Effects of mitotane on testicular adrenal rest tumors in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: a retrospective series of five patients

Abstract

We conducted a retrospective study on the long-term effect of mitotane treatment on testicular adrenal rest tumors (TARTs) in 5 adult patients with classic 21-hydroxylase deficiency,. After 60 months of mitotane treatment, a decrease of adrenal steroids was observed in 4 patients. Testicular ultrasonography showed complete disappearance of TART in 2 patients, stabilization in 2 patients and a halving of TART volume in the remaining patient. Sperm count improved notably in 2 patients who had normal baseline inhibin B levels and small inclusions, thus enabling cryopreservation of the subjects’ semen. Four years of follow-up of these two patients after the withdrawal of mitotane showed no recurrence of TART and persistent normal testicular function. In conclusion, mitotane should be used as a last resort in CAH patients in the cases of azoospermia associated with TARTs but normal inhibin B levels, as it can improve long-term endocrine and exocrine testicular function.

Management challenges and therapeutic advances in congenital adrenal hyperplasia

“…Mitotane is the only agent approved by the FDA and EMA as the first-line agent in managing metastatic adrenocortical carcinoma for over six decades 150 . Mitotane is also rarely used (off-label) in the management of Cushing disease 151 and in CAH in the context of infertility due to TART 152 , 153 .…”

“…Importantly, mitotane is a potent inducer of CYP3A4, which increases glucocorticoid clearance. Patients with CAH who receive mitotane might require a 50–100% increase in their glucocorticoid dose 153 . A retrospective case series highlights the long-term effects (60-months) of mitotane in five men with classic CAH and TART-associated infertility 153 .…”

“…Patients with CAH who receive mitotane might require a 50–100% increase in their glucocorticoid dose 153 . A retrospective case series highlights the long-term effects (60-months) of mitotane in five men with classic CAH and TART-associated infertility 153 . Given the narrow therapeutic index and toxicity, serum levels of mitotane were closely monitored (aimed at <14 mg/l) with dose titration and the glucocorticoid dose was increased to prevent adrenal insufficiency.…”

“…In addition, TART showed resolution by ultrasonography in two patients, with improvements in sperm counts that enabled cryopreservation for future use. Mitotane is a highly lipophilic agent that accumulates in adipose tissue and, given its long half-life (median 53 days) 154 , close monitoring of glucocorticoid therapy is essential as the effects of mitotane can last for several months after discontinuation 153 . Given the teratogenic effects of mitotane, women should be counselled to avoid pregnancy for a minimum of 5 years following therapy 155 .…”

Novel treatments for congenital adrenal hyperplasia

“…While mitotane is the primary treatment option for adrenocortical carcinoma [ 75 ], it is not recommended as routine therapy for CAH, because of its potential teratogenicity and significant toxicities [ 2 ]. Mitotane has been successfully used to restore fertility in men with 21OHD and TART, for men whose TART did not respond to increasing glucocorticoid doses [ 76 , 77 ]. TART size reduced or TART completely disappeared in four of six reported patients [ 76 ].…”