Understanding Side Effects of Androgen Deprivation Therapy
by Dr. C.H. Weaver M.D. updated 3/2020
Treatment options are varied for patients with prostate cancer and depending upon the stage, extent of the disease, presence of biomarkers and age. One component of therapy for prostate cancer is called androgen deprivation therapy (ADT), in which levels of male hormones, particularly testosterone, are reduced in the body.
ADT can be achieved through the surgical removal of the testicles or through drugs that suppress levels of male hormones (hormone therapy) in the body. Male hormones have growth stimulatory effects on prostate cancer cells.
Androgen deprivation therapy is commonly used to decrease the risk of prostate cancer progression and prolong survival in men with most stages of prostate cancer.(15-24) The benefit of ADT has been considered to outweigh its associated negative long-term effects on bone, sexual, and cardiovascular health. (25-27) According to the results of a large-scale clinical trial published in JAMA, ADT appears to be associated with an increased risk of Alzheimer’s disease and other forms of dementia. This new information could significantly alter the risk benefit for many men with prostate cancer considering ADT. (28)
Dementia & Alzheimers Disease
The study found that one to four doses of ADT was associated with a 19% increased risk for both Alzheimer’s disease and other forms of dementia, and the risk increased with the number of doses of ADT. At five to eight doses the increased risk was 28 percent for Alzheimer’s and 24 percent for other dementias. Many men undergoing treatment have a life expectancy measured in decades and often ultimately die from other causes “with” but not “from” their prostate cancer. The study results create a significant dilemma for prostate cancer patients and their doctors who now must add the risk of dementia as an ADT side effect.
Insulin Sensitivity and Obesity
Men with prostate cancer being treated with androgen deprivation therapy have an increased risk of osteoporosis and obesity. (1-3)
To gain more insight on the side effects caused by ADT, researchers from the University of Arizona compared data involving side effects of ADT. The study compared men with prostate cancer who were being treated with ADT and men not being treated with ADT (control group). Obesity developed in 43% of men treated with ADT, compared to only 27% of men in the control group. (1)
The researchers concluded that patients with prostate cancer treated with ADT are at a higher risk for obesity. Appropriate preventive measures or close monitoring may help to prevent or reduce side effects.
Among men with locally advanced or recurrent prostate cancer, short-term treatment with Lupron Depot® (leuprolide) and Casodex® (bicalutamide) increased body fat and decreased insulin sensitivity according to another study published in the Journal of Clinical Endocrinology and Metabolism. (2)
Metabolic changes such as insulin resistance could increase the risk of subsequent cardiovascular disease.
To explore whether androgen deprivation therapy reduces insulin sensitivity, researchers in the U.S. conducted a study among 25 men with locally advanced or recurrent prostate cancer. Average patient age was 68 years. The study excluded men who already had diabetes.
The patients were treated with Lupron Depot for three months to suppress production of testosterone. For the first four weeks of treatment, patients also received the anti-androgen medication Casodex.
- After 12 weeks of hormonal therapy, body fat increased by an average of 4.3%.
- Insulin sensitivity decreased by 12.9%.
- Fasting plasma insulin levels increased by 25.9%.
- One patient developed diabetes.
These changes also appear to increase the risk of diabetes and cardiovascular disease particularly in older men.
Bone Loss - Osteoporosis
A significant side effect associated with ADT is loss of bone density or bone mass. Bone loss increases the risk of osteoporosis, bone fracture, pain, hospitalization, and immobility, and increases medical costs. Studies show that men experience a rapid loss of bone mineral density (BMD) within the first six to 12 months of ADT. Research suggests that exercise and treatment with certain medications can improve bone density and decrease the risk of fractures. (4-8) Many physicians recommend calcium supplementation and bone density scans prior to and during therapy with ADT for these patients.
In a phase III clinical trial among men receiving ADT for non-metastatic prostate cancer, treatment with Xgeva (denosumab) improved bone density and reduced the risk of vertebral fractures.
Xgeva is a drug that targets a protein known as the RANK ligand. This protein regulates the activity of osteoclasts (cells that break down bone).
To evaluate the effect of Xgeva among prostate cancer patients receiving ADT, researchers treated 1,400 men with non-metastatic prostate cancer. Half the men treated with ADT were also assigned to receive either Xgeva and compared to those receiving a placebo. (4)
- Compared with men treated with placebo, men treated with Xgeva experienced significantly greater increases in bone mineral density at the lumbar spine and other skeletal sites.
- Men treated with Xgeva experienced significantly fewer vertebral fractures than men treated with placebo.
These results suggest that Xgeva improves bone density and reduces fracture risk among prostate cancer patients treated with ADT.
In a second clinical trial men undergoing ADT for non-metastatic prostate cancer experienced a 62% reduction in risk of vertebral fractures when treated with Xgeva compared to men treated with placebo, according to the results of a study published in the New England Journal of Medicine.
The HALT Study involved 1,468 men undergoing ADT for non-metastatic prostate cancer. Half the men were given Xgeva every six months for three years and half were given a placebo.
The men receiving Xgeva experienced a 6.7% increase in bone mineral density (BMD) at the lumbar spine at 24 months, though increases in BMD were observed as early as one month after initiating treatment with and continued to increase throughout the study. In addition, men experienced increases in BMD at non-vertebral sites compared to those receiving placebo: total hip 4.8%, femoral neck 3.9%, and distal 1/3 radius 5.5%.
Walking can also help reverse the effects of ADT on bone loss among men with prostate cancer. (6)
Researchers from Johns Hopkins University conducted a clinical trial intended to evaluate effects of exercise on fatigue levels among men with prostate cancer who underwent treatment with ADT. This trial included 70 men with early prostate cancer who were scheduled to undergo radiation therapy; half of these patients were also scheduled to receive ADT. At initiation of the trial, these men were considered to have a sedentary lifestyle. Half the men were instructed to begin exercising with just 20- to 30-minute walks during the week. The remaining half was instructed to continue their sedentary lifestyles.
- The men who exercised and received ADT actually experienced an increase in their bone mass (0.48% increase).
- Men who did not exercise and received ADT had a 2.14% decrease in their bone mass.
The researchers concluded that exercise may prevent the loss of bone mass among men with prostate cancer who are being treated with ADT. Patients who are receiving ADT or who are expecting to receive ADT may wish to speak with their physicians about their individual risks and benefits of an exercise program.
Researchers from the University of Pittsburgh, Pennsylvania, and Roswell Park Institute conducted a clinical trial to evaluate the bisphosphonate Fosamax in prostate cancer. The trial included 112 men with prostate cancer who were treated with ADT and received either Fosamax or placebo (inactive substitute).
- At one year bone density had increased among patients treated with Fosamax but had decreased among patients who received placebo.
- There were no apparent side effects associated with treatment with Fosamax.
- This study was too short to determine the effects of Fosamax on the incidence of bone fractures.
The researchers concluded that these results provide evidence that bisphosphonates may help prevent or reduce bone loss among men with prostate cancer who are treated with ADT. Longer-term follow up will help reveal if bone fractures can be reduced with the use of Fosamax. (8)
Among men with early prostate cancer, the risk of depression is increased with the use of androgen-deprivation therapy (ADT), particularly among men who are treated with ADT for 12 months or longer.
Researchers from the United States conducted a large clinical study in an attempt to clarify whether ADT might increase the risk of depression, in addition to a possible association between the length of treatment with ADT and depression among men with prostate cancer.
The study included over 78,550 men with early-stage prostate cancer who were older than 65 years of age. The patients were identified using the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute-Medicare-linked database from 1992 to 2006. Patients had not received a psychiatric diagnosis of depression or any psychiatric treatment within the year prior to their diagnosis of prostate cancer.
- At 3 years following diagnosis, patients who received ADT had increased rates of depression and inpatient psychiatric treatment, compared to those who did not receive ADT.
- Overall, patients treated with ADT experienced a 23% increased risk of depression, 29% increased risk of inpatient psychiatric treatment, and a 7% increased risk (which was not of significance) of outpatient psychiatric treatment, compared to those who were not treated with ADT.
- The risk of depression increased with longer duration of use of ADT: patients who received 6 months or less of ADT had a 12% risk of depression, which increased to 26% among those who received 7-11 months of ADT, and to 37% among patients who received 12 or more months of ADT.
Based on these results, the researchers stated that “Pharmacologic ADT increased the risk of depression and inpatient psychiatric treatment in this large study of elderly men with localized prostate cancer. This risk increased with longer duration of ADT. The possible psychiatric effects of ADT should be recognized by physicians and discussed with patients before initiating treatment.” (9)
Among men with prostate cancer and a history of heart attack or congestive heart failure, receipt of androgen-deprivation therapy may increase the the risk of cardiac complications and death. (9-13)
To explore how a history of heart problems affects outcomes with hormone therapy, researchers conducted a study among 1,378 men with early prostate cancer treated with radiation therapy. All of the men had a history of either congestive heart failure or heart attack. Forty-three percent of the patients received hormone therapy in addition to radiation therapy. (11)
- Among the men with high-risk prostate cancer, five-year risk of death from any cause was 32% among those treated with radiation therapy plus ADT compared with 20% among those treated with radiation therapy alone.
These results suggest that for men with a history of congestive heart failure or heart attack, the addition of ADT to radiation therapy may result in worse survival than radiation therapy alone, even when the cancer is high-risk. This is different than what is seen in men without a history of these heart problems.
Researchers from the University of California at Los Angeles and Duke University recently conducted a clinical study to evaluate men with prostate cancer who received treatment with ADT. This study included nearly 23,000 men diagnosed with prostate cancer between 1992 and 1996. (10)
- The risk of cardiovascular complications was increased by 20% among men treated with ADT.
- Increased rates of cardiovascular complications began to occur after 12 months of ADT.
- Hispanic men were found to have lower rates of cardiovascular risks than White or African-American men.
To explore whether the risks of ADT are different for men with and without heart disease, researchers conducted a study among 5,077 men with localized or locally advanced prostate cancer (prostate cancer that has not spread to distant sites in the body). Some men were treated with radiation therapy alone, and others were treated with ADT before radiation therapy. (13)
- Among men with no history of heart attack or congestive heart failure, receipt of ADT did not significantly influence the risk of death.
- Among men with a history of heart attack or congestive heart failure due to coronary artery disease, ADT almost doubled the risk of death.
The use of ADT appears to be associated with an increased risk of death from cardiovascular causes in patients undergoing radical prostatectomy for localized prostate cancer. Patients with early prostate cancer may wish to speak with their physician regarding their individual risks and benefits of all treatment options for their disease. (9-13)
Reducing the Impact of ADT
For men who experience a PSA recurrence (rise in prostate-specific antigen levels) after radiation therapy for prostate cancer, hormone therapy given intermittently (with breaks) appears to be as effective as hormone therapy given continuously. (14)
Androgen deprivation therapy is designed to block testosterone from stimulating the growth of hormone-dependent types of prostate cancer. Because continuous androgen deprivation therapy produces side effects such as osteoporosis, hot flashes, and loss of libido, and because many prostate cancers eventually become resistant to hormonal therapy, researchers continue to explore alternatives.Intermittent androgen suppression (IAS) is one such alternative. It involves the administration of hormonal therapy until a sufficient treatment response has been achieved, followed by a period of no treatment. The cycle is repeated as needed. IAS may reduce side effects and delay hormone resistance.In order to assess the effects of IAS among men who experience an increase in PSA after radiation therapy for prostate cancer, researchers evaluated 1,386 men. Half the patients were treated with continuous androgen deprivation and half were treated with IAS. IAS was delivered for eight months at a time, and was restarted if PSA levels off treatment exceeded 10 ng/ml.During follow-up, patients assigned to IAS were on treatment (receiving hormone therapy) 27% of the time.The trial was stopped early when it became apparent that overall survival with IAS was no worse than with continuous androgen deprivation therapy.
- Overall survival was 8.8 months among patients treated with IAS and 9.1 months among patients treated with continuous androgen deprivation.
- The IAS group had more prostate cancer-related deaths than the continuous androgen deprivation group, but fewer deaths from other causes.
- The IAS group experienced fewer hot flashes than the continuous androgen deprivation group. The frequency of other side effects did not differ between the groups.
In terms of overall survival, these results suggest that intermittent hormone therapy is as effective as continuous hormone therapy. Providing hormone therapy only intermittently may improve quality of life and reduce costs for men with prostate cancer.Reference: Klotz L, O’Callaghan J, Ding K et al. A phase III randomized trial comparing intermittent versus continuous androgen suppression for patients with PSA progression after radical radiotherapy: NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/UK Intercontinental Trial CRUKE/01/013. Presented at the 2011 Genitourinary Cancers Symposium. Abstract 3.
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- Smith MR, Lee H, Nathan DM. Insulin Sensitivity During Combined Androgen Blockade for Prostate Cancer. Journal of Clinical Endocrinology and Metabolism. 2006.
- Basaria S, Muller DC, Carducci MA et al. Hyperglycemia and Insulin Resistance in Men with Prostate Carcinoma Who Receive Androgen-Deprivation Therapy. Cancer. 2006;106:581-588.
- Amgen Press Release. Amgen announces positive top-line results for denosumab treatment of bone loss in men with non-metastatic prostate cancer undergoing androgen deprivation therapy. Available at . Accessed July 14, 2008.
- Smith MR, Egerdie B, Hernandez Toriz N et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. New England Journal of Medicine. Early online publication August 11, 2009.
- Chiplis P, et al. Effects of exercise on bone loss and functional capacity during prostate cancer treatment. International Journal of Radiation Oncology, Biology and Physics. 2007;69:supplement S (S321-322).
- Ryan CW, Huo D, Demers LM, et al. Zoledronic Acid Initiated During the First Year of Androgen Deprivation Therapy Increases Bone Mineral Density in Patients with Prostate Cancer. Journal of Urology. 2006;178:972-978.
- Greenspan S, Nelson J, Trump D, et al. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer. Annals of Internal Medicine. 2007;146:416-424.
- Dinh K, Reznor G, Muralidhar B, et al. Association of androgen deprivation therapy with depression in localized prostate cancer. Journal of Clinical Oncology. 2016; Published online before printApril 11, 2016, doi:10.1200/JCO.2015.64.1969.
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- Nguyen PL, Chen M-H, Beckman JA et al. Influence of androgen deprivation therapy on all-cause mortality in men with high-risk prostate cancer and a history of congestive heart failure or myocardial infarction. *International Journal of Radiation Oncology*Biology*Physics*. Early online publication June 27, 2011.
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- D’Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004;292(7):821-827. .
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