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

Quantitating the Need for Testosterone Therapy in Adolescence

The precise prevalence of hypogonadism in adolescent males is difficult to calculate because it can be difficult to distinguish true hypogonadism from CDGP until puberty is initiated. Hypogonadism is classified as primary or secondary. Primary or hypergonadotropic hypogonadism is caused by testicular failure and is associated with elevated gonadotropin levels. Secondary hypogonadism or hypogonadotropic hypogonadism (HH) is caused by a hypothalamic or pituitary defect or injury and is thus characterized by low or seemingly normal gonadotropin levels, but in concert with low T concentrations. Both primary and secondary hypogonadism can be congenital or acquired. Functional HH is caused by the delayed maturation of the hypothalamic-pituitary-gonadal axis due to a variety of underlying conditions.[36,37]

The differential diagnosis of delayed puberty and hypogonadism in children is complex, and the reader can refer to recent reviews for a detailed description of involved conditions.[1,22,37] Klinefelter syndrome, the most common cause of congenital primary hypogonadism, occurs approximately in 1 of 660 males.[23,38] The US estimate of affected adults was approximately 250 000 in 2008.[23] Congenital causes of HH include Kallmann syndrome and other causes of isolated HH, with a combined prevalence of 1 in 10 000.[23,39] This prevalence translates to approximately 1275 affected boys, age 12 to 17 years, in the United States, based on government estimates (US government estimates for 2017, www.census.gov and www.childstats.gov).

Pediatric cancers and their treatments are frequent causes of hypogonadism. The risk of hypogonadism in patients with pediatric cancer is related to the patient's age and pubertal maturation at the time the cancer is diagnosed and the type, dose, and duration of treatment.[40] Current estimates suggest that the rate of hypogonadism in pediatric cancer survivors is between 11% and 56%.[41–43] Mumps orchitis, a traditionally low-incidence cause of primary hypogonadism in developed countries, appears to be increasing in the United States, with reported cases exceeding 6000, both for 2017 and 2018.[23] It is estimated that approximately 33% of affected adolescents will develop orchitis.[23] Additional frequent causes of hypogonadism in pediatric patients include intracranial tumors and traumatic brain injury. Although the exact incidence and prevalence are difficult to calculate, hypogonadism occurs in 20% to 80% of children treated for intracranial tumors.[23,44–46] Given the multiple other disorders that may lead to permanent hypogonadism in pediatric patients, it is reasonable to estimate that the number of boys requiring TRT for induction and maintenance of puberty could rise into the tens of thousands.

The most frequent cause of delayed puberty is CDGP, which affects 2% of the population.[22,47] Although most will do well with "watchful waiting," there is a substantial subgroup who will benefit from TRT. The specific numbers are, however, lacking. Similarly, it is difficult to estimate the number of adolescent boys with functional hypogonadism, who would also benefit from TRT. Functional hypogonadism is found in association with a chronic illness, such as inflammatory bowel disease (IBD), end-stage renal disease, or some genetic diseases such as cystic fibrosis, with those affected now living into their fourth and fifth decades.[48,49] With advances in pediatric care, the number of adolescents with chronic illnesses requiring TRT is rising sharply. Chronic glucocorticoid therapy, such as in boys with Duchenne muscular dystrophy (DMD), leads to hypogonadism. Although no clinical trial has specifically assessed TRT use in these adolescents, the most recent guidelines call for an endocrine evaluation and appropriate therapy.[22,50,51] Eating disorders and excessive exercise may result in decreased activity of the hypothalamic-pituitary-gonadal axis and hypogonadism.[52,53] Finally, the number of adolescent males who experience hypogonadism because of opioid addiction or androgen abuse, although uncertain, is likely significant.[54]

In 2019, the FDA provided information on TRT prescriptions in adolescent males.[23] Outpatient retail pharmacy data were used to determine the number who received T prescriptions. In the year ending August 2010, approximately 7400 boys younger than 19 years received T prescriptions.[23] This number increased over time, and in the year ending August 2017, approximately 11 000 males of this age-group received prescriptions. In a sample of 9696 boys younger than 19 years who received T prescriptions, only 17% met the definition for chronic use. Although the reported numbers involved only commercial insurance and did not capture patients on Medicaid or without health care or pharmacy coverage, these numbers raise concerns that not all pediatric patients with permanent hypogonadism are appropriately treated.

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