscle mass was reported in those treated.[11]

An additional small number of uncontrolled or retrospective studies confirmed a positive effect of TE on growth and pubertal maturation in boys with CDGP.[14,17,21,84] Those studies also used alternative regimens, such as TE 125 mg once every 6 weeks for 3 doses,[84] while Bergadá reported on TE administered at 33 to 50 mg monthly for 20 months.[17] All confirmed an increase of height velocity without an adverse effect on bone age in boys with CDGP.[14,17,21,84] Overall, these studies indicate that various regimens of T esters administered for a short time period can safely induce virilization in boys with delayed puberty, with some evidence of a psychosocial benefit. None tested a titration regimen to adult T doses and the long-term safety and efficacy of this type of treatment. Furthermore, the effect of therapy on bone mass, insulin sensitivity, and other metabolic parameters was not examined.

TE and T cypionate are ester derivatives of T. They both have suboptimal pharmacokinetic profiles and reach supraphysiological T concentrations a few days after injection that gradually decrease to subphysiologic levels within the following 2 to 3 weeks.[58,85] To overcome this limitation, additional T esters were developed by modification of the esterified fatty acid molecule that is attached to the 17β carbon of natural T.[58,86] T propionate results in wide T fluctuations, requires frequent injections, and was therefore deemed unsuitable for treatment of male hypogonadism.[87] IM-injected TU has the longest duration of action.[88] However, its use is restricted because of rare associated cases of pulmonary oil microembolism.[89] Furthermore, its use in pediatrics is limited because of dosing and its long washout period, should complications arise. Finally, to improve pharmacokinetics, formulations that include mixtures of short- and longer-acting T esters, such as Sustanon, which is a mixture of 4 esters, have been used for induction of puberty in adolescent males and treatment of male hypogonadism in Europe.[1,22,62,90,91] The clinical advantages of these preparations over TE are uncertain.[62]

Oral Testosterone Undecanoate

Natural T taken orally is ineffective as TRT because of its first-pass metabolism by the liver and rapid inactivation. Earlier forms of oral testosterone (methyltestosterone and 17α derivatives) led to hepatic dysfunction and are no longer marketed.[86] Oral TU is absorbed into the lymphatic system,[86] and therefore bypasses rapid inactivation by the liver. However, it has a short, unpredictable half-life, requiring multiple daily doses in adults, and its absorption can be unreliable and particularly sensitive to food intake, especially the lipid content of meals.[1,92] Still, oral TU is effective in inducing pubertal maturation in boys with delayed puberty. Two double-blind, randomized, placebo-controlled trials tested 2 different doses of TU (20 mg daily for 6 months in one vs 40 mg daily for 3 months in another) in small numbers of boys with CDGP.[59,60] Results from these studies indicated that TU increased height velocity and circulating T levels compared to controls. Similar effects on growth and pubertal maturation were observed in a larger, retrospective study of 96 Danish boys treated with TU daily (40-mg daily doses escalated up to 80 mg twice daily) for an average of 0.8 years and 63 untreated controls.[66] In another randomized trial, oral TU at the dose of 40 mg daily was equally effective as oxandrolone 2.5 mg daily in terms of growth, pubertal maturation, and bone age advancement in boys with CDGP.[67] In addition, oral TU (40 mg daily for 8 weeks) had an effect on growth similar to an IM T ester mixture (Sustanon 50; Aspen Pharma Trading Limited, Dublin, Ireland) in a randomized crossover comparison study in boys with CDGP.[68] These studies provide significant evidence that short-term use of oral TU at 40 mg daily is safe and effective to promote growth and pubertal changes without an adverse effect on bone age in adolescent males with CDGP.[22] Little is published about the long-term efficacy of oral TU[69] and titration regimens for pubertal progression and completion.[70] To overcome the erratic absorption of oral TU, a new oral formulation that is less affected by the lipid content of meals was approved by the FDA for hypogonadism in men.[93] This formulation has not been studied in adolescents.

Transdermal Testosterone

Transdermal preparations of T (patches or gel) are appealing options for TRT because they combine ease of administration with physiological and constant T levels. For T gel, the pediatric experience is limited to a single prospective study, a few retrospective analyses, and a case series. Rogol et al retrospectively evaluated the clinical response to T gel 1% in a subgroup from a prospective, open-label, observational study of 86 adolescent boys (age 12–17 years) with primary hypogonadism due to Klinefelter syndrome or anorchia. Administration at starting doses of 0.5 g daily for 6 months or less increased serum T concentrations to normal, age-matched levels.[72] No clinically meaningful changes were observed on physical examination, and no significant safety concerns were raised. In this study, proper dosing became an issue, given the variable responses in individual adolescents.[72] In a retrospective study in adolescent males with CDGP, 10 mg daily of 2% testosterone gel for 3 months had a similar effect on height velocity as TE 50 mg monthly for 3 months.[15] In a case series of 3 males with hepatic dysfunction, T gel 2% (Fortesta; Endo Pharmaceuticals Inc., Malvern, Pennsylvania, USA) and 1% (Androgel; AbbVie Inc., North Chicago, Illinois, USA) were safe and effective for pubertal induction and progression of puberty.[73] Finally, treatment with T gel resulted in appropriate and adequate increases in serum T concentrations in 104 boys with Klinefelter syndrome, although specific doses and regimens were not described.[74]

The experience with transdermal T patches to induce puberty is sparse. Patches are designed to deliver adult TRT doses and cannot be fractionated. For this reason, the few available studies in adolescent males applied patches for a shorter time (usually for 12 hours daily) instead of the 24-hour recommended adult application.[76,77] In a case series, puberty was induced in 3 adolescents with IBD by using 2.5-mg or 5-mg patches for 12 hours daily for 4 to 6 months. However, only 2 participants responded.[75] In a prospective, randomized, crossover study, overnight application of a 5-mg patch in 8 boys simulated physiologic T secretion and increased short-term growth.[76] In a final retrospective study of 9 adolescents and young adult males with β thalassemia major, therapy with T patches at various doses induced virilization, promoted growth, and increased bone mineral density (BMD).[77] Skin reactions and poor skin adherence both occur with this formulation.

Testosterone Pellets

T pellets are implanted subcutaneously and are designed for consistent and prolonged release.[79,80] Two reports on adolescent males observed that completion and maintenance of puberty were successful with this formulation.[79,80] Both were uncontrolled and had a small sample size.[79,80] Zacharin and Warne treated 16 boys with hypogonadism and 2 males with tall stature using doses of 8 to 10 mg/kg every 6 months for 18 months,[79] while Moskovic and colleagues treated 4 males with Klinefelter syndrome with implantations every 3 to 4 months for 2 to 3 years.[80] Wide variability in circulating T levels was noted, but overall, the therapy was well tolerated and associated with improvements in patients' mood, emotional well-being, and self-esteem.[79,80] The need for a minor surgical procedure every 3 to 6 months and the associated cost make this formulation appropriate for select patients who have compliance difficulties with other forms of TRT. Pellet extrusion was not observed in these series, although it has been reported to occur in approximately 12% of implants.[94] T pellets have not been evaluated for the induction of puberty.

More Recent Testosterone Formulations

TE for weekly subcutaneous injection has been recently approved in the United States for treating adults with hypogonadism. It has been also successfully used for managing sex transition in transgender males, although its use for pubertal induction has yet to be formally evaluated.[95] Likely advantages for adolescents include its potential for self-administration, reduced peak-to-trough T-concentration variability, and ability to accurately titrate to approximately physiologic T levels.[96] Buccal T in the form of mucoadhesive tablets, and more recently, a nasal T gel formulation have been introduced for adult TRT.[22,56] Lately, a new formulation of TU that fosters more consistent absorption and allows for twice-daily dosing (JATENZO; Clarus Therapeutics) has entered the market for treatment in adult men.[93] None of these formulations have been tested in adolescent males. They all face concerns about metered doses and ease of titration for pubertal induction and progression.

Unmet Needs

A body of pediatric literature supports that short-term use of intermediate-duration T esters, such as TE, and oral TU are effective and safe in puberty induction in adolescents with CDGP.[11,59,60,83] Their use is associated with increased patient satisfaction.[11] Various regimens of TE and oral TU increase growth rate and lead to pubertal progression without reducing adult height.[11,59,60,83] Although there is encouraging evidence for the efficacy of transdermal T therapy (gels and patches), the data are limited.[22,75–77] No pediatric studies have been published with the most recent T formulations.

Data on TRT management of adolescent males with hypogonadism are sparse. After initiation of puberty, T doses are gradually increased to mimic normal pubertal physiology over the course of 2 to 3 years until puberty is clinically completed and adult doses are reached. Various T-titration regimens for pubertal progression and completion have been reported. However, they are all based on expert opinion or consensus rather than evidence provided by carefully designed studies.[10,22,37,62] Although decades of clinical practice suggest that these regimens are largely successful in achieving full virilization, various questions remain. For example, there is little concrete evidence to guide the optimal timing for initiating T therapy in adolescents with either CDGP or hypogonadism.[1] Moreover, questions remain with regard to the appropriate tempo of introducing pubertal changes or how rapidly T doses should be escalated. Once pubertal maturation is complete, the ideal range of serum T concentrations for TRT continuation in a young hypogonadal male is poorly defined. Addressing such questions is likely to improve the outcomes of the multiple physiological processes occurring during puberty, such as growth and bone accrual, and affect the psychosocial well-being of the treated adolescent.

Hypogonadism is linked to low bone mass and an unfavorable metabolic profile characterized by increased visceral adiposity, insulin resistance, and dyslipidemia.[97] The TRT literature on adolescent males is limited on T-induced pubertal changes and growth. There is little reported on changes in body composition due to T administration. The literature on young males with hypogonadism, such as those with Klinefelter syndrome, describes associations between TRT and body composition, bone mass, and metabolic parameters. However, results are mixed and specific TRT regimens are not precisely reported. Furthermore, these studies are observational, with no controlled trials available. Additional TRT studies on the maintenance and completion of puberty that include monitoring of bone mass, body composition, and various cardiometabolic parameters and risk biomarkers are greatly needed.

Finally, the current literature does not provide sufficient guidance for the increasing needs of the many adolescent males with functional hypogonadism, such as those affected with eating disorders, IBD, cystic fibrosis, or DMD.[36,98] It is likely that TRT regimens will require individualization for these different patient groups. Although detailed reviews of each of the disorders is beyond the scope of this work, we will use DMD as an example to highlight some of the multiple unanswered questions relevant to these boys. Hypogonadism affects most adolescents and emerging adults with DMD, likely the result of the underlying condition and high-dose, chronic glucocorticoid treatment.[50,99] Recent DMD guidelines call for assessment of puberty as part of a complete exam and appropriate endocrine referral, despite a lack of relevant clinical trials.[51,100] For these affected adolescents, ethical questions related to quality of life, issues around sexuality, and concerns about bone and cardiometabolic health remain.[51,100] Similar challenges face other adolescents with chronic illnesses resulting in hypogonadism.[100,101]

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