Side effects of androgen deprivation therapy

INTRODUCTION — Androgen deprivation therapy (ADT) is the main therapeutic approach for males with metastatic prostate cancer. ADT is also frequently used in patients whose only manifestation of disseminated disease is a rising or elevated serum prostate-specific antigen and in the setting of adjuvant or neoadjuvant therapy in conjunction with initial treatment of males with intermediate- or high-risk prostate cancer. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer" and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement" and "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)

Despite the potential benefits associated with its use, ADT can cause a range of side effects that negatively affect quality of life and may necessitate a change in therapy. Many of these side effects also occur with alternative hormone therapy strategies that target androgen signaling pathways (ie, androgen receptor pathway inhibitors, including abiraterone, enzalutamide, apalutamide, and darolutamide), although less is known about their adverse effects [1,2]. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)

The side effects of hormone therapy for prostate cancer, their prevention and management, and the potential role of an alternative hormonal strategy are discussed here.

SEXUAL DYSFUNCTION — The vast majority of males receiving continuous ADT who are potent prior to therapy develop sexual dysfunction. Loss of libido in males receiving gonadotropin-releasing hormone (GnRH) agonists usually develops within the first several months, and erectile dysfunction follows [3]. While the majority of males report diminution or total lack of sex drive on ADT, it is not universal. In addition, studies have shown that sexual activity is not solely driven by libido and that libido can be maintained while on ADT [4].

Sexual dysfunction should be anticipated and couples counseled before ADT is started. Sex therapists may be helpful in managing these issues once they become problematic. (See "Overview of sexual dysfunction in male cancer survivors" and "Treatment of male sexual dysfunction".)

Recovery of erectile function is possible after discontinuation of short-term ADT (eg, in males who receive neoadjuvant and adjuvant ADT with radiation therapy for high-risk localized or locally advanced disease) [3]. However, it may be delayed and incomplete.

OSTEOPOROSIS AND BONE FRACTURES — ADT increases bone turnover, decreases bone mineral density, and increases the risk of bone fractures in males with prostate cancer [5]. Loss of bone mineral density can be detected after six to nine months of ADT, and longer therapy confers a higher risk [6-9]. Osteoporotic skeletal fractures occur in up to 20 percent of males within five years of starting ADT [6,10].

Other factors contributing to osteoporosis can include reduced intake of calcium, low vitamin D levels, alcohol abuse, smoking, and chronic use of corticosteroids. (See "Etiology of osteoporosis in men".)

Assessment of bone density — We obtain a baseline assessment of bone density in all males who will be treated with long-term ADT (ie, ≥18 months).

Baseline measurement of bone density is appropriate in males who will be treated with ADT, although guidelines differ as to whether the recommendation should be influenced by ADT duration. As an example, consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) [11] and American Society of Clinical Oncology (ASCO) [12,13] recommend a baseline assessment via dual x-ray absorptiometry (DXA) at initiation of ADT treatment without specifying a minimum duration, while other expert guidelines suggest screening only for those receiving long-term (≥18 months) ADT [14]. Regardless, the available data suggest that although prior DXA screening is associated with a modestly decreased risk of future fractures in males receiving ADT, fewer than 10 percent of patients initiating ADT for localized or regional prostate cancer undergo a baseline DXA scan [15].

After the initial baseline study, retesting is based upon clinical judgment, and usually recommended at least every two years [12].

Although the diagnosis of osteoporosis in males is typically accomplished using a DXA scan, at least some data suggest that conventional DXA measurement of bone density may not provide an adequate assessment of fracture risk in males with prostate cancer on ADT [16,17]. Results may be better with quantitative CT, the indications for which are discussed elsewhere. (See "Clinical manifestations, diagnosis, and evaluation of osteoporosis in men" and "Clinical manifestations, diagnosis, and evaluation of osteoporosis in postmenopausal women".)

Preventive strategies

Lifestyle modification — Beneficial lifestyle modifications include smoking cessation, moderating alcohol and caffeine consumption, vitamin D and calcium supplementation, and regular weight bearing or resistance exercises. (See 'Role of structured exercise' below.)

Consistent with guidelines from ASCO, we recommend dietary calcium intake (food and supplements) of 1000 to 1200 mg daily and supplemental vitamin D of 800 to 1000 international units daily for all males receiving ADT [12]. We also recommend weight bearing exercise, decreased alcohol consumption, and smoking cessation [18-21].

Osteoclast inhibitors — For males without bone metastases who are treated with long-term (>6 month) ADT, an osteoclast inhibitor such as a bisphosphonate or denosumab can decrease bone turnover and increase bone mineral density. We suggest an osteoclast inhibitor to reduce the risk of fracture in the setting of osteoporosis (T scores of -2.5 or less in the femoral neck, total hip, or lumbar spine), or when the 10-year probability of hip fracture (using the FRAX algorithm or a different tool) is ≥3 percent or the 10-year probability of a major osteoporosis-related fracture is ≥20 percent. When an osteoclast inhibitor is indicated, for most men, we suggest denosumab (60 mg subcutaneously every six months) rather than a bisphosphonate. The optimal duration is not known. For most men, we continue an osteoclast inhibitor for up to 36 months.

Osteoclast inhibitors (either bisphosphonates or denosumab) are recommended for males with advanced prostate cancer and bone metastases to reduce the risk of a skeletal-related event [13,22]. (See "Bone metastases in advanced prostate cancer: Management", section on 'Osteoclast inhibitors'.)

Osteoclast inhibitors can also decrease bone turnover and increase bone mineral density in males without bone metastases who are treated with long-term ADT and are at risk for bone fracture. There is no consensus on the optimal way to define males who are at elevated risk of fracture, and guidance from expert groups is variable (see "Screening for osteoporosis in postmenopausal women and men", section on 'Fracture risk assessment' and "Osteoporotic fracture risk assessment"):

●Our approach is consistent with guidelines from ASCO [12,13], Cancer Care Ontario (CCO) [22], and the NCCN [11]. Estimates of fracture risk using the FRAX algorithm, or the Canadian Association of Radiologists and Osteoporosis Canada tool [23], and periodic bone density measurements may provide guidance when considering the use of an osteoclast inhibitor to prevent fracture, although none of these tools have been validated in patients with secondary osteoporosis caused by hormonal deprivation therapies [17]. These guidelines all suggest the addition of an osteoclast inhibitor to reduce the risk of fracture in the setting of osteoporosis (T scores of -2.5 or less in the femoral neck, total hip, or lumbar spine) or when the estimated 10-year probability of hip fracture is ≥3 percent or the 10-year probability of a major osteoporosis-related fracture is ≥20 percent. However, the ASCO guidelines also state that the short-term bone loss associated with ADT can be rapid, and because of this, clinicians should consider treatment at a higher bone density or T score than is recommended using FRAX or similar tools, and males receiving ADT should be considered as having secondary osteoporosis in the FRAX assessment tool [12].

●On the other hand, year 2021 guidelines on bone health from the European Society of Medical Oncology (ESMO) suggest the addition of a bone targeted agent for individuals with a T score less than -2, and for those with T score >-2 and any two of the following risk factors [24]:

•Age >65

•T score <-1.5

•Smoking (current or past history)

•Body mass index (BMI) <24

•Family history of hip fracture

•Personal history of fragility fracture above age 50

•Oral glucocorticoid use for >6 months

When an osteoclast inhibitor is indicated, for most males with non-metastatic prostate cancer who are receiving ADT, we prefer denosumab (60 mg subcutaneously every six months). Guidelines from CCO [22], the National Osteoporosis Foundation [25], the NCCN [26], and ASCO [12,13] all recommend that males who require drug therapy to prevent bone loss/fractures receive denosumab, an approved drug, at the dose and schedule recommended for prevention of osteoporosis (60 mg subcutaneously every six months). Bisphosphonates such as zoledronic acid are an alternative, but they are not approved specifically for prevention of bone loss/fractures in males receiving ADT. In this population, denosumab at this dose and schedule has been shown to reduce fractures, while other agents, including bisphosphonates, only improved bone mineral density [27,28]. However, there is substantial indirect evidence for fracture reduction in other populations with osteoporosis with the use of bisphosphonates. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)

Nevertheless, in situations or jurisdictions where denosumab is contraindicated or not available, a bisphosphonate is a reasonable option [13]. CCO guidelines suggest zoledronic acid at a dose of 5 mg by intravenous infusion once per year in this setting [22].

The optimal duration of therapy with an osteoclast inhibitor is unknown. Current studies provide results up to 36 months of therapy [13]. ESMO guidelines suggest continuation of the bone targeted agent for the duration of endocrine treatment or for up to five years.

The risks and complications of osteoclast inhibitors are discussed elsewhere. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy" and "Medication-related osteonecrosis of the jaw in patients with cancer".)

Denosumab — Denosumab is a humanized monoclonal antibody that specifically binds to the receptor activator of nuclear factor kappa B ligand (RANKL), which is a key factor in osteoclast formation and function [29].

The utility of denosumab for the prevention of osteoporosis in males with non-metastatic, hormone-sensitive prostate cancer was demonstrated in a double-blind, trial in which 1468 males were randomly assigned to denosumab (60 mg subcutaneously every six months) or placebo [29,30]. Overall, 912 patients (62 percent) completed the three year trial.

All subjects had undergone bilateral orchiectomy or were receiving a gonadotropin-releasing hormone (GnRH) agonist on enrollment and were expected to remain on the GnRH agonist for at least 12 months. Patients were either ≥70 years old, or if <70 years, had a low mineral density (T score less than -1 at the lumbar spine, hip, or femoral neck). Patients receiving treatment with bisphosphonates were excluded.

Key results included the following:

●At 36 months, denosumab significantly increased bone density at all measured sites (lumbar spine, hip, femoral neck, and distal third of radius) compared with placebo. For the primary endpoint of the study, the bone mineral density in the lumbar spine, the increase with denosumab was 5.6 percent, compared with a decrease of 1 percent with placebo. The increase in bone density was progressive over the course of time at all sites and was statistically significant beginning one month after the start of treatment.

●Treatment with denosumab resulted in a statistically significant decrease in the incidence of new vertebral fractures at 12 and 36 months (cumulative incidence 0.3 versus 1.9 and 1.5 versus 3.9 percent, respectively). The incidence of fracture at any site was also decreased, although the difference was not statistically significant (5.2 versus 7.2 percent, relative risk 0.72, 95% CI 0.48-1.07).

●The overall rate of adverse events was approximately 87 percent in both the denosumab and placebo arms, with approximately equal rates of drop-out due to side effects (6.7 versus 6.5 percent). Cataracts developed more frequently in patients treated with denosumab (4.7 versus 1.2 percent), although these were not attributed to the study drug. Serious adverse events were slightly more common with denosumab (35 versus 31 percent). Deaths possibly related to treatment were observed in three patients treated with denosumab and four treated with placebo.

●Metastasis to bone was diagnosed in three patients (0.4 percent) treated with denosumab and ten (1.4 percent) treated with placebo.

Bisphosphonates — Multiple small randomized trials have demonstrated that bisphosphonates can prevent the decrease in bone density associated with ADT [31-35]. As an example, in one trial, zoledronic acid (4 mg every three months for one year) was compared with placebo in 106 males initiating ADT for non-metastatic prostate cancer [32]. At one year, mean bone mineral density in the lumbar spine increased by an average of 5.6 percent in males receiving zoledronic acid, while it decreased by an average of 2.2 percent in those given placebo. For most men, we prefer zoledronic acid if a bisphosphonate is chosen over denosumab. Although there is uncertainty as to the optimal frequency and duration of therapy, CCO guidelines (which have been endorsed by ASCO [13]) suggest the use of 5 mg intravenously once every 12 months [22].

In settings where intravenous zoledronic acid is unavailable, oral alendronate may be an acceptable alternative [33,34].

The risks and complications of long-term bisphosphonate use are discussed elsewhere. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

FALLS AND FRACTURES WITH ANDROGEN RECEPTOR INHIBITORS — Second generation antiandrogens (androgen receptor inhibitors [ARIs]) may be added to conventional ADT in males with metastatic or non-metastatic castration-resistant prostate cancer (enzalutamide, apalutamide, or darolutamide) and for advanced castration-sensitive prostate cancer (enzalutamide, apalutamide). (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway".)

All three ARIs have been associated with an increased risk for falls and fractures. The best data come from a meta-analysis of eleven trials that included a total of 6536 males treated with enzalutamide, apalutamide, or darolutamide in combination with ADT or other enzalutamide combinations for metastatic or non-metastatic, castration-resistant or castration-sensitive advanced prostate cancer, and 4846 males in the control group, who could have received placebo plus ADT, bicalutamide (a first generation androgen receptor inhibitor), or abiraterone [36]. Use of an ARI was associated with a significantly increased risk for falls (risk ratio [RR] for all-grade falls 1.8, 95% CI 1.42-2.24) and fractures (RR for all-grade fractures 1.59, 95% CI 1.35-1.89). Both falls and fractures were most frequent with apalutamide (12 percent risk for falls and 10 percent risk for fracture).

Data on the use of osteoclast inhibitors were not available for all studies, and the authors could not conclude whether use of one of these agents might have reduced the fracture rate. The reason(s) for the higher rate of falls with ARI could also not be discerned. Possible explanations include the ability of some these drugs to cross the blood-brain barrier (enzalutamide, apalutamide), treatment-induced sarcopenia or fatigue, and/or the use of concomitant medications or other predisposing conditions.

Although the risk is overall low, clinicians might consider incorporating a fall-risk screening tool in older active males who are initiating an ARI for advanced prostate cancer (algorithm 1). (See "Falls in older persons: Risk factors and patient evaluation" and "Falls: Prevention in community-dwelling older persons".)

VASOMOTOR SYMPTOMS — The best treatment for hot flashes in males undergoing ADT is unclear. Megestrol and estrogen appear substantially more effective than venlafaxine. However, the side effects differ between these agents (estrogen - breast symptoms, megestrol - increased appetite and weight, venlafaxine - dry mouth). We typically start with a selective serotonin reuptake inhibitor and reserve hormonal treatment (estrogen, megestrol) for refractory cases.

The majority of males who receive ADT for prostate cancer experience hot flashes, including up to 80 percent of those receiving gonadotropin-releasing hormone (GnRH) agonists. Hot flashes affect quality of life, particularly if there are associated sleep problems.

Hot flashes are usually described as an intense sensation of warmth in the face and upper part of the body. They may be associated with nausea and sweating, and may occur during sleep. Assessment should include duration, frequency, accompanying emotional or physical symptoms, and the degree of associated sleep disturbance.

Treatment — Numerous approaches have been explored, similar to those used in postmenopausal females [37]. However, at least one trial has suggested that agents that are effective in females may not be active in males who are androgen deprived [38]. (See "Menopausal hot flashes".)

Medications — The success of various agents for treatment of vasomotor symptoms in males ranges widely, and benefits must often be balanced against treatment-related side effects. The available evidence suggests that the pharmacologic approach to the management of hot flashes in males being treated with ADT is similar to that in women. (See "Menopausal hot flashes".)

Potentially effective agents that have been evaluated in randomized trials include serotonin reuptake inhibitors, progestational agents, cyproterone, selective serotonin uptake inhibitors, and gabapentin [39-41].

●The most extensive data on the treatment of hot flashes in males come from a trial in 311 males who had been treated with a GnRH agonist for six months and either were requesting treatment for hot flashes or had a minimum of 14 hot flashes per week [39]. The males were randomly assigned to medroxyprogesterone (20 mg/day), cyproterone (100 mg/day), or the serotonin uptake inhibitor venlafaxine (75 mg/day). Symptoms were reassessed at 4, 8, and 12 weeks after therapy initiation.

All three regimens significantly reduced hot flashes compared with baseline, but medroxyprogesterone and cyproterone acetate were significantly more effective than venlafaxine (84 and 95 versus 47 percent reductions in symptom scores one month after starting treatment).

●Although megestrol acetate can successfully treat vasomotor symptoms, it should be used with caution as its use has been reported to cause rapid progression of prostate cancer [42,43].

●Gabapentin was evaluated in a phase III trial in which 223 males who had at least 14 bothersome hot flashes per week while receiving ADT were randomly assigned to gabapentin at doses of 300, 600, or 900 mg daily or placebo [40]. Gabapentin 900 mg daily was well tolerated and associated with a significant reduction in the frequency and intensity of hot flashes compared with placebo (46 versus 22 and 44 versus 27 percent reductions, respectively, at week 4 compared with baseline).

●Oxybutynin has been shown to be beneficial for females with menopausal hot flashes [44]. While randomized trials are not available, there is anecdotal experience supporting a potential benefit for oxybutynin in males receiving ADT [45]. (See "Menopausal hot flashes", section on 'Nonhormonal pharmacotherapy'.)

Alternative strategies — Alternative or complementary therapies are increasingly popular as "natural remedies" for males who have side effects of ADT:

●Acupuncture may have some activity in ameliorating vasomotor symptoms due to ADT [46-48]. In a small phase II study, 60 consecutive males receiving a GnRH analog were treated with acupuncture to the ear lobe; of these, 95 percent reported a significant decrease in the severity of symptoms [46].

●Soy products, vitamin E, and herbal remedies have also been used with variable success in females with hot flashes. However, in a randomized, placebo controlled trial in 120 males with prostate cancer who were being managed with androgen deprivation neither soy protein nor venlafaxine was more effective than placebo, which also significantly reduced the frequency and severity of hot flashes [38].

The lack of large, well organized prospective double-blind placebo-controlled trials makes it difficult to determine the true efficacy of any of these approaches.

BODY COMPOSITION AND METABOLISM — Males who are receiving ADT as well as those receiving androgen receptor pathway inhibitors (ARPIs) for prostate cancer should be encouraged to maintain a moderate exercise regimen. Greater intensity of screening for new onset diabetes and elevated cholesterol may also be appropriate. (See 'Role of structured exercise' below.)

Treatment with ADT causes loss of lean body mass, increased body fat, decreased muscle strength, and decreased insulin sensitivity, all of which are probably due to reduced testosterone levels.

●Gonadotropin-releasing hormone (GnRH) agonists significantly decrease lean body mass (sarcopenia) and increase fat mass [49,50]. Most of the fat accumulation is subcutaneous adipose tissue [51,52].

●The decrease in lean body mass and increase in fat mass appear to begin within the first year, although some further decrease in muscle mass may be seen for at least three years [50].

●Males being managed with ADT have a statistically significant increase in newly diagnosed (incident) diabetes [53-56]. Further support for a causal relationship between ADT and diabetes comes from an analysis of 2237 propensity matched pairs of males with prevalent diabetes at the diagnosis of prostate cancer [57]. Males who were treated with ADT had statistically significant increases in their use of diabetes pharmacotherapy and in their hemoglobin A1c levels at one and two years after initiation of ADT.

Treatment-related changes in body composition are accompanied by important metabolic changes including reduced insulin sensitivity [58,59] and increases in serum LDL-cholesterol, HDL-cholesterol, and triglycerides [51,59-61]. These changes may also be seen with bilateral surgical orchiectomy [62]. The US Food and Drug Administration (FDA) has issued a class labeling for GnRH agonists indicating that treatment may produce hyperglycemia and an increased risk of developing diabetes; insufficient data exist to conclude a similar risk in males treated with GnRH antagonists.

Long-term use of newer forms of hormonal therapy such as ARPIs, including abiraterone, enzalutamide, apalutamide, and darolutamide, are also associated with metabolic changes including an increased risk of diabetes [1].

POTENTIAL CARDIOVASCULAR HARM — The most common noncancer-related cause of death among prostate cancer survivors is cardiovascular disease (CVD) [63]. There are conflicting results regarding the impact of long-term ADT on CVD risk, but none of the trials (until recently) were designed to specifically answer that question. However, taken together, the majority of studies, mainly observational, suggest that ADT increases cardiovascular morbidity and/or mortality, especially in those with pre-existing CVD. These risks are sufficient to support counseling and risk reduction measures for males initiating ADT [5,64]. The potential benefits for males in whom long-term ADT is being considered as part of the management of their prostate cancer should always be balanced against any potential harm from ADT.

Cardiac disease — There are conflicting results regarding the impact of long-term ADT on various cardiac parameters, with the majority of studies suggesting that ADT increases cardiovascular morbidity and/or mortality [55,65-69], but a few failing to identify a statistically significant effect [53,54]. An increased risk may be more evident in males who have had two or more prior CVD events, especially in the first six months after initiation of ADT [70].

No placebo-controlled randomized trials have prospectively addressed the risks of CVD associated with conventional ADT, but retrospective data are available from both randomized trials and large observational series:

●A meta-analysis incorporated data from 4141 patients who were enrolled on eight multicenter randomized phase III trials of injectable gonadotropin-releasing hormone (GnRH) agonists with median follow-ups ranging from 8 to 13 years [71]. The incidence of cardiovascular death was not significantly different in those assigned to ADT compared with placebo (11 versus 11.2 percent, relative risk 0.93, p = 0.41). There was no increase in risk of cardiovascular death in those who received ADT for a short (six months or less) or long (three years or more) duration. Furthermore, the meta-analysis found that in 11 trials with 4805 patients, both the prostate cancer specific mortality and all-cause mortality were significantly lower in those assigned to ADT compared with placebo.

●On the other hand, in a second meta-analysis on observational data from eight large studies that included approximately 415,000 males managed with any form of ADT (GnRH agonist, orchiectomy, oral antiandrogens), the relative risk for males treated with a GnRH and any type of CVD was 1.38 (95% CI 1.29-1.48) [72]. An increased risk of similar magnitude was observed for orchiectomy and antiandrogens.

●An increased risk of cardiovascular toxicity, particularly in males with pre-existing CVD, has also been seen with androgen synthesis inhibitors and androgen receptor antagonists, including abiraterone, enzalutamide, darolutamide, and apalutamide [1,73,74]. (See "Castration-resistant prostate cancer: Treatments targeting the androgen pathway" and "Overview of approach to prostate cancer survivors", section on 'Side effects of novel hormonal therapies'.)

GnRH antagonists — A particular area of uncertainty is the relative cardiovascular toxicity of GnRH antagonists versus agonists. GnRH agonists (eg, leuprolide) are by far the most commonly used form of medical castration while GnRH antagonists (degarelix, and the oral agent relugolix) are used infrequently despite the fact that some data suggest that there may be less cardiovascular toxicity with GnRH antagonists as compared with agonists, making these agents particularly attractive for use in those with preexisting CVD. However, the choice of a GnRH agonist or antagonist may not be as important if aggressive risk-reduction cardiology care is provided to males with known CVD who are about to start ADT. (see "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'GnRH antagonists')

The available data are as follows:

●A pooled analysis from six phase III, prospective, randomized trials that recruited 2328 males receiving ADT (injectable GnRH agonists or GnRH antagonist degarelix) concluded that the risk of cardiac events among males with pre-existing CVD within one year of initiating therapy was significantly lower in patients treated with a GnRH antagonist compared with a GnRH agonist (hazard ratio [HR] 0.44, 95% CI 0.26-0.74; p = 0.002) [75].

●A similar conclusion was reached in the phase III HERO study, which randomly assigned 934 males with advanced prostate cancer to the investigational oral GnRH antagonist relugolix or to an injectable GnRH agonist [76]. The primary endpoint was sustained testosterone suppression to castrate levels, and all other endpoints, including cardiovascular toxicity, were secondary. After 48 weeks of treatment, the incidence of major cardiovascular events was 54 percent lower with relugolix (2.9 versus 6.2 percent, HR 0.46, 95% CI 0.24-0.88), and the difference was even more marked in the subgroup of males with a history of cardiovascular events (3 of 84, 3.6 percent, versus 8 of 45, 17.8 percent).

●A later study reported that degarelix was associated with a lower cardiovascular risk than leuprolide [77], but emphasized that none of the relevant trials addressing this issue was designed with cardiovascular morbidity as a primary endpoint.

●On the other hand, the long-term relationship between ADT and cardiovascular risk, and potential differences between GnRH agonists versus antagonists were directly addressed in the PRONOUNCE trial, a phase III trial of males with pre-existing CVD, which compared adjudicated major adverse cardiac events after degarelix or leuprolide [78]. The study failed to show a lower cardiovascular risk profile with degarelix compared with leuprolide. Notably, all patients on the study were required to have their cardiac care optimized by a cardiologist prior to and during the trial, and this may have resulted in the lower rates of observed versus anticipated cardiovascular events in the leuprolide arm.

These disparate results have led some to conclude that the potential for lower cardiovascular risk cannot solely justify the use of GnRH antagonists in prostate cancer patients who have preexisting CVD [79].

The potential benefits of ADT when used for appropriate indications in prostate cancer must always be weighed against the potential risks of toxicity, especially of cardiovascular events. A simple screening tool called STAMP identifies males at highest risk of CVD by asking if the patient has had a diagnosis of Stroke; Transient ischemic attack; Abdominal aortic aneurysm or other aortic disease; Myocardial infarction, angina, or previous revascularization; or Peripheral vascular disease [80]. If an individual has any of these conditions, they should be considered at risk for an adverse cardiovascular event during ADT.

Thromboembolic events — Males with prostate cancer who are treated with ADT appear to be at increased risk of thromboembolic events (deep venous thrombosis, pulmonary embolus, arterial embolism).

●A meta-analysis that analyzed data from 10 studies including more than 250,000 individuals found that the use of ADT was associated with an increased risk of thromboembolic events (risk ratio [RR] 1.43, 95% CI 1.15-1.77) [81]. In those studies in which the use of ADT was limited to patients with localized prostate cancer, there was also a significant increase (RR 1.10, 95% CI 1.05-1.16).

●Similarly, in a Surveillance, Epidemiology, and End Results (SEER) database study that included approximately 155,000 men, 38 percent of whom received ADT, there was a significantly increased risk of thromboembolic events compared with those not on ADT (15 versus 7 percent, HR 1.56) [82]. A Swedish study that included approximately 77,000 males with prostate cancer found that the risk of thromboembolic events was increased in all males with prostate cancer, and that the risk was greatest in those who were treated with endocrine therapy [83].

Risk reduction strategies — Males starting on ADT, especially those at high risk, should be followed and managed by a multidisciplinary team and treated according to best practices including [80]:

●If lipids are abnormal, use statin therapy to lower low-density lipoprotein cholesterol. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

●If blood pressure exceeds goal based on cardiovascular risk, add antihypertensive therapy. (See "Goal blood pressure in adults with hypertension".)

●If fasting glucose is elevated and hemoglobin A1c is abnormal, approaches to lowering glucose are appropriate. (See "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Diagnostic tests'.)

●Patients with known CVD should take aspirin (generally 81 mg/day) unless contraindicated. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)

●Males who continue to smoke should be referred to smoking cessation programs. (See "Overview of smoking cessation management in adults".)

●Identify patients who might benefit from referral to a cardio-oncology clinic (eg, myocardial dysfunction, atrial fibrillation, uncontrolled hypertension or diabetes [84]).

KIDNEY INJURY — Two large studies observed an association between treatment with ADT and an increased risk of acute kidney injury [85-87]:

●In a retrospective, nested case control analysis, 232 cases of acute kidney injury were observed in 10,250 males with newly diagnosed, non-metastatic prostate cancer diagnosed between 1997 and 2008 for an incidence of 5.5 cases per 1000 patient years [85]. These cases were matched with 2721 controls with attention to identifiable risk factors. Overall, the current use of ADT was associated with an increased risk of acute kidney injury compared with those who had never used ADT (odds ratio 2.48, 95% CI 1.61-3.82). When cases were analyzed based upon the type of ADT, most of the excess risk was related to combination regimens that included a gonadotropin-releasing hormone (GnRH) agonists and an antiandrogen.

●A study from the Surveillance, Epidemiology, and End Results (SEER) database identified 69,292 males diagnosed with non-metastatic prostate cancer between 1995 and 2009 [86]. The 10-year rate of acute kidney injury was significantly elevated in males treated with ADT compared with those who were ADT naïve (30.7 versus 24.9 percent, p <0.001). These differences were predominantly seen in males treated with GnRH agonists (31.1 versus 26 percent, p <0.001), and the differences were not significant in those managed with orchiectomy.

However, it is unclear whether these observations represent a causal relationship between ADT with a GnRH agonist and acute kidney injury and additional studies are required. A number of confounding factors that could not be controlled for, such as the use of bisphosphonates or the progression of underlying prostate cancer, may account for these observed differences [87].

FATIGUE — Fatigue or lack of energy is a highly prevalent and often annoying side effect of ADT. In one study, fatigue was severe in 14 percent of males after only three months of therapy [88]. The extent of fatigue does not seem to correlate with anemia or emotional cognitive issues.

Regular exercise appears to be beneficial in ameliorating the fatigue associated with ADT [89]. (See 'Role of structured exercise' below and "Cancer-related fatigue: Prevalence, screening, and clinical assessment" and "Cancer-related fatigue: Treatment".)

ANEMIA — Anemia develops in up to 90 percent of males receiving long-term ADT [5]. It is usually mild to moderate, normochromic, and normocytic [90-93]. The relationship between anemia and fatigue symptoms is unclear [92,93].

Anecdotal evidence suggests that the anemia associated with ADT is highly responsive to erythropoietin (EPO) therapy. However, EPO is rarely necessary, and we reserve it for symptomatic patients.

ISSUES RELATED TO BODY IMAGE

Gynecomastia — Gynecomastia is caused by an increased ratio of estrogen to androgen activity. Gynecomastia is common in males with prostate cancer undergoing ADT, and it is particularly prevalent with antiandrogen monotherapy. Gynecomastia causes significant alterations in body image and is often associated with breast tenderness as well [5].

Drug therapy (tamoxifen) and prophylactic radiation therapy (RT) are effective in most cases when initiated prior to the development of gynecomastia. However, both approaches have limited benefit once gynecomastia is established. (See "Management of gynecomastia", section on 'Men with prostate cancer'.)

Weight gain — Self-image is central to self-confidence and sexual performance. The prevalence of obesity (BMI >30 kg/m²) at the time of diagnosis was 26 percent in one study [94], and obesity after diagnosis of prostate cancer is associated with higher cardiovascular and all-cause mortality [95]. While obesity in males with newly diagnosed prostate cancer has usually developed over many years, up to 70 percent of males gain an average of 10 pounds within one year of starting ADT [96]. The weight gain is typically due to an increase in body fat in the waist, hips, and thighs, resulting in a feminizing effect. Many males report increased hunger and more snacking between meals. In order to minimize weight gain or achieve weight loss, referral to a dietician is suggested at initiation of ADT to review healthy eating habits and snacking strategies. The importance of adequate exercise in addition to dietary changes is discussed in detail below. (See 'Role of structured exercise' below.).

Decreased penile and testicular size — A decrease in the size of the penis and/or testicles is a common side effect of ADT, which may be distressing to the patient [5,97,98]. Males should be warned of this potential complication; there are no treatments to mitigate this side effect.

Thinning of body hair — Thinning of body hair is another unexpected and disconcerting side effect that should be discussed with the patient before therapy is started. Although facial and most body hair are decreased, bald males may regrow some scalp hair [99].

EMOTIONAL AND COGNITIVE CHANGES — Circulating testosterone levels have behavioral and neurologic effects in humans, and both testosterone concentration and neurocognitive function decrease with aging in normal men.

There is some evidence to suggest a link between ADT and neurocognitive dysfunction, including Alzheimer disease and other forms of dementia; however, it is inconsistent and nonspecific. At least some data support the view that advanced age, comorbidity, and advanced disease stage may account for much of the cognitive disorders seen in these men, and that cognitive dysfunction may have preceded the diagnosis of prostate cancer [100-106]. As an example, in an analysis of 1.2 million Medicare beneficiaries treated for prostate cancer over a 14-year period, 9 percent were diagnosed with Alzheimer disease, and 19 percent developed dementia [102]. There was a slight increase in the unadjusted risk of both Alzheimer disease and dementia among males receiving ADT. However, after adjusting for cancer therapy and other variables, there was no increased risk of Alzheimer disease (hazard ratio [HR] 0.98) and only a trivial increased risk of dementia (HR 1.01). No ADT dose effect on Alzheimer disease or dementia was noted (less than one year versus longer).

On the other hand, others note an elevated risk for dementia even after adjusting for factors such as age and comorbidity:

●In a population-based cohort study of 154,089 older adult males diagnosed with prostate cancer between 1996 and 2003 derived from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, 62,330 received ADT within two years of diagnosis, while 91,759 did not [105]. At a mean follow-up of 8.3 years, exposure to ADT was associated with a diagnosis of Alzheimer disease (13.1 versus 9.4 percent; HR 1.56, 95% CI 1.51-1.60) and dementia (21.6 versus 15.8 percent, HR 1.61. 95% CI 1.57-1.65), and risk was still significantly elevated after adjustment for age at diagnosis, race/ethnicity, geographic area, marital status, comorbidity score, cancer stage, and socioeconomic status (propensity score-adjusted HR for Alzheimer disease 1.14 [95% CI 1.10-1.18] and risk for dementia 1.20 [95% CI 1.17-1.24]). Risk was higher for longer duration of ADT therapy (for >8 doses, the propensity score-adjusted HR was 1.24 for Alzheimer disease [95% CI 1.16-1.34] and 1.21 [95% CI 1.15-1.28] for dementia); for one to four doses, the corresponding HRs were 1.19 (95% CI 1.15-1.24) for Alzheimer disease and 1.19 (95% CI 1.15-1.23) for dementia.

●A meta-analysis of 14 studies of males with prostate cancer who did or did not receive ADT using a GnRH agonist or antagonist included nine studies reporting all-cause dementia, eight reporting Alzheimer disease, and five assessing outcomes according to the duration of ADT [107]. The risk of new-onset dementia or Alzheimer disease saw modestly but significantly higher in males receiving ADT compared with those who did not (HR 1.21, 95% CI 1.11-1.33, and HR 1.16, 95% CI 1.09-1.24). When five studies were analyzed according to treatment duration, the elevated risk for all-cause dementia seemed limited to those who received ADT for longer than 12 months (HR 1.36, 95% CI 1.07-1.72), but not for shorter durations (HR 1.06, 95% CI 0.77-1.28). For Alzheimer disease, the higher magnitude of risk that was observed with longer duration therapy was not statistically significant (HR 1.39, 95% CI 0.69-2.79).

Updated year 2019 guidelines for management of prostate cancer in older patients from the International Society of Geriatric Oncology (SIOP) suggest that clinicians discuss the risk of neurocognitive dysfunction with older patients with prostate cancer who are considering use of ADT [108]. However, in our view, ADT clearly benefits males with metastatic hormone sensitive or locally advanced prostate cancer, and we do not consider that the risk of neurocognitive dysfunction, if it exists, should form the basis for refusing ADT in these settings. (See "Prostate cancer in older males".)

Treatment with ADT has also been associated with an increased incidence of depression and anxiety. In a systematic review and meta-analysis that included results from 18 studies with 169,000 individuals, there was a 41 percent increase in the risk of depression [109]. Anxiety was increased in an analysis of 79,000 males aged ≥66 years treated with ADT (three-year cumulative incidence 4.1 versus 3.5 percent) [110].

ROLE OF STRUCTURED EXERCISE — For most men receiving ADT for prostate cancer, we suggest moderate exercise, to include three or more hours of aerobic activity weekly, plus resistance training and weight-bearing exercises.

Structured exercise programs have been studied in a number of trials as a way to prevent or ameliorate ADT-related complications. Overall, there is good evidence that exercise can provide benefit for muscle mass and strength, cardiorespiratory fitness, fatigue and declining physical function, less robust evidence for exercise-induced improvements in bone loss, prevention of falls and fractures, sexual dysfunction, and anxiety and depression. The following data are available:

●A systematic review analyzed the impact of various aerobic and/or resistance training programs in males being treated with ADT for prostate cancer in 10 studies that were published between 1980 and 2013 [111]. The studies analyzed included five that were randomized trials and five that evaluated males pre- and postexercise program. Although the specific exercise interventions varied, exercise resulted in substantial improvements in muscular strength, cardiorespiratory fitness, functional task performance, lean body mass, and fatigue in males on ADT. (See "Cancer-related fatigue: Treatment", section on 'Exercise'.)

●Resistance exercise training and high-impact loading exercises may also help to mitigate ADT-related bone loss, improving bone health, and reducing fracture risk, but the data are inconsistent [112]. While two systematic reviews and meta-analyses of the most effective method for preventing osteoporosis in males receiving ADT for prostate cancer concluded that exercise alone was insufficient to address bone loss [113,114], improvements in, or preservation of bone mineral density for males with prostate cancer receiving ADT who participated in an exercise intervention (endurance training, resistance exercises, impact loading exercise) has been shown in at least three contemporary trials [115-117].

●Evidence from one systematic review [114] and one small randomized trial [118] suggest that exercise can help to maintain or improve sexual health following prostate cancer treatment.

●At least six systematic reviews have concluded that physical activity improves quality of life, including mental health domains [111,119-124].

There currently are inadequate data to define the optimal exercise regimen. In one analysis of 21 trials involving 1748 patients with prostate cancer, structured resistance-based exercise improved fat mass, lean mass, and fitness outcomes including muscle strength with no change in body mass index or PSA [125]. Meta-regression indicated no association between exercise type, duration, weekly volume or intensity on any of the primary outcomes. There was an association between exercise intensity and chest press muscle strength favoring moderate intensity, but not in other endpoints.

These data are consistent with published guidelines, which generally endorse moderate exercise for individuals with cancer [126].

ALTERNATIVE HORMONE STRATEGIES — Because of the side effects associated with ADT and their impact on quality of life, alternative hormone strategies such as antiandrogen monotherapy or intermittent ADT may occasionally be required to minimize these problems. However, the potential benefit from the use of these approaches should not be allowed to compromise disease control.

Antiandrogen monotherapy — Antiandrogen monotherapy has been advocated as an alternative to ADT as a way to avoid some of the side effects associated with medical or surgical castration, but this approach is not considered an accepted alternative in current management guidelines. In two small randomized trials, the antiandrogen bicalutamide increased bone density at multiple sites, while medical castration with a gonadotropin-releasing hormone (GnRH) agonist was associated with a decrease in bone density [127,128].

However, the use of antiandrogen monotherapy appears to be associated with a decrease in antitumor efficacy in multiple randomized clinical trials when compared with medical castration. A meta-analysis that included 2717 patients found a trend toward shorter overall survival with antiandrogen monotherapy compared with castration that approached, but did not reach, statistical significance (hazard ratio [HR] 1.22, 95% CI 0.99-1.40) [129]. Antiandrogen monotherapy may be a reasonable option for carefully selected males with well-differentiated tumors and a prostate-specific antigen (PSA)-only recurrence who wish to minimize side effects during therapy. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Continuous versus intermittent ADT'.)

Intermittent androgen deprivation — Intermittent androgen deprivation (IAD) refers to cyclic administration of GnRH agonists with temporary withdrawal of therapy once a response has been achieved. Treatment is then reinitiated when there is evidence of progression.

●For males with metastatic disease, a phase III trial found that IAD could not be considered noninferior compared with continuous ADT in terms of overall survival [130]. However, a preliminary analysis of quality of life suggested an improvement in sexual functioning; additional analyses are ongoing [131]. Based upon the available evidence, IAD cannot be recommended in this setting. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer", section on 'Intermittent versus continuous ADT'.)

●For males whose only evidence of disseminated disease is an elevated serum PSA, a phase III trial found that males treated with IAD had more disease-related deaths but fewer unrelated deaths compared with continuous ADT [132]. Patients treated with IAD had a reduced frequency of hot flashes, but there were no other differences in adverse events. IAD cannot be routinely recommended and patients must be fully counseled that there are limited data to support a benefit for this approach. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Continuous versus intermittent ADT'.)

SUMMARY AND RECOMMENDATIONS — Androgen deprivation therapy (ADT) is the main therapeutic approach for males with metastatic prostate cancer and is frequently used in combination with other treatments (including androgen synthesis inhibitors and androgen receptor antagonists) in selected patients with locoregional disease. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)

●Sexual dysfunction – Most males who are potent prior to therapy develop sexual dysfunction when treated with continuous ADT. While not inevitable, loss of libido develops in most males receiving gonadotropin releasing hormone (GnRH) agonists, usually within the first several months, and erectile dysfunction typically follows. (See 'Sexual dysfunction' above.)

●Osteoporosis and risk of bone fractures – ADT increases bone turnover and decreases bone mineral density, thereby increasing the risk of clinical bone fractures. (See 'Osteoporosis and bone fractures' above.)

•For all males beginning long-term ADT, we recommend dietary calcium intake (food and supplements) of 1000 to 1200 mg daily and supplemental vitamin D 800 to 1000 international units daily, as well as weight bearing exercise, decreased alcohol consumption, and smoking cessation. (See 'Preventive strategies' above and 'Role of structured exercise' above.)

•In males without bone metastases who are treated with long-term ADT, an osteoclast inhibitor such as a bisphosphonate or denosumab can decrease bone turnover and increase bone mineral density. An osteoclast inhibitor may be offered to reduce the risk of fracture in the setting of osteoporosis (T scores of -2.5 or less in the femoral neck, total hip, or lumbar spine), or when the 10-year probability of hip fracture (using the FRAX algorithm or a different tool) is ≥3 percent or the 10-year probability of a major osteoporosis-related fracture is ≥20 percent.

When an osteoclast inhibitor is indicated, for most men, we suggest denosumab (60 mg subcutaneously every six months) rather than a bisphosphonate (Grade 2B). (See 'Osteoclast inhibitors' above.)

The optimal duration is not known. For most men, we continue an osteoclast inhibitor for up to 36 months.

●Cardiovascular disease and diabetes – The most common noncancer-related cause of death among prostate cancer survivors is cardiovascular disease (CVD). There are conflicting results regarding the impact of long-term ADT on CVD risk, but few trials were designed to specifically answer that question. However, taken together, the majority of studies, mainly observational, suggest that ADT, as well as other forms of hormone therapy such as androgen synthesis inhibitors and androgen receptor antagonists, increase cardiovascular morbidity and/or mortality, especially in those with pre-existing CVD. These risks are sufficient to support counseling and risk reduction measures for males initiating ADT. The potential benefits for males in whom long-term ADT is being considered as part of the management of their prostate cancer should always be balanced against any potential harm from adverse cardiovascular events. (See 'Potential cardiovascular harm' above.)

●Decreased muscle and increased fat – Reduced testosterone levels associated with ADT result in a decrease in lean body mass and an increase in subcutaneous adipose tissue. Most of these changes occur during the first 18 months of treatment. (See 'Body composition and metabolism' above.)

●Cognitive dysfunction – A growing body of evidence supports a link between ADT and cognitive dysfunction, including Alzheimer disease and other forms of dementia, although the data are inconsistent. Nevertheless, updated year 2019 guidelines from the International Society of Geriatric Oncology (SIOP) suggest that clinicians discuss the risk of cognitive dysfunction with older males with prostate cancer who are considering the use of ADT. (See 'Emotional and cognitive changes' above.)

●Other quality of life issues – ADT may result in a number of other changes that can adversely affect quality of life. These include:

•Hot flashes. The optimal management of vasomotor symptoms is unclear. We typically start with a selective serotonin reuptake inhibitor or oxybutynin and reserve hormonal treatment (estrogen, megestrol) for refractory cases. (See 'Vasomotor symptoms' above.)

•Lack of energy, which may only partially be related to anemia or emotional and cognitive issues. (See 'Fatigue' above and 'Anemia' above.)

•Changes in body image, including gynecomastia, decreased penile and testicular size, and thinning of body hair. (See 'Issues related to body image' above.)

•Decreased cognitive performance or depression, although these changes may be related to aging and disease rather than ADT. (See 'Emotional and cognitive changes' above.)

●Role of exercise – For most males, we suggest three or more hours of aerobic activity weekly in conjunction with resistance training and weight bearing exercises. (See 'Role of structured exercise' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges E David Crawford, MD, who contributed to an earlier version of this topic review.

We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.