Pattern of testosterone recovery after androgen deprivation therapy.
Authors: Tam Andrew , Feng Qianhua , Shi Juncong Ashley , Ladbury Colton John , Correnti Nicholas , Zheng Stephanie , Wong Jeffrey Y.C. , Dandapani Savita V. , Glaser Scott , Rock Adam , Chehrazi-Raffle Alexander , Tripathi Abhishek , Pal Sumanta Kumar , Dorff Tanya B. , Li Yun Rose 
Published: January 2024

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Background: Androgen deprivation therapy (ADT) is the cornerstone of systemic therapy for prostate cancer. Leuprolide, a luteinizing hormone-releasing hormone (LHRH) agonist, is the most commonly used form of ADT. Counseling patients about the long-term toxicity and risks associated with ADT including those associated with delayed testosterone recovery is increasingly important as cancer control and overall survival improves. Existing studies have reported a wide range of average testosterone recovery intervals (4-18 months) and rates of non-recovery, with recent meta-analysis suggesting that a large fraction of patients may never recover to normal testosterone levels after ADT. Methods: We retrospectively reviewed the electronic medical records of 1903 prostate cancer patients who received leuprolide prescribed for a duration of 4 to 32 months as a part of curative-intent therapy between January 2000 and January 2023. After excluding those who were treated with palliative intent, intermittent ADT, or LHRH antagonists, 736 men remained evaluable. Patient characteristics including age, race/ethnicity, stage/PSA/Gleason score at diagnosis, duration of ADT (injection doses and dates), and testosterone levels were collected. Time to Testosterone Recovery (TTR) was estimated based on date and duration of last dose of leuprolide injection to date on which testosterone rose to laboratory-defined normal limits. TTR was analyzed using the Kaplan-Meier method, log-rank test, and Cox-Proportional Hazard models using R. Results: The mean age was 74.6 years (range 46.8 to 97.2 years). A majority (55.6%) of men identified as White (not Hispanic/Latino), with 12.1% Hispanic/Latino, 9.5% Asian/Pacific Islander (API), and 9.2% Black/African American (AA). After a median follow-up time of 33.4 months (range 0.3 to 103.3 months), 413 men (56.1%) achieved testosterone recovery with a mean TTR of 15.6 months and a median TTR of 9.4 months. Risk factors for non-recovery include age >80 years (p=0.001), and duration of ADT >6 months (p=0.0012). Marginal difference in risk of non-recovery was observed when considering race/ethnicity as a whole (p=0.084). However, compared to AA, API had a delayed median TTR (16.7 months vs. 8.7 months; p=0.037). For men who achieved testosterone recovery, no significant difference in TTR between ADT ≤6 months versus >6 months (p=0.67) was observed (median TTR for both was 9 months). Conclusions: Although over 50% of men never achieved testosterone recovery, we observed a median TTR of 9 months in men who achieved TTR. Risk factors for non-recovery include age >80 years and long-term ADT use. Surprisingly, among men who achieved testosterone recovery, there was no difference in TTR with respect to ADT duration. Larger multi-institutional datasets are needed to confirm these findings and help inform patients on risk factors that impact probability of testosterone recovery.