SUN-204 Transient Hypergonadotropism Upon Pubertal Entry In A Boy With Delayed Puberty And A Heterozygous Mutation In TACR3

A boy presented with delayed puberty at age 13.5 years. His mother had idiopathic hypogonadotropic hypogonadism (IHH) with a heterozygous mutation in the gene TACR3 that the son had inherited. He had a normal sense of smell, no chronic diseases, and no use of medications. At his first physical examination, testicular volumes were 1 mL bilaterally. Blood tests revealed FSH 0.99 IU/L (prepubertal <3.1 IU/L), LH 0.03 IU/L (prepubertal <0.7 IU/L), total testosterone 5 ng/dL (prepubertal <10 ng/dL). At age 14.5 years, he started treatment with testosterone enanthate 50 mg every 4 weeks. Because his genetic testing suggested that he may have IHH like his mother, he underwent full pubertal induction with gradual increases in the testosterone dose and a plan to withdraw treatment to assess endogenous function when growth was finished. Treatment induced appropriate pubertal growth and development of secondary sex characteristics such as voice breaking and pubic and body hair. At 16 years 11 months of age, he was noted to have testicular enlargement to 3 mL. Laboratory tests on that occasion, collected 2 weeks after the last dose of testosterone enanthate 120 mg, showed elevated gonadotropins: LH 13.5 IU/L (adult male: 1.4 - 11.1 IU/L) and FSH 17.1 IU/L (adult male: 1.3 - 12.7 IU/L). Repeat tests at age 17 years and 2 months, after 2 months without testosterone treatment, showed an increase in FSH to 23 IU/L, LH within the normal range (6.8 IU/L) and testosterone 466 ng/dL (adult male: 700 +/- 300 ng/dL). After stopping testosterone treatment, testicular volume continued to increase, most recently 8 mL on the right and 10 mL on the left at age 17.5 years. Blood tests at that time showed FSH 13.9 IU/L and inhibin B 84 pg/mL (11-18 years: 50 - 475 pg/mL). We present a boy with self-limited delayed puberty and a heterozygous mutation in TACR3 who underwent full pubertal induction with exogenous testosterone. After almost 2.5 years of treatment, he had testicular enlargement and a surprising finding of hypergonadotropism. His LH and testosterone normalized, but to date his FSH remains elevated. We hypothesize that this patient had spontaneous pubertal maturation of the hypothalamus and pituitary, but a delay in gonadal development because of suppression of gonadotropins by exogenous testosterone. He now appears to be slowly acquiring gonadal function, with Leydig cell function developing faster than Sertoli cell function. Alternatively or in addition, he may have a primary gonadal defect (either related or unrelated to his TACR3 mutation); he has no history of chemotherapy or radiation treatment, testicular injury or surgeries, or mumps in childhood, and a karyotype to evaluate for Klinefelter syndrome is pending. Another possibility is that his TACR3 mutation is affecting the balance of FSH/LH secretion, as has been reported in IHH patients with TACR3 mutations, though hypergonadotropism has not been reported in these patients.