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

The Current Practice of Testosterone Therapy in Adolescent Boys

The current TRT practice in adolescent males is captured in published consensus or expert opinion statements and reviews,[10,22,37,62,102] but official guidelines are lacking. Frequently used therapeutic regimens and proposed monitoring schemes, adopted by recent reviews, use TE for induction and escalation of puberty and are depicted in Figure 1. This figure also lists oral TU and transdermal T as alternative T formulations that can be used for puberty induction. Experience with puberty progression has concentrated on TE.[1,22]

Figure 1.

An illustration describing testosterone (T) therapy for initiation and completion of puberty in males with hypogonadism (orange and blue arrows, respectively) and for induction of puberty in adolescent males with constitutional delay of growth and puberty (CDGP; green arrow). Specifically, frequently used therapeutic regimens and proposed monitoring schedules, adopted by recent reviews, are depicted in the figure. Briefly, in males with delayed puberty and suspected CDGP, puberty is initiated by using small T doses such as intramuscular testosterone enanthate (TE) 50 mg monthly or oral testosterone undecanoate (TU) 40 mg daily for 3 to 6 months. Transdermal T (1 or 2% gel providing 10 mg of T daily or 5-mg testosterone patch worn for 12 hours daily) can be used, although experience is limited. An increase in testicular volume, typically up to 6 to 8 mL, heralds the presence of central puberty, and T replacement therapy can be discontinued. If sexual maturation is not induced, therapy can be extended to a year or more. Lack of hypothalamic-pituitary-gonadal axis activation is likely to indicate hypogonadism. In boys with permanent hypogonadism, T doses should be gradually increased to mimic normal pubertal physiology over the course of 2 to 3 years until adult doses are reached. Experience with puberty progression has concentrated on TE. T doses are increased by 50 mg per month at 4- to 6-month intervals until the monthly dose reaches 150 mg. At this point, transitioning to 100 mg twice monthly may help patients maintain more steady serum T concentrations. Patients may then be able to transition to a newer T formulation, such as a testosterone gel, beginning at 1.25 or 2.5 g per day, if desired. BA, bone age; DXA, dual-energy X-ray absorptiometry; FSH, follicle-stimulating hormone; Hb, hemoglobin; Hct, hematocrit; LFT, liver function testing; LH; luteinizing hormone; PE, physical examination. Based on Mason and Stancampiano [1, 22].

Therapeutic Regimens and Their Challenges

T therapy in males with delayed puberty is hindered by the lack of reliable biomarkers differentiating between CDGP and HH. These 2 entities can be indistinguishable at presentation.[1,102] Functional hypogonadism can be particularly difficult to differentiate from CDGP.[36] Because CDGP is by far the most common diagnosis, most physicians adopt an approach of watchful waiting, monitoring for signs of spontaneous puberty, especially testicular enlargement. In a recent review of a pediatric endocrine practice, only 13% of the referred boys with delayed puberty were treated with T at the mean age of 14.2 years (range, 12.1–17.7 years).[103] The treated boys included those with CDGP and all types of hypogonadism. The data may suggest a high threshold for starting TRT. What is unclear is for how long clinical monitoring without initiating TRT is prudent. Whereas the psychosocial sequelae of untreated hypogonadism and delayed puberty are well documented,[1,104–109] there is emerging evidence that the timing of exposure to sex steroids in adolescents may affect various physiological parameters in adulthood, including skeletal and cardiometabolic health.[1,108,110] An optimal age window to introduce sex steroids has been proposed.[111] As it stands, many adolescents with delayed puberty start TRT much later than age 14 years, an age set to define delayed puberty in males.[73,111,112]

The biochemical distinction between CGDP and HH can be challenging with the current diagnostic modalities. Basal gonadotropin and gonadotropin-releasing hormone stimulation tests have limited diagnostic specificity, with an overlap in gonadotropin levels between CDGP and HH.[113] Measurements of inhibin B and antimüllerian hormone, both markers of Sertoli cell number, and insulin-like factor 3, a marker of Leydig cell function, have been proposed as diagnostic tools.[102,113,114] Indeed, whereas very low serum concentrations are indicative of congenital HH, there is considerable overlap between adolescents with CDGP and other causes of HH.[102,114,115] The diagnostic dilemma between CDGP and HH may be addressed clinically with 3 to 6 months of T therapy to induce pubertal maturation. If physiologic puberty does not ensue, clinical monitoring can be extended and T can be administered for an additional 3 to 6 months.[22] Failure to progress in central puberty, as signaled by lack of testicular enlargement, is likely to support the diagnosis of HH.[22]

Males with Klinefelter syndrome represent the most common genetic category of primary or hypergonadotropic hypogonadism among adolescents.[1,116] TRT is routinely prescribed, although the most appropriate time to initiate therapy varies significantly among practices.[117,118] In these individuals, onset of puberty is age-appropriate. The first stages of puberty are usually normal and characterized by some virilization and an increase in serum T concentrations into the pubertal range, followed by a rise in gonadotropin levels and a plateau in circulating T.[119] Most of these adolescents and young adults are actually able to maintain a spontaneous serum T concentration in the low-normal adult range, despite markedly elevated gonadotropin levels.[119] Early TRT is advocated by some investigators, but is not universally adopted.[118] The differences in practice stem from the lack of controlled studies linking TRT to health outcomes. Beyond the well-described concerns of untreated hypogonadism on sexual development, bone, and cardiometabolic health, questions regarding the impact of sex steroids on neurocognition and executive function in these adolescents remain.[7]

Monitoring Therapy

The goals of monitoring during therapy are to ensure appropriate growth and virilization and screen for potential adverse effects. For hypogonadal individuals, monitoring entails additional surveillance for associated comorbidities, such as low bone mass and cardiometabolic risk factors. A proposed monitoring plan is shown in Figure 1. Similar to TRT regimens for adolescent males, this monitoring plan is driven by consensus[22,62] and by adoption of adult guidelines. For example, the Endocrine Society recommends screening adults for polycythemia 3 and 6 months after therapy initiation. Because the response of hemoglobin to T administration is dose-dependent,[32] monitoring for polycythemia is applicable to adolescent males as they reach adult T doses but not during the initial steps of T-dose titration.

While surveillance for low bone mass, dyslipidemia, and metabolic syndrome has been suggested for hypogonadal adolescents on TRT, there is no clear consensus when such screening should be initiated and how frequently it should be performed.[22,62,102] Research confirms the multiple anabolic effects of T, including those on bone.[1,3,4,22,120] Some reports have suggested an association between low BMD and delayed puberty, but findings have not been consistent enough to recommend the routine adoption of bone mass measurement in adolescent males with CDGP.[22,121–127] For hypogonadal adolescents, measurement of BMD may influence decisions concerning TRT initiation and titration;[22] however, there are no specific pediatric data to guide such decisions.

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