Testosterone Recovery Uncertain after Androgen Deprivation Therapy for Prostate Cancer

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By John P. Mulhall, MD

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Despite the intention to reduce testosterone temporarily, androgen deprivation therapy (ADT) may lower it for prolonged periods in patients over the age of 65 or those who take ADT for more than six months, according to the results of our recent retrospective study. Given the range of duration for the use of ADT and the adverse health events associated with low testosterone (low T), clinicians should discuss these findings with patients before initiating ADT.

Our study, published recently in the Journal of Sexual Medicine, is the largest to date on the subject. We analyzed data for 307 men who received ADT following primary prostate cancer treatment at Memorial Sloan Kettering Cancer Center for whom baseline ADT levels were available. Approximately one-quarter of these patients failed to normalize their total testosterone (TT) levels (above 300 ng/dL), and one-tenth remained at castrate levels (below 50 ng/dL) two years after ADT cessation. (1)

The odds of remaining castrate after two years were almost four times higher for patients who received ADT for more than six months and more than three times higher for those with baseline TT levels below 400 ng/dL. (1)

Given these results, our next step is to develop a nomogram that incorporates weighted clinical factors to better predict the likelihood of the return to normal as well as above castrate and baseline TT levels following ADT for prostate cancer.

Androgen Deprivation Therapy

Testosterone stimulates the growth of prostate cancer, the most common nonskin cancer diagnosed in men. (2)ADT is used to lower serum testosterone to a castrate level in patients with metastatic or intermediate-high-risk prostate cancer who undergo radiation therapy. It is also used as a neoadjuvant therapy on an investigational basis in men undergoing a high-risk radical prostatectomy. (3), (4)The duration of the use of ADT varies widely, ranging from single doses of short-term medications (5)to more than 48 months of continuous therapy. (6)

Testosterone is involved in many bodily functions, including physical, sexual, metabolic, and cognitive processes. Persistently low T levels are associated with significant health risks and a lower quality of life. Adverse effects include the loss of bone mineral density, (7)glycemic control issues, (8)lipid abnormalities, (9)cardiovascular events, and cognitive dysfunction. (10)

More specifically, ADT reduces insulin sensitivity within a few months of treatment initiation (8), (9) and increases the risk of developing diabetes by up to 60 percent. (11) Its use is associated with an increased risk of coronary heart disease, myocardial infarction, and sudden cardiac death. (12) Prolonged use of ADT over two years is also associated with a bone density loss of 7.6 percent and an increase in fractures related to osteoporosis. (13), (14), (15) Finally, ADT is known to reduce sex drive, impair the ability to achieve orgasm, and cause changes in the cavernosal smooth muscle structure that lead to erectile dysfunction. (16)

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Study Details

There is a growing body of literature suggesting that testosterone recovery after ADT cessation may be only partial and take longer than expected. (6), (17), (18), (19) However, the definition for recovery in previous studies has been inconsistent, and reported rates have varied widely, from 7 to 96 percent. (6), (19)Further, return to baseline TT levels has rarely been reported. (17), (20)We aimed to evaluate TT recovery after ADT cessation in men with prostate cancer, analyzing time and chance of recovery back to baseline and normal levels (above 300 ng/dL), and remaining castrate (below 50 ng/dL).

Given these results, our next step is to develop a nomogram that incorporates weighted clinical factors to better predict the likelihood of the return to normal as well as above castrate and baseline TT levels following ADT for prostate cancer.
John P. Mulhall Director, Male Sexual and Reproductive Medicine Program

We analyzed data for 307 men who received ADT after primary prostate cancer treatment for whom there was an available baseline TT value before initiating ADT. The mean age of patients was 65, plus or minus (±) eight years. Primary prostate cancer treatment was a radical prostatectomy in 10 percent of patients, radiation therapy in 31 percent, a radical prostatectomy and radiation therapy in 55 percent, and primary ADT in 5 percent. (1)

A majority of patients (71 percent) received multiple ADT agents: 94 percent received a gonadotrophin-releasing hormone agonist, 17 percent received a gonadotrophin-releasing hormone antagonist, and 10 percent received other forms of ADT. The mean duration of ADT was 17 ± 25 months (range: 0.5 to 146). The mean baseline TT value was 379 ± 148 ng/dL. (1)

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Study Results

Overall, mean TT levels recovered over time to 216 ± 205 ng/dL, 275 ± 241 ng/dL, 292 ± 199 ng/dL, and 321 ± 193 ng/dL at six to 12 months, 12 to 18 months, 18 to 24 months, and more than 24 months after ADT cessation, respectively.

However, at the two-year mark after ADT cessation, testosterone recovery varied according to age, duration of treatment, and baseline TT levels. Eight percent of patients remained castrate, 76 percent returned to a normal TT level (above 300 ng/dL), and 51 percent recovered baseline TT.

Baseline TT levels under 400 ng/dL and ADT duration greater than six months were associated with a lower likelihood of recovery to normal TT at 24 months. Our analysis found that the odds of remaining castrate were four times higher for patients who received ADT for more than six months and three times higher for those with baseline TT levels below 400 ng/dL. (1)

Patients younger than 65 years who were exposed to less than six months of ADT recovered to normal TT levels above 300 ng/dL more quickly than other groups. Recovery to baseline and above castrate levels was also faster for younger patients. (1)

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Advancing Prostate Cancer Treatment

The duration for which a man is exposed to ADT and, more specifically, to castrate or very low T levels is an important consideration for ongoing health and quality of life after primary treatment for prostate cancer.

The findings from our study indicate that before initiating ADT, clinicians should assess baseline TT levels and patients’ individual risk factors, and discuss with them the possibility that their levels may remain impaired for a longer time than expected.

At MSK, we plan to develop a nomogram that will incorporate weighted clinical risk factors to better predict the likelihood of the return to normal as well as above castrate and baseline levels of TT for men who take ADT for prostate cancer.

Our multidisciplinary team of prostate cancer experts collaborates to develop individualized treatment plans for each patient. We are committed to helping patients achieve their best possible cancer outcomes and minimizing the negative effects of cancer treatment on their quality of life. We are currently conducting more than 40 clinical trials, testing new drugs and drug combinations, surgical and radiation therapy techniques, diagnostic advances, and strategies for preserving the quality of life for men undergoing treatment.

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The authors declare no conflicts of interest. The research was funded in part through a National Institutes of Health/National Cancer Institute Cancer Center Support Grant (P30 CA008748).

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