ADT decreases bone mineral density (BMD). It was shown that ADT significantly increases risk for any clinical fracture, hip fractures, and vertebral fractures in men with prostate cancer, and the duration of treatment affects the onset of complications [40, 41]. Calcium (1000–1200 mg daily from diet and supplements) and vitamin D (800–1000 IU daily) are recommended to reduce the ADT side effects [42]) Osteoclast inhibition with either bisphosphonates or denosumab is recommended for men with bone metastases. Osteoclast inhibition can decrease bone turnover and increase bone mineral density in men receiving ADT [43].

The first report identifying a possible CV risk with LHRH agonists was by Keating et al., who analyzed the Surveillance, Epidemiology, and End Results (SEER) Medicare data of 73,196 men with locoregional prostate cancer [44]. A significantly increased risk of coronary heart disease, myocardial infarction, and sudden cardiac death was reported for men receiving an LHRH agonist compared with those not undergoing ADT. Prospective clinical trials have demonstrated that ADT may increase cardiovascular disease risk by increasing body weight, reducing insulin sensitivity, and/or resulting in dyslipidemia. In a prospective 12-month study of 40 men with prostate cancer, ADT increased serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides by 9%, 7%, 11%, and 27%, respectively [45].

It is advisable that patients in whom ADT is initiated be on periodic follow-up that includes assessment of blood pressure, lipid profile, and glucose level. Some of the effects of ADT occur within the first 3 months of treatment; thus it may be reasonable for an initial follow-up evaluation to occur within 3–6 months after initiation of therapy. There are no data to guide at what intervals periodic further follow-up should occur, and this is left to the discretion of the physician initiating ADT and to the patient’s primary care physician. Prudence and good medical care dictate that patients with cardiac disease receive appropriate secondary preventive measures as recommended by the American Heart Association and other expert organizations, including, when appropriate, lipid-lowering therapy, antihypertensive therapy, glucose-lowering therapy, and antiplatelet therapy [46].

Since the incidence of prostate cancer is higher among older patients, at least one-third of men have sexual problems at diagnosis. However, most of the patients receiving continuous ADT who are potent prior to therapy develop sexual dysfunction. Loss of libido in patients receiving LHRH agonists usually develops within the first months followed by erectile dysfunction [47]. Erections do not recover in about one-half of men, even if ADT is discontinued. Although intermittent ADT allows some recovery of sexual function, serum testosterone requires 9–12 months off ADT to recover [48].

The most common symptom associated with ADT is hot flashes . Hot flashes are usually described as an intense sensation of warmth in the face and upper part of the body which seems similar to postmenopausal symptoms in women. The treatment should be decided depending on the degree of symptoms and potential side effects of the treatment. Megestrol and estrogen appear substantially more effective than venlafaxine. However, estrogen is associated with breast symptoms, megestrol is associated with increased appetite and weight, and venlafaxine is associated with dry mouth. It is recommended to start with a selective serotonin reuptake inhibitor and reserve hormonal treatment (estrogen, megestrol) for refractory cases.

A prospective study of 32 men receiving 12 months of GnRH agonists found a 2.4% weight gain, 9.4% increase in body fat percentage, and 2.7% decrease in lean body mass at 12 months [49]. Another prospective study of 25 patients without diabetes found that 12 weeks of combined androgen blockade resulted in a 12.8% decrease in insulin sensitivity and a 25.9% increase in fasting plasma insulin [50]. Basaria et al. conducted a cross-sectional study among 53 men, including 18 men with PCa who received ADT for at least 12 months prior to the onset of the study (the ADT group), 17 age-matched men with nonmetastatic PCa who had undergone prostatectomy and/or received radiotherapy and who were not receiving ADT (the non-ADT group), and 18 age-matched controls (the control group). It was shown that men on long-term ADT had significantly higher fasting glucose (131 vs. 103; p < 0.01) and greater insulin resistance (17 vs. 6; p < 0.01) and that 44% of the men on ADT had fasting glucose in the diabetic range (>126 mg/dL) compared with 11–12% for the controls [51].

Per the Adult Treatment Panel III (ATP III) guidelines, the diagnosis of metabolic syndrome requires the presence of three of the following five criteria: (1) serum triglycerides ≥150 mg/dL, (2) high-density lipoprotein (HDL) < 40 mg/dL, (3) fasting serum glucose >110 mg/dL, (4) waist circumference ≥ 40 inches, and (5) blood pressure ≥ 130/85 [52]. As noted earlier, patients receiving ADT are at risk for higher fasting serum glucose and increased waist size due to central weight gain. Triglycerides have also been reported to rise by 26.5% (±10%; p = 0.01) with 1 year of ADT [49]. There are currently no specific recommendations regarding the management of insulin resistance and lipid increases for men on ADT.

Gynecomastia and breast pain may be seen in patients on ADT. The incidence of gynecomastia was reported to be as high as 85% in patients receiving high-dose 150 mg daily bicalutamide antiandrogen monotherapy [53]. However, the incidence is lower (13–22%) in men receiving combined androgen blockade [54]. Di Lorenzo et al. investigated the role of tamoxifen and radiotherapy for the prevention and treatment of gynecomastia and breast pain during adjuvant bicalutamide monotherapy after RP in patients with prostate cancer [55]. It was shown that gynecomastia and breast pain induced by bicalutamide monotherapy after RP can be prevented and treated. Tamoxifen has been shown to be more effective and safe than RT (12 Gy) in this setting, and QOL and sexual function are not negatively influenced by these two treatment options. Ozen et al. investigated the efficacy of prophylactic radiotherapy for gynecomastia/breast pain induced by 150 mg bicalutamide in a prospective, randomized, multi-institutional trial [56]. After definitive treatment for localized prostate cancer, 125 patients were randomized to 12 Gy radiotherapy before bicalutamide as prophylactic radiotherapy or bicalutamide only for nonprophylactic radiotherapy. With a follow-up of 12 months, the gynecomastia rate was 15.8% in the prophylactic group and 50.8% in the nonprophylactic group (p < 0.001). Although prophylactic breast irradiation seemed to decrease the gynecomastia rate in patients on 150 mg bicalutamide, not all patients need prophylaxis since only 52% were significantly bothered by gynecomastia. Thus, it was recommended to select patients who need prophylactic radiation based on individual assessment.

Fatigue is another side effect of ADT. The main strategy to reduce fatigue is exercise. Anemia and reduction in penile and testis size may be seen. Hypogonadism has been linked to cognitive declines in patients on ADT [57].

Abiraterone was evaluated in 1088 chemonaïve metastatic CRPC patients in the phase 3 trial. Patients were randomized to abiraterone acetate or placebo, both combined with prednisone [62]. After a median follow-up of 22.2 months, there was significant improvement of radiographic PFS (median: 16.5 vs. 8.2 months; HR: 0.52; p < 0.001). At the final analysis, with a median follow-up of 49.2 months, the OS end point was significantly improved (34.7 vs. 30.3 months; HR: 0.81; 95% CI, 0.70–0.93; p = 0.0033) [63].

PREVAIL is a randomized phase 3 trial that included a similar patient population and compared enzalutamide with placebo. It was conducted in 1717 chemonaïve mCRPC patients and showed significant improvement in both radiographic PFS (HR: 0.186; 95% CI, 0.15–0.23; p < 0.0001) and OS (HR: 0.706; 95% CI, 0.6–0.84; p < 0.001). The most common clinically relevant AEs were fatigue and hypertension. The results showed that enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer [64].