Hot Flashes. Hot flashes can significantly affect quality of life for men undergoing ADT. Up to 80% of patients undergoing treatment with GnRH-A report hot flashes and up to 27% report this as the most troublesome adverse effect. Most intervention studies for hot flashes have evaluated treatments in breast cancer patients taking tamoxifen or women who are postmenopausal.

A randomized, double-blind, placebo-controlled trial of megestrol acetate for prevention of hot flashes in women with a history of breast cancer and men undergoing ADT for prostate cancer showed a reduction in hot flashes in 74% of the megestrol group and 20% of the placebo group by intention to treat (P<.001).The efficacy of megestrol was similar in men and women. However, PSA levels have been reported to increase in men who commence megestrol while receiving ADT and decline with discontinuation of megestrol. Although antidepressants are sometimes used and have been evaluated in small pilot trials, we could find no large-scale placebo-controlled trials demonstrating efficacy in men undergoing ADT.

Skeletal Complications. Several prospective trials have established that bone mineral density (BMD) is significantly decreased in men receiving ADT compared with a control group. Notably, these losses surpass bone loss in women who are in early menopause. A recent study of more than 50 000 men from the Surveillance, Epidemiology and End Results program (SEER) and Medicare databases compared the risk of fracture in men with a diagnosis of prostate cancer who were treated with ADT vs those not receiving ADT. Men who were treated with ADT had an increased risk of fracture starting 1 year after diagnosis. The risk of fracture increased with an increase in the number of doses of GnRH-A received. The number needed to harm for an occurrence of fracture 1 to 5 years after diagnosis was 28 for men treated with GnRH-A and 16 for men treated with orchiectomy.

Therapeutic intervention to prevent skeletal complications for men treated with ADT has been examined in both nonmetastatic and metastatic clinical settings. In a randomized trial of 47 men with nonmetastatic prostate cancer, GnRH-A alone was compared with GnRH-A plus 60 mg of pamidronate given every 12 weeks. Men in the GnRH-A-only arm had a mean decrease in lumbar, trochanter, total hip, and trabecular lumbar spine BMD of 3.3% (P<.001), 2.1% (P = .003), 1.8% (P = .005), and 8.5% (P = .02), respectively, after 48 weeks. Mean BMD did not change significantly in the GnRH-A plus pamidronate group. In a multicenter, double-blind study, 106 men with nonmetastatic prostate cancer who were starting ADT were randomized to receive placebo vs 4 mg of zoledronic acid every 3 months for 1 year. Mean lumbar spine BMD decreased in the placebo group by 2.2%, whereas BMD increased by 5.6% in the zoledronic acid group (P<.001).¹¹ A randomized, placebo-controlled trial of zoledronic acid in patients with androgen-independent metastatic prostate cancer showed a significant decrease in skeletal-related events in the zoledronic acid arm (33% vs 44%; P = .02).

Men receiving or starting ADT should be evaluated for risk of osteoporosis. These risks include family history of osteoporosis, low body weight, prior fractures, excessive alcohol use, smoking, glucocorticoid use, low vitamin D levels, and other medical comorbidities. All men should start calcium and vitamin D supplementation. Baseline BMD should be determined. Routine use of bisphosphonates in patients undergoing ADT is not recommended unless there is documented osteoporosis or androgen-independent prostate cancer with skeletal metastasis. Men who smoke or have excessive alcohol consumption should be urged to abstain.

Sexual Function. Testosterone plays an important role in normal male sexual function. Decreasing serum testosterone can have a significant negative impact on quality of life for patients treated with ADT. Although erectile dysfunction is not uncommon after radical prostatectomy, men who undergo ADT have a further decline in ability for sexual intercourse and a decrease in sexual desire compared with men who are not treated with ADT.

The Prostate Cancer Outcomes Study of the SEER program examined quality-of-life outcomes for 431 men with all stages of prostate cancer who were treated with ADT and no other treatment within 1 year of initial diagnosis. The impact on sexual function of treatment with a GnRH-A or an orchiectomy was noted. Men reporting no sexual interest increased from 27.6% to 63.6% after orchiectomy and 31.7% to 58.0% after GnRH-A. Men who achieved no erections increased from 35.0% to 78.6% after orchiectomy and 37.9% to 73.3% after GnRH-A. Men with no sexual activity increased from 47.9% to 82.8% after orchiectomy and 45.0% to 80.2% after GnRH-A. Surprisingly, despite the cosmetic effects and psychological impact of orchiectomy, GnRH-A and orchiectomy had similar effects on sexual function.Although phosphodiesterase type 5 inhibitors are an option, there has been no study specifically evaluating these drugs in men treated with ADT. Penile implants, vacuum devices, and intracavernosal injections of prostaglandin are other available options.

Metabolic Changes. Serum testosterone levels have a negative correlation with fat mass and a positive correlation with muscle mass. Testosterone replacement has been shown to increase lean body mass in men who are deficient in testosterone because of age or chronic disease states.

Three prospective studies have compared body composition and metabolism in cohorts of men with prostate cancer before ADT and 6 to 12 months after ADT. These studies have noted increases in body mass index of 1.6% to 2.4%. Among 35 men in 1 study, fat body mass increased 10% to 20% in 7 men (20%), 20% to 50% in 8 men (22.8%), and more than 50% in 5 men (14.3%). Lean body mass was found to decrease between 2% and 5% in 8 men (22.8%) and greater than 5% in 7 men (20%).Both studies that examined total cholesterol and triglycerides found a significant increase in both of these measures. One of these studies noted increases in high-density lipoproteins, low-density lipoproteins, total cholesterol, and triglycerides of 11.3% (P<.001), 7.3% (P = .05), 9.0% (P<.001), and 26.5% (P = .01).The only study that examined changes in fasting glucose levels noted a significant increase after ADT. A retrospective analysis of men receiving ADT suggests that such metabolic changes lead to increases in Hb_A1c.

A caveat for all of these studies is that they are comparisons of the same patients before and after ADT and, therefore, lack a control group. Nonetheless, these data are consistent with the physiologic changes that have been recognized in other forms of testosterone deficiency. The combination of increasing fat mass, increasing cholesterol, and glucose intolerance may be related to what is recognized as the metabolic syndrome. While metastatic prostate cancer provides a compelling reason for ADT, the impact of negatively modifying cardiovascular risk factors with ADT in other clinical settings for prostate cancer patients, who have a median age of 70 years, should, we believe, be measured carefully, especially in men with biochemical recurrence in the absence of data on survival.

Cognitive and Mood Changes. There is conflicting literature on the issue of cognitive function changes in men undergoing ADT. A study that randomized 82 men to GnRH-A vs close clinical monitoring suggests that there may be worsening on some tests of attention and memory. However, a second study does not suggest any cognitive impairment in men being treated with ADT but, rather, noted an improvement in object recall. A more recent prospective study associates declines in verbal fluency, visual memory, and visual recognition with declines in estradiol induced by ADT.

A quality-of-life study of 144 men given a choice of immediate or deferred ADT found significantly worse scores for fatigue and psychological distress for the men receiving ADT.  Men with prostate cancer surveyed at Massachusetts General Hospital were found to have 8 times the national rate of depression. However, this was not associated with ADT.

Other Changes. Normocytic, normochromic anemia is seen in many patients receiving ADT. Strum prospectively evaluated patients receiving combined androgen blockade. They found a hemoglobin decrease of at least 10% in 90% of their patients and a hemoglobin decrease of at least 25% in 13% of patients. Anemia may be a contributing factor to fatigue that is associated with ADT.

Gynecomastia occurs in 1% to 16% of men treated with ADT. Treatment options include breast irradiation, surgery, and tamoxifen. Surgical therapies are also an option. Other adverse effects of ADT include dry eyes, body hair loss, and vertigo.