Yonah Krakowsky1, Abraham Morgentaler2. 1. Men's Health Boston, Beth Israel Deaconess Medical Center, Harvard Medical School, Chestnut Hill, MA, USA. 2. Men's Health Boston, Beth Israel Deaconess Medical Center, Harvard Medical School, Chestnut Hill, MA, USA. Electronic address: dr.morgentaler@menshealthboston.com.
Abstract
CONTEXT: When luteinizing hormone-releasing hormone (LHRH) agonists were introduced in the 1980s, it was universally believed that the initial transient rise in serum testosterone (T), termed T flare, caused rapid prostate cancer (PCa) growth and led to disease progression, complications, and death. It became routine to offer antiandrogens (AAs) to prevent these risks. However, over the last decade, it has become recognized that androgens have a finite ability to stimulate PCa growth (the saturation model), providing a theoretical challenge to the risks of T flare. OBJECTIVE: To review evidence for the risks associated with T flare from a modern perspective, specifically prostate-specific antigen (PSA) flare, disease progression, and spinal cord compression. EVIDENCE ACQUISITION: An Ovid Medline database search was conducted to identify articles related to "testosterone flare", "disease flare", and "PSA flare" associated with LHRH agonists. The literature review included papers published from May 1, 1980 through May 1, 2016. Key search terms included, luteinizing hormone-releasing hormone, gonadotropin-releasing hormone, and antiandrogens. EVIDENCE SYNTHESIS: Initial administration of LHRH agonists uniformly results in peak increases in serum T by 40-100% on days 2-3, returning to baseline by days 7-8, after which T declines to castrate levels by approximately 2-3 wk. Of six LHRH agonist studies reporting PSA during the period of T flare, five showed no significant rise in PSA despite the presence of advanced disease with mean baseline PSA as high as ≥500ng/ml. Evidence for disease flare was limited to one report of greater bone pain with LHRH agonists alone versus LHRH agonists with AAs. Three other RCTs reported no disease flare. Rates of spinal cord compression were no greater for LHRH agonists alone compared with castration or estrogen treatment. We identified no studies of men treated with LHRH agonists versus placebo/no treatment to assess the effects of LHRH agonists compared with the natural history of advanced PCa. CONCLUSIONS: Although T flare has been considered risky for 30 yr, a modern review of the evidence collected primarily in the 1980s and 1990s fails to support this view. Specifically, T flare does not appear to be associated with significantly increased PSA, disease progression, or adverse events, even in men with widely metastatic disease. These results are consistent with the saturation model, first introduced in 2006. There seems little value in adding AA to LHRH agonists, except possibly for men with extensive vertebral metastases and serum T concentrations well below the saturation point of approximately 250ng/dl (8.7nmol/l). PATIENT SUMMARY: A review of the literature reveals no evidence for increased risks associated with testosterone flare from the initiation of luteinizing hormone-releasing hormone (LHRH) agonists. This appears to be an unsupported belief from an earlier era when our understanding of testosterone's relationship to prostate cancer was less sophisticated. Except in rare instances, there appears to be no need to use an androgen blocker when beginning treatment with LHRH agonists.
CONTEXT: When luteinizing hormone-releasing hormone (LHRH) agonists were introduced in the 1980s, it was universally believed that the initial transient rise in serum testosterone (T), termed T flare, caused rapid prostate cancer (PCa) growth and led to disease progression, complications, and death. It became routine to offer antiandrogens (AAs) to prevent these risks. However, over the last decade, it has become recognized that androgens have a finite ability to stimulate PCa growth (the saturation model), providing a theoretical challenge to the risks of T flare. OBJECTIVE: To review evidence for the risks associated with T flare from a modern perspective, specifically prostate-specific antigen (PSA) flare, disease progression, and spinal cord compression. EVIDENCE ACQUISITION: An Ovid Medline database search was conducted to identify articles related to "testosterone flare", "disease flare", and "PSA flare" associated with LHRH agonists. The literature review included papers published from May 1, 1980 through May 1, 2016. Key search terms included, luteinizing hormone-releasing hormone, gonadotropin-releasing hormone, and antiandrogens. EVIDENCE SYNTHESIS: Initial administration of LHRH agonists uniformly results in peak increases in serum T by 40-100% on days 2-3, returning to baseline by days 7-8, after which T declines to castrate levels by approximately 2-3 wk. Of six LHRH agonist studies reporting PSA during the period of T flare, five showed no significant rise in PSA despite the presence of advanced disease with mean baseline PSAas high as ≥500ng/ml. Evidence for disease flare was limited to one report of greater bone pain with LHRH agonists alone versus LHRH agonists with AAs. Three other RCTs reported no disease flare. Rates of spinal cord compression were no greater for LHRH agonists alone compared with castration or estrogen treatment. We identified no studies of men treated with LHRH agonists versus placebo/no treatment to assess the effects of LHRH agonists compared with the natural history of advanced PCa. CONCLUSIONS: Although T flare has been considered risky for 30 yr, a modern review of the evidence collected primarily in the 1980s and 1990s fails to support this view. Specifically, T flare does not appear to be associated with significantly increased PSA, disease progression, or adverse events, even in men with widely metastatic disease. These results are consistent with the saturation model, first introduced in 2006. There seems little value in adding AA to LHRH agonists, except possibly for men with extensive vertebral metastases and serum T concentrations well below the saturation point of approximately 250ng/dl (8.7nmol/l). PATIENT SUMMARY: A review of the literature reveals no evidence for increased risks associated with testosterone flare from the initiation of luteinizing hormone-releasing hormone (LHRH) agonists. This appears to be an unsupported belief from an earlier era when our understanding of testosterone's relationship to prostate cancer was less sophisticated. Except in rare instances, there appears to be no need to use an androgen blocker when beginning treatment with LHRH agonists.