#63764: Men's Health Issues

Risky behavior affects health and well-being beginning at a young age. The overall rate of fatal injuries is approximately two times higher among boys than girls (0 to 19 years of age) [22]. Motor vehicle accidents are the leading cause of death for both genders, especially in the age category of teenage drivers (15 to 19 years of age). Although not all of these injuries and deaths are related to risky behavior, Youth Risk Behavior Surveillance (YRBS) data indicate that many of them are related; other risky behaviors identified in this survey are related to morbidity and mortality in adolescence and are also contributors to habits that affect health in adulthood. The 2019 YRBS showed that the rate of risky behaviors is predominantly higher among male respondents (Table 3) [23]. The rates of many of these behaviors continued to be higher among male adults (Table 4), which plays a role in premature deaths among men [1,24].

Men's predilection for risky behavior is reflected in the high rate of unintentional injury, which accounts for 7.4% of deaths among men (compared with 4.3% for women) [7,8]. There is wide variation in this rate across race/ethnicity, with much higher rates among American Indian/Alaska Native men (13.7%) and Hispanic/Latino men (11.3%) [11]. The trend of more fatal unintentional injuries among men is evident in countries around the world; an analysis of accidental deaths among men and women in 36 countries showed higher rates for men [2]. Across all age-groups, the rates were higher in the United States than the median rate for all countries. Accidental deaths are related primarily to motor vehicle injuries, violence, and occupation, and the rates in all categories are higher for men than for women. The rate of death related to motor vehicle injuries for men is slightly higher than for women (16.0 vs. 6.3 per 100,000), and the percentage of fatal unintentional firearm-related injuries deaths occur overwhelmingly more often among men (82.7%) than women (17.3%) [25]. Similarly, fatal occupational injuries occur predominantly in men (57% vs. 6%) [26].

Substance misuse plays a significant role in both risky behavior and the development of chronic diseases. As demonstrated by the YRBS data, the use of tobacco, alcohol, and illicit drugs begins in the teenage years, with more boys than girls engaging in such behavior [23]. One exception appears to be prescription opioids, which are more likely to be misused by female adolescents than male adolescents. Among adults, substance misuse continues to be more prevalent among men than women [27]. Misuse of tobacco, alcohol, and drugs are associated with high rates of unintentional injuries, violence, STIs, and masking of depression [25,28,29,30].

The rate of tobacco use among men has declined over the past decade, but the rate continues to be higher than that among women [31]. The Centers for Disease Control and Prevention (CDC) estimates that men who smoke increase their risk of death from lung cancer by 25 times, with tobacco being the cause of approximately 90% of all lung cancer deaths in men [32]. In addition, smoking is a significant risk factor for many cancers, especially those that are more prevalent among men, and is linked to a two to four times greater likelihood of cardiovascular disease or stroke [32].

Excessive alcohol use is the third leading lifestyle-related cause of death for both men and women, and long-term use of alcohol is a well-recognized contributor to several chronic diseases [33]. Even consumption that is considered to be less than "hazardous" (three to five drinks per day) has been associated with increased morbidity and mortality [34].

Help- and information-seeking behavior related to male gender identity is another factor that affects men's health. In general, men are reluctant to seek health care or talk about their health because they see such help-seeking as a sign of weakness or vulnerability and a threat to their masculinity [4,35,36]. These reports are substantiated by data on utilization of healthcare resources, which indicate that men have fewer office visits to doctors or other health care professional than women; in 2018, 23.9% of men had no office visits, compared with 12.5% of women [37]. In addition, men are more likely to lack a usual source of health care (18.6% vs. 10.7%) [37]. Men have reported several reasons for not having a usual source of care, and the reasons vary among racial/ethnic populations [39]. The reason given most often is that they are seldom or never sick, and this may be related to men's perceptions of invulnerability [39,40]. Other reasons given include not finding time and not being able to take time away from work [38]. Cultural values, such as machismo, lead many Hispanic men to avoid health care until there is no other choice [40]. This may contribute to the low rate of healthcare use among Hispanic men, which is the lowest across racial/ethnic populations [40]. Other reasons for the low use of healthcare services among Hispanic men are lack of health insurance, low understanding of the healthcare system, fear of poor functional outcomes, and a low perception of the quality of the patient-clinician interaction [40]. In the Black population, men have reported to avoid healthcare services because of fears and concerns about their negative health behaviors and history [41].

Lower rates of healthcare use among men have a negative impact on preventive care, and rates of routine health assessments and recommended vaccinations and screening procedures have been lower among men than among women [42]. Several factors contribute to the avoidance of screening tests, including men's belief that they are healthy; their focus on their present, rather than future, health; the need for more information about the screening procedure; and other issues related to masculinity [42]. For example, Black men have reported avoiding screening for prostate and colorectal cancer because they see these procedures as "violating their manhood" [41,43].

Among men who do have physician office visits, many are not forthcoming about symptoms or information they seek [44]. Because of their traditional discomfort with expressing feelings and emotions, they are less likely to seek help for psychosocial problems or emotional symptoms [17,45]. Men tend to be more motivated to seek health care for male-oriented conditions, such as erectile dysfunction or sports-related injuries, or when their health or symptoms interfere with their routine activities [45].

Effective communication is essential in the healthcare setting but can be challenged by several factors. Specific challenges in communicating with men are related to male gender identity as well as to low health literacy and language and cultural barriers.

Male Gender Identity

Men's beliefs about masculinity and traditional male roles affect health communication, and healthcare practitioners should consider male-specific beliefs and perceptions when communicating with male patients. For example, because men tend to focus on present rather than future health, concepts of fear, wellness, and longevity often do not work well in health messages [40]. Instead, healthcare practitioners should focus more on "masculine" concepts, such as strength, safety, and performance, all of which tie into men's perceptions of their roles as providers and protectors. To address men's reluctance to admit pain, practitioners should avoid asking questions such as "Do you have pain?" and instead use phrases such as "Most men I see with this condition say they have quite a bit of pain—what about you?" Using numbers/statistics and metaphors relating the body to a machine may also help to communicate effectively by addressing male gender identity. In addition, practitioners should be nonjudgmental about their male patients' health and risk behaviors and develop open lines of communication to encourage them to express their health concerns.

Health Literacy, Language, and Culture

According to the National Assessment of Health Literacy, 14% of individuals in the United States have "below basic" health literacy, which means they lack the ability to understand health information and make informed health decisions [21,46]. The findings of the assessment demonstrated that the rate of "below basic" literacy was higher among men than women (16% vs. 12%) [21]. Although the rate of "basic" health literacy was similar for men and women, rates of "intermediate" and "proficient" health literacy were lower for men [21]. Similar rates of health literacy have been found in subsequent studies, with rates of adequate health literacy consistently lower among men and even lower among non-White men [47,48]. In one study, the rate of adequate health literacy was 48% among White men (compared with 63% among White women) and 23% among non-White men (compared with 30% among non-White women) [48].

Recognition of the importance of adequate health literacy to good health outcomes has led to assessment of health literacy being deemed "the newest vital sign," with development of an assessment tool by that name [48,49]. The Newest Vital Sign (NVS) tool has been shown to demonstrate the health literacy status in fewer than three minutes, with results that are comparable to those of more extensive literacy tests [48]. Clinicians are encouraged to use this tool to assess the literacy of their patients, especially those of racial/ethnic minorities, and to adapt discussions to literacy levels and provide low-literacy educational resources. Compounding health literacy are language and cultural barriers, which have the potential for far-reaching effects, given the growing percentages of racial/ethnic populations. According to U.S. Census Bureau data from 2020, 21.5% of the American population speak a language other than English, and of those, 8.2% speak English less than "very well" [50]. Clinicians should ask their patients what language they prefer for their medical care information, as some individuals prefer their native language even though they have said they can understand and discuss symptoms in English [51]. Translation services should be provided for patients who do not understand the clinician's language. "Ad hoc" interpreters (family members, friends, bilingual staff members) are often used instead of professional interpreters for a variety of reasons, including convenience and cost. However, clinicians should check with their state's health officials about the use of ad hoc interpreters, as several states have laws about who can interpret medical information for a patient [52]. Even when allowed by law, the use of a patient's family member or friend as an interpreter should be avoided, as the patient may not be as forthcoming with information and the family member or friend may not remain objective [52]. Children should especially be avoided as interpreters, as their understanding of medical language is limited and they may filter information to protect their parents or other adult family members [52]. Individuals with limited English language skills have actually indicated a preference for professional interpreters rather than family members [53].

Most important, perhaps, is the fact that clinical consequences are more likely with ad hoc interpreters than with professional interpreters [54]. A systematic review of the literature showed that the use of professional interpreters facilitates a broader understanding and leads to better clinical care than the use of ad hoc interpreters, and many studies have demonstrated that the lack of an interpreter for patients with limited English proficiency compromises the quality of care and that the use of professional interpreters improves communication (errors and comprehension), utilization, clinical outcomes, and patient satisfaction with care [55,56].

Clinicians should use plain language in their discussions with their patients who have low literacy or limited English proficiency. They should ask them to repeat pertinent information in their own words to confirm understanding, and reinforcement with the use of low-literacy or translated educational materials may be helpful.

The prevalence of prostatitis has been reported to be approximately 8%, ranging from about 2% to 10% [66]. In patients younger than 35 years of age, the most common variant of the syndrome is acute bacterial prostatitis. Among older patients, nonbacterial prostatitis (NIH types II and IV) is the most common [67]. The results of studies have suggested that the symptoms of prostatitis increase the risk for BPH, lower urinary tract symptoms, and prostate cancer [66].

The cause of acute and chronic bacterial prostatitis is usually lower urinary tract infection with gram-negative organisms, most notably Escherichia coli [60,61]. Most men with prostatitis, however, have no evidence of urinary tract infection [61]. Other causes may include a primary voiding dysfunction problem; presence of Chlamydia trachomatis, Ureaplasma species, or Trichomonas vaginalis; uncommon organisms (e.g., Mycobacterium tuberculosis); HIV; cytomegalovirus; and inflammatory conditions (e.g., sarcoidosis) [67].

The risk factors for prostatitis have not been clearly defined. In a study of 463 men with chronic prostatitis/chronic pelvic pain and 121 asymptomatic age-matched controls, the lifetime prevalence of several self-reported medical conditions were significantly greater among men with prostatitis, specifically neurologic disease (41% vs. 14%); hematopoietic, lymphatic, or infectious disease (41% vs. 20%); psychiatric conditions (29% vs. 11%); nonspecific urethritis (12% vs. 4%); and cardiovascular disease (11% vs. 2%) [68]. The authors of that study noted that more research is needed to determine if such conditions contribute to the pathogenesis of chronic prostatitis/chronic pelvic pain. A history of STIs has been noted to be associated with an increased risk for prostatitis symptoms [66].

Several other urogenital conditions should be considered in the differential diagnosis of prostatitis, including BPH, cystitis, erectile dysfunction, prostate cancer, STI, and urolithiasis [69,70,353]. Of the four types of prostatitis, acute bacterial prostatitis is the easiest to diagnose and treat. Patients with acute prostatitis present with irritative symptoms (dysuria, urinary frequency, and urgency), and obstructive voiding symptoms (hesitancy, incomplete voiding, straining to urinate); the syndrome may also include signs of systemic infection, such as chills and fever [70,353]. Pain most commonly occurs in the prostate/perineum and scrotum and/or testes; pain referred to the penis or lower back also occurs [70]. Urine samples should be cultured to determine the causative micro-organism.

Chronic bacterial prostatitis is distinguished from acute disease by time, being defined by persistence of symptoms for at least three months, and systemic symptoms are usually absent [58,70]. The condition should be suspected when the patient's history includes recurrent urinary tract infections, usually with the same bacterial strain [61]. The patient should complete an NIH Chronic Prostatitis Symptom Index to obtain a baseline score for the severity of symptoms [59]. This index includes questions related to three domains—pain, urinary symptoms, and quality-of-life impact—and has been shown to be a valid, reliable tool for measuring prostatitis symptoms [70,71]. Computed tomography (CT) can determine if there are structural or functional abnormalities of the urinary tract [60,61].

The diagnostic evaluation for acute or chronic bacterial prostatitis includes a urinalysis and urine culture [61,70]. When acute prostatitis is suspected, digital rectal exam should be performed gently so as not to precipitate bacteremia and sepsis. The prostate will usually be enlarged, boggy, and tender, though absence of tenderness on initial examination does not exclude the diagnosis of prostatitis. There are no standardized criteria for the diagnosis of chronic prostatitis/chronic pelvic pain syndrome [61,69]. The Meares-Stamey four-glass test was developed in the late 1960s to screen for prostatitis; the test involves collecting urine samples before and after prostatic massage, as well as collecting prostatic fluid during the massage [72]. Cultures are done on the specimens, and the presence of micro-organisms in the prostatic fluid indicates chronic prostatitis [61,72]. The accuracy and reliability of the test has not been established, and studies have shown that the test is not used often, even by urologists [61,69]. There is also a two-glass version of the test that has correlated well with the four-glass version, but that, too, is not often used [61]. The Meares-Stamey test is not helpful for diagnosing chronic pelvic pain syndrome. Men who have substantial lower urinary tract symptoms and pelvic pain may be candidates for urodynamic evaluation, as voiding dysfunction is common in such cases [61].

No U.S.-based guidelines have been developed, to date, for the treatment of prostatitis, but the European Association of Urology included recommendations for the treatment of prostatitis in its 2008 guidelines on the management of urinary and male genital tract infections [70]. Most patients with bacterial prostatitis can be managed as outpatients with oral antibiotics (e.g., a fluoroquinolone or trimethoprim-sulfamethoxazole) and close follow-up. Hospitalization and broad-spectrum parenteral antibiotics (e.g., piperacillin/tazobactam or ceftriaxone plus ciprofloxacin) should be considered in patients who are systemically ill, are unable to urinate voluntarily, or have risk factors for antimicrobial resistance [70,353]. An aminoglycoside may be added to any of these antibiotics as initial therapy [70]. A fluoroquinolone is the preferred choice for oral therapy because of the spectrum of antibacterial activity and good penetration into prostatic tissue. Duration of antibiotic treatment should be individualized in relation to duration of symptoms and clinical response; 10 to 14 days will suffice for most acute cases of prostatitis, but 21 to 28 days may be required for those with a more subacute onset or slow resolution of symptoms.

For chronic bacterial prostatitis, the choice of antibiotic depends on the sensitivity of the micro-organism, and the antibiotic should be one that penetrates the prostate [61]. The typical first-line treatment is a four- to six-week course of a fluoroquinolone, and treatment is usually more effective if begun soon after symptoms begin [61,70,73,74]. Trimethoprim-sulfamethoxazole may also be considered [70].

Treatment for chronic prostatitis/chronic pelvic pain syndrome is complex; evidence on the effect of traditional treatment options has been conflicting, and treatment options are often not effective in managing symptoms. The most commonly studied pharmacologic options are antibiotics, alpha-blockers, anti-inflammatory agents, steroid inhibitors, and muscle relaxants, and often, a combination of these agents provides the most effective management [74]. Antibiotics, particularly fluoroquinolones, have improved symptoms, even in some patients in whom a bacterial cause has not been identified [74]. Studies have shown that an antibiotic and an alpha-blocker is more effective than an antibiotic alone [70]. A meta-analysis showed that alpha-blockers, antibiotics, and a combination of the two all significantly improve symptoms (according to scores on the NIH Chronic Prostatitis Symptom Index), with the combination providing the greatest benefit [75]. However, another meta-analysis showed that these same agents—alone and in combination—were not associated with a statistically or clinically significant decrease in symptom scores [76]. The combination of an alpha-blocker (doxazosin) with an anti-inflammatory agent (ibuprofen) and a muscle relaxant (thiocolchicoside) led to a statistically and clinically significant reduction in the total score on the NIH Chronic Prostatitis Symptom Index in one systematic review; according to the findings of another systematic review, the three-agent combination was not superior to monotherapy [74,76]. Researchers have cautioned that publication bias may cause overestimation of the beneficial effects of alpha-blockers and that the placebo effect has been significant in many studies [75,76]. Addressing a hypothesis that the pain related to chronic prostatitis may have a neuropathic origin, pregabalin has been evaluated as a management strategy, but a systematic review found that the drug did not improve symptoms and caused side effects in a large percentage of men [77].

Trigger point release/paradoxical relaxation training to release trigger points in the pelvic floor musculature was found to significantly improve symptoms in men who had chronic prostatitis/chronic pelvic pain syndrome [63]. Seventy percent of the men in the study had a significant decrease in the score on the NIH Chronic Prostatitis Symptom Index, with improvement in pelvic pain, urinary symptoms, libido, ejaculatory pain, and erectile and ejaculatory dysfunction [63].

The prevalence of BPH increases with age, from approximately 8% of men 31 to 40 years of age to approximately 90% of men in their 80s [80,81]. Risk factors identified in one study included increased age, prostatic volume, and peak urinary flow rate [82]. Other factors, including some that are modifiable, include obesity, diet, dyslipidemia, hypertension, alcohol use, and smoking [83]. The relative risk for BPH (and common comorbidities) may be higher for Black and Hispanic men than for White men and is thought to be related in part to genetic differences based on race/ethnicity; however, observational studies have produced variable results [81,84].

As previously noted, distinguishing BPH from other prostate-related diseases is often difficult, as lower urinary tract symptoms are similar for a variety of conditions. The American Urological Association (AUA) evidence-based guidelines for the management of BPH, updated in 2021, recommend the following tests [78]:

The National Institute for Health and Care Excellence recommends offering men with lower urinary tract symptoms information, advice, and time at initial assessment to decide if they wish to have prostate-specific antigen (PSA) testing if their symptoms are suggestive of benign prostatic enlargement.

(https://www.nice.org.uk/guidance/cg97 Last Accessed: June 6, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

Determination of a serum PSA level is also recommended if the patient has a life expectancy of more than 10 years (and the diagnosis of prostate cancer will alter management), and a frequency-volume chart is recommended if substantial nocturia is a predominant symptom [78]. Routine measurement of a serum creatinine level is not recommended as part of the initial evaluation of men with lower urinary tract symptoms related to BPH [78].

In obtaining a history, clinicians should ask about urinary tract symptoms, sexual function, previous surgical procedures, and general health issues in an attempt to identify other causes of voiding dysfunction or comorbidities that may complicate treatment. Diabetes, cerebrovascular disease, and Parkinson disease can cause urinary symptoms secondary to neurogenic bladder, and STIs or trauma may cause urethral stricture [85]. It may be appropriate to have the patient keep a diary of voiding habits (frequency, volume, etc.) [78].

Assessment of symptoms is an integral aspect of the initial evaluation for BPH, as it helps to determine the severity of disease. The International Prostate Symptom Score (IPSS) (previously called the AUA Symptom Index) is a validated, self-administered symptom frequency and severity assessment questionnaire originally developed by the AUA Measurement Committee [78]. The IPSS is a widely available, seven-question assessment tool that has been validated for clarity, test/retest reliability, internal consistency, and criteria strength [78,86]. The IPSS addresses [86]:

Symptoms should be discussed with the patient and questions addressed as necessary [78].

The physical examination should include a digital rectal examination (DRE) to determine the size, consistency, and shape of the prostate [78]. A symmetrically firm and enlarged prostate by DRE is indicative of BPH [79]. The true size of the prostate is often underestimated by DRE compared with transrectal ultrasound [78]. Examination should also include neurologic evaluation to assess the patient's general mental status, ambulatory status, neuromuscular function of the lower extremities, and anal sphincter tone [78].

A urinalysis (dipstick test) to screen for hematuria, proteinuria, pyuria, and other abnormalities can help to rule out such conditions as bladder cancer, carcinoma in situ of the bladder, urinary tract infection, urethral strictures, distal urethral stones, and bladder stones, which are less likely if the results of urinalysis are normal [78].

Optional studies that may be used to confirm the diagnosis or evaluate the presence and severity of BPH include post-voiding residual urine measurement (PVR) and uroflowmetry studies [78]. A PVR is useful in determining a baseline ability of the bladder to empty and detecting severe urinary retention that may not be amenable to medical therapy. Uroflowmetry is a simple, office-based procedure, an adjunct to evaluation of lower urinary tract symptoms and probability of bladder outlet obstruction. Flow rates of <10 mL/second have shown a specificity of 70%, a positive predictive value of 70%, and a sensitivity of 47% for bladder outlet obstruction [78].

According to the AUA guideline, the benefits, risks, and costs of treatment options should be discussed with patients who have moderate-to-severe symptoms (IPSS score of 8 or more) who are bothered enough by the symptoms to consider therapy [78]. The treatment options for BPH include:

The AUA guideline recommends watchful waiting as the preferred approach for men who have mild symptoms (a score of less than 8 on the AUA Symptom Index) [78]. This approach may also be taken for men with moderate-to-severe symptoms (score of 8 or more) who are not bothered by the symptoms and have no complications [87]. Watchful waiting should include yearly evaluations similar to the initial one [78]. Lifestyle changes and behavioral interventions are considered reasonable first-line treatments for all patients. Symptoms may be reduced by avoiding decongestants and antihistamines, decreasing fluid intake (and avoiding caffeine and alcohol) prior to bedtime, and increasing physical activity and weight loss [78].

AUA guidelines recommend offering monotherapy with an alpha-blocker as initial preferred option for patients with bothersome -to-severe symptoms [78]. Clinicians should consider performing a PVR measurement or uroflowmetry prior to treatment intervention. Five alpha-blockers have FDA-approved indications for BPH (Table 5). Clinical studies show that all five of these drugs—alfuzosin, doxazosin, tamsulosin, terazosin, and silodosin—are equally effective in terms of symptom relief and expected range of improvement in symptom index (IPSS) score [78]. The choice of alpha-blocker should be based on the patient's age and comorbidities, and different adverse event profiles (e.g., ejaculatory dysfunction, changes in blood pressure).

The adverse events associated with alpha-blockers are orthostatic hypotension, dizziness, fatigue (asthenia), and ejaculatory problems [78]. These drugs should not be used for men who are taking medication for erectile dysfunction, as the interaction between the two drugs can cause profound hypotension [79]. Alpha-blocker agent use also has been associated with the rare complication of intraoperative floppy iris syndrome; patients anticipating cataract surgery should be informed of the risks and advised to discuss these risks with their ophthalmologist [78].

Two 5-alpha reductase inhibitors, finasteride and dutasteride, are also approved for treatment of BPH-related symptoms and are recommended options in the AUA guideline [78]. This is less effective than therapy with alpha-adrenergic antagonists for relieving lower urinary tract symptoms, leading to an average improvement of 3 points on the AUA Symptom Index [78]. The advantage of 5-alpha reductase inhibitors is that they also act to prevent progression of disease and reduce the size of the prostate. As such, the AUA notes that these drugs should be used only for men who have evidence of prostatic enlargement [78]. Men should be made aware of the need for long-term therapy with either of these drugs, and clinicians should also discuss the possible adverse events, which include decreased libido, ejaculatory dysfunction, and erectile dysfunction. These effects usually resolve within one year [78,79].

In 2011, the FDA issued a safety announcement that the Warnings and Precautions section of the labels of 5-alpha reductase inhibitors was revised to include new safety information about the increased risk of a diagnosis of high-grade prostate cancer [92]. The revision came after FDA review of two prostate cancer prevention trials, in which finasteride and dutasteride reduced the incidence of lower risk forms of prostate cancer but were associated with an increased incidence of high-grade prostate cancer [92].

The AUA guideline also supports the use of combination therapy with an alpha-blocker and a 5-alpha reductase inhibitor for men with lower urinary tract symptoms and evidence of prostate enlargement, as demonstrated on volume measurement, PSA level as a proxy for volume, or on DRE [78]. A fixed-dose combination of dutasteride (0.5 mg) and tamsulosin (0.4 mg) is available, and the results at four years showed that, for men with a baseline prostate volume ≥40 mL and PSA level of ≥1.5 ng/mL, the combination led to greater reductions in the relative risk of clinical progression, acute urinary retention, or BPH-related surgery than either drug alone [93].

The AUA guideline also notes that anticholinergic agents are appropriate and effective options for managing BPH-related symptoms in men who do not have an elevated post-void residual and when symptoms are predominantly irritative [78].

Phosphodiesterase type-5 inhibitors have also been shown to be effective for reducing the symptoms associated with BPH [94]. This class of drugs also offers advantages over other drugs in its rapid onset of action, fewer adverse events, and enhanced sexual function [94]. Potential adverse events include back pain, dyspepsia, headache, and dizziness [95]. In 2011, the first phosphodiesterase type-5 inhibitor—tadalafil—was approved by the FDA for BPH-related symptoms, with indications for symptoms in men who have prostate enlargement, with or without erectile dysfunction [95]. Before prescribing tadalafil, clinicians should ensure that patients are not taking drugs that interact with tadalafil, such as nonselective alpha-blockers, nitrates, and cytochrome P450 inhibitors [95].

Saw palmetto, a commonly used alternative therapy for BPH, is not recommended for BPH-related symptoms, as the most recent data have shown no clinically meaningful effect on symptoms [78].

Minimally invasive therapies such as transurethral needle ablation and transurethral microwave thermotherapy are treatment options for men with bothersome moderate or severe symptoms [78]. However, the AUA guideline notes that, although these therapies improve symptoms, flow rate, and quality of life, the outcomes are not as good as those after transurethral resection of the prostate [78].

Surgical interventions are typically reserved for worsening disease and severe symptoms that do not respond to medical treatment. The AUA guideline recommends surgery for patients with renal insufficiency secondary to BPH, refractory urinary retention secondary to BPH, recurrent urinary tract infections, bladder stones, or gross hematuria due to BPH; or symptoms refractory to other therapies [78]. The most common procedure is transurethral resection of the prostate, which comprises 90% of all prostate surgeries done for BPH and is the benchmark for therapy [78,96]. Open prostatectomy; transurethral laser ablation or enucleation; laser resection; photoselective vaporization; and transurethral incision, vaporization, and resection are other surgical options, and the selection of intervention is based on the surgeon's experience, the patient's anatomy, and a discussion of the benefits and risk of complications [78].

In 2022, the estimated projected number of new prostate cancer diagnoses was 268,490, with 34,500 prostate cancer-related deaths [16]. The majority of newly diagnosed prostate cancers have localized disease. The highest incidence is found among Black men (172.6 per 100,000), and the lowest is among Asian American and Pacific Islander men (55.0 per 100,000) [16]. The death rate related to prostate cancer is also highest for Black men, with a rate that is more than twice that for men of all other races/ethnicities (37.9 per 100,000 vs. 17.8 [White], 21.0 [American Indian and Alaska Native], 15.6 [Hispanic/Latino], and 8.6 [Asian American and Pacific Islander]) [16]. The mortality rate associated with prostate cancer decreased 4.1% per year between 2009 and 2019, in part, because of improvements in early detection and treatment [16].

The known risk factors for prostate cancer are advanced age, Black race, and a family history of the disease (especially when diagnosed at a younger age) [16,97]. The risk for prostate cancer may also be increased for men with symptoms of prostatitis [66].

Several studies have been undertaken to determine the efficacy of chemoprevention agents and dietary supplements to reduce the risk of prostate cancer. The chemoprevention agents evaluated belong to the class of 5-alpha reductase inhibitors, a class of drugs approved for the treatment of BPH. One drug in this class, finasteride, was evaluated in the first large-scale chemoprevention study, the Prostate Cancer Prevention Trial (PCPT), a seven-year study involving nearly 19,000 men 55 years of age or older. In that study, finasteride significantly reduced the prevalence of prostate cancer (18% vs. 24% for the placebo group) [98]. Dutasteride was shown to decrease the risk of prostate cancer in the REDUCE trial, and extended follow-up indicated a low rate of new prostate cancer diagnoses [99,100]. The initial results of the PCPT and REDUCE trials led the American Society of Clinical Oncology (ASCO) and the AUA to develop a joint guideline recommending finasteride and dutasteride for the prevention of prostate cancer [90]. However, reanalysis of the results of the trials showed that the risk for high-grade prostate cancer was increased and the reduction in prostate cancer risk was seen primarily for less fatal subtypes of prostate cancer that are often not treated [100,101]. In 2011, the FDA decided against approving the two drugs for the prevention of prostate cancer, noting that the risk-benefit profile is not favorable for chemoprevention [91,101,102]. As stated earlier, the FDA revised the labels of all 5-alpha reductase inhibitors to note the increased risk of higher-grade prostate cancer associated with the drugs [92]. The ASCO/AUA guideline was withdrawn, and experts have called for more research to determine whether 5-alpha reductase inhibitors have a role in the prevention of prostate cancer [101,102,103].

Dietary supplements have not been shown to substantially reduce the prevalence of prostate cancer. In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized study of more than 35,000 men, neither of those two vitamins, alone or in combination, prevented prostate cancer in relatively healthy men [104]. A subsequent phase III trial showed that selenium supplementation had no effect on prostate cancer risk among men with high-grade prostatic intraepithelial neoplasia [105]. There is insufficient evidence for the routine recommendation of other dietary supplements, such as soy, milk thistle, omega fatty acids, lycopene, or green tea, to prevent prostate cancer [106,107,359].

There is no question that available screening methods and enhanced awareness has led to an increased number of men in whom prostate cancer is diagnosed at an earlier stage. The primary benefit of screening is a lower stage and grade of cancer at the time of diagnosis, and the high rate of localized disease at the time of diagnosis (92% to 96%) reflects, in part, the increased number of cancers that are detected earlier through screening [102,108,109]. Despite this benefit, an effect of screening on mortality has not been clearly demonstrated. After 13 years of follow-up in the National Cancer Institute's Prostate, Lung, Colon, and Ovary (PLCO) trial, there was no benefit of annual screening on mortality [110]. A meta-analysis (five randomized controlled trials) similarly demonstrated no effect of screening on prostate cancer-specific or overall mortality [111]. However, data from the European Randomized Study of Screening for Prostate Cancer demonstrated that screening reduced the risk for prostate cancer death by 7% to 9% per year [112].

In addition to a lack of effect on mortality, screening is associated with high rates of false-positive results, overdiagnosis and subsequent overtreatment, and complications. Among men who had four PSA tests, the cumulative risk for at least one false-positive result was 12.9% [102]. Rates of overdiagnosis have been estimated at 17% to 50%, and 23% to 42% of all screen-detected prostate cancers are overtreated [102,113]. Furthermore, treatment is associated with complication rates of 20% to 50% [102,114]. These findings led several expert panels to update their screening recommendations (Table 6) [97,102,108,114,115,116,117]. Overall, experts recommend against routine screening for most men and emphasize the need to consider life expectancy and the patient's age and risk factors for the disease. The age to start a discussion about screening varies slightly among the guidelines. The AUA guideline notes that decisions about screening should be individualized for men younger than 55 years who are at high risk for the disease (positive family history or Black race) [114]. The guideline also states that the greatest benefit of screening appears to be for men 55 to 69 years of age and strongly recommends shared decision making for men in this age-group. The ACS guideline notes that screening should be discussed beginning at 50 years of age for men at average risk and before 50 years of age for men at higher risk [108]. The NCCN guideline suggests that clinicians talk to patients about the risks and benefits of a baseline DRE and PSA beginning at 40 years of age [97]. The American College of Physicians (ACP) recommends that clinicians inform their male patients, 50 to 69 years of age, about the limited potential benefits and substantial harms of screening [115].

Researchers continue to investigate ways to make screening more effective. Using a higher PSA threshold for biopsy for older men and less frequent screening for men with low PSA levels are strategies that may reduce the risk of overdiagnosis as well as prostate cancer-related mortality [118].

Informed decision making is integral in selecting approaches to screening, with every guideline emphasizing the need to discuss the potential benefits, harms, and limitations associated with screening with their male patients. The American Cancer Society notes that men should receive information about screening directly from their healthcare provider or be referred to reliable and "culturally appropriate" sources [108]. Decision aids can be especially useful in helping men and their healthcare providers weigh the benefits and risks of screening, and studies of decision aids have led to improved knowledge and have increased men's desire for an active role in decision making [108,114,119,120,121]. The NCCN guideline offers talking points for discussion, and ASCO provides a decision aid tool (https://www.asco.org/sites/new-www.asco.org/files/content-files/practice-and-guidelines/documents/2012-psa-pco-decision-aid.pdf).

Despite the continued emphasis on informed decision making, the percentage of men who report having had a discussion with their healthcare providers about screening has been suboptimal, with a rate of about 63% to 66% of the general male population [122,123]. Black men were most likely to have had a discussion, and men without a usual source of care were the least likely [123].

For men who choose to have screening for prostate cancer, the combination of DRE and PSA is the preferred method, providing better predictive value than either method alone [102]. The sensitivity of PSA testing is higher than that of DRE, especially for tumors that are more aggressive [109]. However, the PSA level can vary as a result of several factors.

PSA and Its Derivatives

In an effort to enhance the specificity of PSA testing, variations of the PSA test have been developed, including free PSA, PSA density, PSA velocity, and complexed PSA [97]. Each has its benefits and limitations, and the AUA notes that none increases the benefits-harms ratio of screening [114]. Levels of free PSA have been shown to be significantly lower in men with prostate cancer than in men without the disease [97]. The FDA has approved percent-free PSA for the early detection of prostate cancer in men with PSA levels between 4 ng/mL and 10 ng/mL [97].

PSA density is the result of dividing the PSA level by the volume of the prostate, as measured by transrectal ultrasonography, and a higher result suggests a greater likelihood of prostate cancer [97]. Greater PSA density has correlated with the presence of prostate cancer, as well as with the pathologic stage of the tumor and its aggressiveness and progression after treatment [124]. The use of PSA density has been limited by the lack of precision of total PSA, of measurement of prostate volume, and of the need to carry out transrectal ultrasonography [97]. In addition, PSA density does not offer much benefit compared with other PSA derivatives [97]. PSA velocity is the rate at which a PSA level increases over a period of time, and it has been most helpful for longitudinal monitoring of men younger than 50 years of age who have normal PSA levels and no prostate enlargement [97]. A high PSA velocity alone should not prompt biopsy but instead, aid in decision making [97]. The test is not useful for men with PSA values greater than 10 ng/mL [97]. The ratio of complexed PSA to total PSA provides information comparable to the ratio of free to total PSA, and the use of complexed PSA has been approved as a detection aid (in conjunction with DRE) for men 50 years of age or older; however, the test is not widely used in practice [97].

Threshold for Biopsy

Prostate cancer is found in about 25% of biopsy specimens, illustrating a problem regarding a well-defined threshold at which to obtain a biopsy specimen [125]. Although most cancer is detected with use of a PSA threshold of 4 ng/mL, some studies have shown that prostate cancer is subsequently found in men with levels in the range of 2.5–4.0 ng/mL [97]. The NCCN concluded that while these values have been used by many, a level of 3.0 ng/mL is supported by trials and would more robustly limit the risk of overdetection. However, there was not a consensus among NCCN panel members regarding limiting the option to biopsy to prespecified PSA thresholds [126]. The NCCN panel also concluded that DRE alone is not an absolute indication for biopsy in men with low PSA, as the positive predictive value of DRE in this population is poor. However, a very suspicious DRE, independent of PSA, could indicate high-grade cancer in men with normal PSA values, and therefore, biopsy should be considered in these men [126].

Men with early prostate cancer are usually asymptomatic. More advanced disease may be associated with changes in urinary habits, such as a slowing of the urinary stream, sense of incomplete voiding, nocturia, and frequency, as well as dysuria, hematuria, or pain in the lower back or pelvis. Because many of these symptoms are similar to those linked to benign prostate conditions, prostate cancer cannot be diagnosed on symptoms alone. The diagnostic methods are the same as those used for screening: PSA, DRE, and transrectal ultrasonography. In performing the DRE, the clinician should focus on the size, consistency, and abnormalities within or beyond the gland. Prostate cancers are characteristically hard, nodular, and irregular.

In its 2013 Best Practice Statement on PSA, the AUA emphasizes the importance of PSA in staging, noting that the PSA level predicts response of prostate cancer to local therapy [127]. Response is most likely in men with a PSA level <10 ng/mL [127].

Biopsy of the prostate with analysis of the tissue provides the most definitive diagnostic procedure. It also gives evidence of the aggressiveness of the tumor when cancer is detected. The pathologist quantifies the aggressiveness of the tumor with use of the Gleason score, assigning a number between 2 and 10 (with 10 representing the most aggressive). Pathologic review involves both staging according to the American Joint Committee on Cancer staging manual and classification of the tumor with the Gleason score [128]. Further staging with imaging (CT, MRI, bone scan) is done only for tumors that are confined to the prostate with a Gleason score of 8 or higher or a PSA level of greater than 20 ng/mL or for tumors that extend beyond the prostate or are symptomatic [97]. As part of the Choosing Wisely campaign, the AUA notes that a routine bone scan is not necessary for men with newly diagnosed prostate cancer with a PSA level <20.0 ng/mL and a Gleason score of ≤6 [127].

Recognizing that many prostate cancers have an indolent natural history, guidelines recommend utilization of a risk stratification classification for patients with newly diagnosed localized disease [358]. Stratification facilitates patient counseling and should be used with a shared decision-making approach in which treatment decisions are based on the patient's estimated life expectancy and the risk of biochemical recurrence [126]. Risk of biochemical recurrence has been classified by the NCCN into five categories (Table 7) [126].

A new prostate cancer grading system was developed during a 2014 consensus conference of the International Society of Urological Pathology (ISUP). The new system resulted in changes to the assignment of Gleason pattern based on pathology. This system assigns grade groups from 1 to 5, derived from the Gleason score. Many experts believe that the ISUP grade groups enable patients to better understand their true risk level and limit overtreatment. The NCCN has accepted the new grade group system. Patients remain divided into very-low-, low-, intermediate-, high-, and very-high-risk groups [126].

The primary options for localized prostate cancer are watchful waiting (also known as active surveillance), radiation therapy (either three-dimensional external-beam radiation or brachytherapy), and radical prostatectomy. Other options include androgen-deprivation therapy (ADT, also referred to as hormone therapy), chemotherapy, cryosurgery, and immunotherapy.

Each treatment option is associated with benefits and harms, and clinicians should discuss each option in detail and provide educational resources and decision aids [129,130,131]. To gain a true understanding of a patient's preferences, treatment options should be discussed only after the patient has described his preferences [132]. Clinicians should carefully assess their patients' understanding of treatment options; studies of underserved men have shown low comprehension of common terms used in prostate cancer treatment discussions [133,134]. Attention should also be paid to how to best communicate risk. A study has shown that such terms as "number needed to treat," "odds ratio," and "relative risk reduction" were confusing to men [135]. In that study, men best understood information when it was presented as an absolute risk reduction and in a positive context; men preferred that treatment options be discussed in terms of the probability of an increase in survival (rather than a decrease in mortality) and that the discussion include the impact of treatment on patient-centered quality-of-life outcomes [135].

Active Surveillance

Active surveillance has also been referred to as watchful waiting, but the terms have not always been defined the same way, and researchers are calling for a distinction between the two terms. Active surveillance denotes an approach in which men with localized, low-risk prostate cancer are followed up closely for clinical signs that prompt definitive treatment with curative intent should this become necessary [136,358]. Watchful waiting refers to the strategy recommended for asymptomatic patients with prostate cancer and limited life expectancy [358]. Some studies draw further distinction, defining watchful waiting as observation and provision of palliative care when prostate cancer becomes symptomatic, and active surveillance as close follow-up (with DRE, PSA levels, and biopsies) and provision of treatment at signs of disease progression [138]. Patients with a life expectancy of less than five years do not benefit from prostate cancer screening, diagnosis, or treatment as prostate cancer treatment does not improve survival within five years of follow-up [358].

For patients with favorable intermediate-risk prostate cancer, clinicians should discuss with patients the options of active surveillance, radiation therapy, or radical prostatectomy [358]. Choosing active surveillance rather than definitive treatment is difficult because of the myriad advantages and disadvantages to the approach (Table 8) [126]. Data on active surveillance have also conflicted. In a cohort of 450 men followed up for a median of nearly seven years, the rate of prostate cancer-specific mortality was low [139]. Two later systematic reviews indicated that the evidence was insufficient to determine whether active surveillance with curative intent was an appropriate option for men with localized prostate cancer [136,137]. Most recently, radical prostatectomy was compared with active surveillance, and the intervention did not significantly reduce all-cause or prostate cancer-specific mortality through at least 12 years of follow-up [140]. In addition, a cost-effectiveness analysis demonstrated that active surveillance was most effective and least expensive compared with several interventions (brachytherapy, intensity-modulated radiation therapy, or radical prostatectomy) [138].

The NCCN Panel recommends active surveillance for all men with very-low-risk prostate cancer and a life expectancy of less than 20 years and believes that surveillance should be considered for men with very-low-risk prostate cancer and a life expectancy of 20 years or more [126]. In addition, the Panel recommends active surveillance for all men with low- and favorable intermediate-risk prostate cancer and a life expectancy of less than 20 years and believes that it should be considered for men with low- and favorable intermediate-risk and a life expectancy of 10 years or more [126]. With active surveillance, recommended monitoring is measurement of a PSA level no more than every 6 months, unless clinically indicated, and physical exam with DRE every 12 months [126]. An increase in PSA should prompt re-testing as transient PSA elevations are common; serial PSA increases, new DRE abnormalities, or other concerns for clinical progression should prompt re-evaluation with prostate MRI and possible prostate biopsy [126,358].

Radiation Therapy

Radiation therapy is an option for men at various levels of risk for biochemical recurrence, except for men for whom active surveillance is recommended [126]. Radiation to pelvic lymph nodes may be considered for men with intermediate risk and should be done for men at high risk [126]. Radiation therapy offers progression-free survival similar to that of prostatectomy while avoiding the complications associated with surgery [126].

The advent of three-dimensional (3D) CRT, which integrates external-beam radiation with CT images, has allowed for the delivery of higher radiation doses but with a lower risk of side effects because of enhanced precision [126]. About half of men will have temporary bladder or bowel symptoms during treatment with external-beam radiation therapy [126]. The disadvantage to external-beam radiation therapy is the time needed for treatment, as the recommended duration of treatment is eight to nine weeks [126].

Intensity-modulated radiation therapy (IMRT), a second-generation 3D technique, has been used increasingly in clinical practice [141]. IMRT reduced the risk of gastrointestinal toxicities and rates of salvage therapy compared with 3D-CRT in some retrospective, population-based studies, but treatment cost was increased [142,143]. More recently, moderately hypofractionated image-guided IMRT regimens have been tested in randomized trials, but additional research is needed [126].

Brachytherapy has been used increasingly for men with early localized prostate cancer; however, increasing evidence suggests that technical advancements in brachytherapy may have a role in treatment of high-risk localized and locally advanced prostate cancer [126,144,145]. This approach is a recommended option as monotherapy for men at low risk and a life expectancy of at least 10 years and in combination with external-beam radiation therapy for men at intermediate risk, regardless of life expectancy [126,146]. Complications are increased when the two forms of radiation therapy are used together [126]. Brachytherapy alone yields control rates comparable to those of surgery (approximately 90%), and added advantages are short treatment duration, minimal risk of incontinence, and short-term preservation of erectile function; the seeds are implanted in one procedure, and men typically recover in one day [126]. Disadvantages include the need for general anesthesia and a risk of acute urinary retention [126].

Radical Prostatectomy

Radical prostatectomy is an option for men with a life expectancy of at least 10 years who have clinically localized disease that can be completely excised [126]. It also may be an option for men with high-risk disease and for select patients with very-high-risk disease, although several factors (e.g., PSA >10 ng/mL, stage T2b or higher, Gleason score 9 or 10, higher number of biopsy cores with high-grade cancer, more than 50% core involvement) predict unfavorable outcome in these patients [147]. Radical prostatectomy is a salvage option for patients experiencing biochemical recurrence after primary external beam radiation therapy, but morbidity remains significantly higher than when the treatment is used as initial therapy [148,149]. This treatment option has been most often associated with the highest survival rates but also with side effects that have been reported to have a significant impact on quality of life, such as impotence, incontinence, urethral stricture, and surgery-related morbidity [126,150,151]. Despite the potential side effects, the sense of being cancer free has led men who chose to have radical prostatectomy to be satisfied with their decision [152]. Laparoscopic and robot-assisted procedures have been found to yield results similar to those for open procedures, but rates of incontinence and erectile dysfunction may be higher [126]. The AUA notes that no conclusive benefit to pelvic lymph node dissection has been found [127]. Such dissection for clinically localized disease may not be necessary if the PSA is less than 10 ng/nL and the Gleason score ≤6 [127].

Androgen Deprivation Therapy (ADT)

ADT involves medical or surgical castration (with luteinizing hormone-releasing hormone [LHRH] agonists or orchiectomy, respectively). It is recommended as an adjunct to radiation therapy or prostatectomy for men with local or locally advanced disease and at high or intermediate risk for recurrence [126]. Meta-analyses have shown clinical benefit for adjuvant ADT after either radiation therapy or prostatectomy or neoadjuvant therapy before radiation therapy [153; 154].

Both NCCN and ASCO recommend ADT as initial treatment for metastatic prostate cancer [126,155]. Researchers have evaluated the timing of ADT—early (before symptoms occur) or delayed—and early therapy has provided no overall survival benefit and only a modest decrease in risk for prostate cancer-specific mortality; because of this, the ASCO guideline does not make a recommendation for early ADT [155]. Several studies have demonstrated that intermittent ADT is as effective as continuous ADT for metastatic or locally advanced disease, with better quality of life and fewer side effects [156,157,158].

Use of ADT as a primary therapy for men with localized prostate cancer has increased significantly among men at low and intermediate risk, but this approach should not be considered standard [126,146]. ADT is associated with several adverse events, including osteoporosis, increased risk for fracture, obesity, insulin resistance, and increased risk for cardiovascular disease and diabetes [126].

Chemotherapy

The use of chemotherapy is typically reserved for men with metastatic castration-resistant prostate cancer, and docetaxel-based regimens have been shown to confer survival benefit [159,160]. The duration of therapy is not well-defined, but 10 cycles were used in the phase III trials in which these regimens were evaluated.

Cryosurgery

Cryosurgery is a minimally invasive procedure that is an option for prostate cancer (of any grade) that is clinically confined to the prostate in men at low, intermediate, or high risk [161]. The five-year biochemical disease-free survival rates have ranged from 48% to 92%, depending on the risk of recurrence, but long-term data on prostate cancer-specific survival are not yet available and there are no clearly defined guidelines for patient selection for cryosurgery as a salvage procedure [161]. The authors of a meta-analysis published in 2007 and updated in 2018 concluded that it was difficult to determine the relative benefits of this treatment because of the poor quality of the available studies [162].

Options for Metastatic Castration-Resistant Prostate Cancer

Since 2010, three agents, an immunotherapy, and a radiopharmaceutical have been approved for metastatic castration-resistant prostate cancer. Cabazitaxel (Jevtana), enzalutamide (Xtandi), and abiraterone acetate (Zytiga) are indicated for treatment following docetaxel [126]. Sipuleucel-T (Provenge), an autologous cellular immunotherapy, is approved for men with metastatic castration-resistant prostate cancer who are asymptomatic or minimally symptomatic. Lastly, radium 223 dichloride (Xofigo) was approved in May 2013 for the treatment of metastatic castration-resistant prostate cancer with bone metastases (but not visceral involvement) [126].

Survival after treatment of prostate cancer is related to the extent of the tumor at the time of diagnosis, and the relative five-year survival rate is 100% for localized or regional prostate cancer [16]. The five-year survival rate is substantially lower (30%) when prostate cancer is metastatic at the time of diagnosis [16].

Primary care physicians, nurses, and other healthcare professionals who see patients on a regular basis play an important role in the follow-up evaluation for men who opt for active surveillance, as well as for those who have been treated by an oncologist. After treatment for prostate cancer, men should be followed up with an annual DRE and PSA testing every 6 to 12 months for five years and annually thereafter [163]. Primary care clinicians can also aid in the management of the side effects of treatment and screening for secondary cancers.

Patient A is an active man, 59 years of age, who missed his yearly DRE and PSA. The results of these tests had been within normal limits in all previous examinations. At his next examination, a firm prostate nodule, approximately 2 mm in diameter, is palpated, and the PSA level is 14 ng/mL. A needle biopsy of the prostate is performed within one week of the PSA measurement. The biopsy shows several sites containing cells indicative of adenocarcinoma of the prostate, with a Gleason score of between 8 and 9.

After carefully evaluating the treatment options for an aggressive tumor, Patient A chooses radical prostatectomy and seeks care at an institution where nerve-sparing surgery is performed with the assistance of a robotic, computer-controlled device, to help reduce the risk of adverse events. According to the pathologic evaluation, the tumor is an adenocarcinoma that has extended beyond the capsule of the gland but has not involved the seminal vesicles.

Staging studies, including an MRI of the pelvis and abdomen and a bone scan, confirm the extent of the tumor and demonstrate lack of lymph node involvement or distant metastasis (T3a, N0, M0). Because of the T3a finding, a course of external-beam radiation therapy to the local site is prescribed.

At the three-month follow-up visit, the PSA level has increased to 20 ng/mL, and a bone scan demonstrates multiple skeletal lesions, primarily in the ribs, pelvis, and skull, none of which had been seen on the previous scan. Due to the rapid progression of disease and the metastatic lesions, the patient's survival is estimated to be less than three years.

After a discussion with his surgeon, oncologist, and urologist, the patient decides to forego ADT, choosing instead to enroll in a clinical trial for treatment consisting of chemotherapy with docetaxel in combination with the angiogenesis inhibitor bevacizumab over a course of several months. The treatment causes some nausea, malaise, and hair loss, but the patient tolerates the effects well. The primary bothersome adverse effect is oral ulcers, which require topical treatment. The PSA level drops steadily during follow-up, reaching a level of 0.4 ng/mL after approximately six months of treatment.

Patient A continues to feel well after two years of follow-up, and the PSA level has remained at 0.2 ng/mL or less. Incontinence that was present after the surgery has ended, but erectile dysfunction remains, despite the use of medications.

In 2019, there were an estimated 283,792 men living with testicular cancer in the United States [190]. In 2022, there will be an estimated 9,910 new cases of testicular cancer and 460 deaths. According to 2000–2019 SEER data, the incidence is highest among non-Hispanic White men (7.3 per 100,000), followed by American Indian/Alaska Native (10.6 per 100,000) and Hispanic men (5.9 per 100,000), Asian/Pacific Islander men (2.4 per 100,000), and Black men (1.5 per 100,000) [191].

Among the several risk factors for testicular cancer, the primary one is cryptorchidism, which can increase the risk 11-fold [177]. Other risk factors include a family history of the disease, testicular dysgenesis, and Klinefelter syndrome [177]. A history of cancer in one testicle confers an increased risk (2% to 5%) of cancer in the contralateral testicle over the 25 years following diagnosis [192].

The European Association of Urology recommends high-frequency (i.e., >10 MHz) testicular ultrasound be used to confirm a testicular tumor even in the presence of a clinically evident testicular lesion.

(https://uroweb.org/guidelines/testicular-cancer Last Accessed: June 6, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

The USPSTF does not recommend routine screening for testicular cancer—by either clinician examination or self-examination—for asymptomatic adolescent and adult male individuals, as there is no evidence that screening reduces mortality [193]. The USPSTF notes that instead of screening, men should be advised to report testicular problems promptly, as cure rates are high for any stage of testicular cancer [193].

Testicular cancer usually presents as discomfort or swelling in the testicles that is suggestive of epididymitis or orchitis [177]. Physical examination will demonstrate a palpable mass [177]. Occasionally, the patient may note tender or swollen breasts or loss of sex drive.

According to the NCCN guideline for the treatment of testicular cancer, testicular ultrasonography is optional if a diagnosis is obvious from the physical examination, but the guideline notes that this diagnostic test is usually done to define the lesion [177]. Both the NCCN and ASCO recommend measuring serum levels of alpha-fetoprotein (AFP), human chorionic gonadotropin (beta-hCG), and lactate dehydrogenase (LDH) to help determine if the testicular mass is a germ cell tumor and, if so, whether it is a seminoma or a nonseminoma [177,194]. A nonseminoma is associated with an elevated AFP level; in contrast, an elevated level of beta-hCG, with a normal AFP level, usually indicates a seminoma [177]. Additional evaluation should include a chest x-ray and CT of the abdomen and pelvis to determine if lymph nodes are involved [177]. If metastatic disease is suspected, further imaging studies, such as bone scan, magnetic resonance imaging, or positron emission tomography, may be necessary. Open biopsy is not usually performed [177].

Men with suspected testicular cancer should be referred to an oncologist who will discuss treatment options, which include orchiectomy and radiation therapy or chemotherapy, depending on the type of tumor and the stage of disease. Lymph node dissection may also be necessary for metastatic disease. The possibility of sperm banking should be discussed before any type of treatment is initiated [177].

Treatment options for early-stage seminoma (stage I, confined to the testicle and epididymis) are active surveillance (preferred), single-agent carboplatin (one or two cycles), or radiation therapy [177].

Radiation therapy is recommended for stage II seminoma (involvement of nearby lymph nodes), with the treated area extended to include the ipsilateral iliac lymph nodes [177]. If radiation is contraindicated, chemotherapy with three cycles of bleomycin, etoposide, and cisplatin (BEP) or four cycles of etoposide and cisplatin (EP) is recommended. If chemotherapy is given, both regimens are recommended [177]. Chemotherapy with EP or BEP is recommended for stage III seminoma (involvement of distant lymph nodes and/or viscera) [177].

Treatment options for nonseminoma include surveillance, chemotherapy, and retroperitoneal lymph node dissection [177]. Selecting the appropriate therapy involves consideration of many factors, including the extent of disease in the lymph nodes, the levels of serum tumor markers before and during treatment, radiographic findings, and the commitment of the patient to adhere to surveillance protocols that involve frequent blood work and CT [177]. Chemotherapy involves either EP or BEP [177].

The cure rates for testicular cancer are high, even when cancer is at an advanced stage at the time of diagnosis [177]. The overall five-year survival for testicular cancer (all stages) is 95.2% [190].

Men who have been treated for testicular cancer should be followed up at regular intervals to monitor for signs of recurrence. Follow-up visits typically include a history and physical examination and serum tumor markers. The ASCO guideline on the serum tumor markers for male individuals with germ cell tumors notes that there is insufficient evidence to determine whether monitoring tumor markers improves survival or health outcomes but nonetheless recommends measuring AFP and beta-hCG levels during each surveillance visit, and the NCCN also recommends an LDH as part of surveillance [194]. Evidence is also lacking regarding optimal surveillance intervals, and the intervals vary according to diagnosis (seminoma or nonseminoma) and stage of disease [177]. In general, the recommended intervals are every two months in the first year, every three months in the second year, every six months in the third and fourth years, and annually thereafter [177]. It is recommended that surveillance continue for at least 10 years [177,194]. Chest x-ray and computed tomography of the abdomen and pelvis are recommended at greater intervals [177].

The follow-up evaluation plays an important role in assessing for the long-term effects of treatment. The primary effect of chemotherapy is oligospermia, but sperm production can be recovered [195,196]. A population-based study found that 70% of testicular cancer survivors fathered children [197]. Secondary acute leukemias have been reported to develop after chemotherapy and radiation therapy, and other consequences of platinum-based chemotherapy include hearing deficits and impaired renal function [198,199]. Melanomas and cancers at many sites have been associated with radiation therapy, occurring 10 years or more after treatment [198]. Lastly, the risk of cardiac events has been increased for testicular cancer survivors who had been treated with radiation therapy and/or chemotherapy [200].

The reported prevalence of premature ejaculation in the United States has varied widely, ranging from 5% to 40%, depending primarily on the definition [210,212]. The highest prevalence is found among men who are 60 years of age or older [214].

According to the Male Training Center for Family Planning and Reproductive Health, asking men about problems with sexual function is particularly important to identify underlying cardiovascular disease among men who present with symptoms of sexual dysfunction routinely starting at 25 years of age. Specific questions include if the man is experiencing sexual dysfunction such as inability to obtain and maintain an adequate erection for satisfactory sexual activity (impotence, erectile dysfunction), premature or delayed ejaculation, loss of libido, painful intercourse, and also priapism, a prolonged painful erection not associated with sexual desire.

(https://rhntc.org/sites/default/files/resources/mtc_male_prevrhc_2014.pdf Last Accessed: June 6, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

There are no established criteria for the diagnosis of premature ejaculation; clinicians should assess medical, relationship, and sexual history and perform a focused physical examination to make the diagnosis [354]. Laboratory studies or physiologic testing is needed only if the history or physical examination suggests a complex cause [212,354]. Among the details to be elicited from the history are [212]:

The patient's partner may be helpful in providing a description of the problem, and care should be taken to distinguish premature ejaculation from erectile dysfunction [212]. The AUA recommends that, for men with concomitant premature ejaculation and erectile dysfunction, erectile dysfunction should be treated first [212].

The treatment approaches for premature ejaculation include psychologic, behavioral, and pharmacologic therapies, and the risks and benefits of all options should be discussed with the patient and, when possible, his partner [212,354]. Behavioral therapy was once considered to be the standard therapy, but studies have shown that the best approach may involve a combination of therapies to address the limitations of each approach as well as the multimodal causes of premature ejaculation [210,217,218]. The 2022 AUA/Sexual Medicine Society of North America guideline recommends that, in addition to pharmacologic treatment, providers consider referring men with premature ejaculation to a mental health professional with expertise in sexual health [354].

No medication has been approved for the treatment of premature ejaculation, leaving the pharmacologic treatment to involve the off-label use of serotonin reuptake inhibitors or topical anesthetics that act by prolonging the latency of ejaculation [210,212,218,219,354]. The recommended first-line pharmacotherapeutic options are "on demand" clomipramine; a nonselective serotonin reuptake inhibitor; daily selective serotonin reuptake inhibitor (e.g., fluoxetine, paroxetine, sertraline); and topical penile anesthetics [212,354]. The doses studied have varied, and dosing is prescribed as either continuous (daily regimen) or situational (taken only before sexual activity); the optimal duration of therapy has not been determined (Table 10) [212,354]. The side effects of these drugs have not been evaluated outside the depression setting, but the effects appear to be similar for men who are not using the drug for depression, with the most common effects being nausea, dry mouth, and drowsiness [212].

Treatment with topical lidocaine/prilocaine has also been shown to be effective in increasing the latency of ejaculation and is another option recommended by the AUA [212,220,221]. The drug is typically applied 20 to 30 minutes before sexual activity; earlier application (30 to 45 minutes prior to sexual activity) has led to numbness of the penis and loss of erection in a substantial number of men [221]. Topical treatment avoids adverse events associated with systemic therapy [222]. In 2016, the European Union approved a topical eutectic lidocaine/prilocaine metered-dose spray (Fortacin) for use in the treatment of primary premature ejaculation [223,224]. The spray has not been approved for this use in the United States [225].

One drug, dapoxetine, a short-acting selective serotonin reuptake inhibitor, is the first drug developed specifically for premature ejaculation, and it has been approved for use in several European countries, but not in the United States or Canada [222]. Several studies and systematic reviews have shown dapoxetine to substantially improve (compared with placebo) intravaginal ejaculatory latency time, perceived control, and patient-reported global impression of change and decrease related personal distress and difficulty [222,226,227,228]. However, the agent is characterized by discontinuation rates of up to 90%, primarily due to side effects, cost issues, efficacy below expectations, and the need for scheduling sexual intercourse [224]. The most common side effects have been nausea, dizziness, diarrhea, insomnia, and headache.

Psychological and behavioral therapies are valuable components of treatment [210,217,218]. Relationship counseling and sex therapy can help facilitate communication between the patient and his partner and ease tension surrounding sexual activity. Psychologic and behavioral therapies should focus on gaining confidence, learning control techniques, lessening performance anxiety, overcoming barriers to intimacy, achieving pleasure, and gaining satisfaction [210,217].

Erectile dysfunction is estimated to affect 50 million men in the United States and more than 150 million men worldwide [231]. The prevalence has ranged from 10% to 30% among men 40 to 49 years of age and from 25% to 76% among men older than 70 years of age [232,233,234]. Ethnicity has also been a factor, with a higher rate for Black men and a lower rate for Hispanic men compared with White men [232]. However, another study showed that Hispanic men were more likely to report erectile dysfunction [234].

Erectile dysfunction has been reported to be more common among men with comorbidities; independent risk factors include age, diabetes, metabolic syndrome, cardiovascular disease, obesity, and sedentary lifestyle [214,234,235]. Among men with no known cardiovascular disease, erectile dysfunction has preceded coronary artery disease, stroke, and peripheral artery disease by an average of three years (range: two to five years) [236]. In addition, a meta-analysis (14 cohort studies; 92,757 men) showed that erectile dysfunction was an independent risk factor for cardiovascular and cerebrovascular events [237]. Other risk factors for erectile dysfunction include hormone disorders, neurologic conditions, psychologic disorders, history of surgery or radiation in the pelvic region, use of illicit drugs, and some prescription drugs (most notably, antihypertension agents) [238]. Encouraging men with these risk factors to modify their lifestyle and/or treating comorbidities may help reduce the risk of erectile dysfunction [239].

A detailed medical history is integral to diagnosing erectile dysfunction, as the history may elucidate an underlying cause. It is important to also document a psychosocial and sexual history to evaluate the potential of other related or contributing factors [230]. The physical examination should involve assessment of the abdomen, genitals, and pulses in the lower extremity [230]. Validated questionnaires are recommended to assess the severity of erectile dysfunction, to measure treatment effectiveness, and to guide future management [355]. A morning serum total testosterone should be measured routinely; selected laboratory studies to consider are fasting glucose and serum lipid profile, hemoglobin A1c, and thyroid function tests [355].

Erectile dysfunction is best managed with a combination approach [235]. Because of the strong relationship between erectile dysfunction and modifiable risk factors, lifestyle changes should be a first-line approach to managing the condition. The importance of achieving or maintaining a healthy body mass index, increasing exercise, and smoking cessation should be emphasized, especially given the relationship between erectile dysfunction and cardiovascular disease.

After treatment of erectile dysfunction is initiated, referral to a mental health professional should be considered to promote treatment adherence, reduce performance anxiety, and integrate therapies into a sexual relationship [355]. Both the AUA and the ACP recommend oral phosphodiesterase-5 inhibitors as first-line pharmacotherapy for erectile dysfunction in men for whom this class of drugs is not contraindicated [230,231,355]. Four drugs in the class have been approved for use in the treatment of erectile dysfunction: sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra, Spedra). Sildenafil and vardenafil differ from tadalafil with respect to the time to maximum serum level (1 hour vs. 2 hours) and serum half-life (4 hours vs. 18 hours) [230]. Furthermore, the duration of action is longest for tadalafil (up to 36 hours) [240]. The inhibitory effect of these drugs causes vascular smooth muscle relaxation in the corpus cavernosum, resulting in increased erection hardness and prolonged duration in men with erectile dysfunction who have sufficient intact vasculature [355].

Data from multiple trials and systematic reviews have demonstrated similar efficacy for phosphodiesterase-5 inhibitors in treating erectile dysfunction, particularly for sildenafil, tadalafil, and vardenafil [355]. Each of these drugs substantially improves erectile function and successful sexual intercourse compared with placebo [231]. Relative efficacy is less clear for avanafil because published comparative studies are limited. The ACP notes that there is insufficient evidence for recommending one drug over another and suggests that the choice be made according to the preferences of an individual patient with respect to ease of use, cost, and the adverse effects profile [231]. One systematic review and meta-analysis found evidence that tadalafil is the most effective agent, followed by vardenafil, with no major differences in the safety profile of any of the phosphodiesterase-5 inhibitors [241].

The side effects of all four drugs are similar, with headache, dyspepsia, facial flushing, nasal congestion, and visual disturbances being the most common events [230,240,242]. The FDA has issued two mandates to revise labeling of these agents. In 2005, the agency required labels for sildenafil, tadalafil, and vardenafil to reflect the possibility of sudden vision loss after taking the drugs for a period of time [243]. The alert was associated with several case reports suggesting a temporal association between use of one of the drugs and nonarteritic anterior ischemic optical neuropathy (NAION), a rare disorder characterized by sudden loss of vision in one eye [243,355]. However, subsequent studies showed that the risk of NAION was similar among men who were and were not taking a phosphodiesterase-5 inhibitor [244,245]. Risk factors for spontaneous NAION include older age, White race, small optic discs with low cup-to-disc ratio, and vascular disease, leading some investigators to suggest an examination of the fundus be performed on men who may be at higher risk for NAION before a phosphodiesterase-5 inhibitor is prescribed [243].

In 2007, the FDA mandated changes to the labels of phosphodiasterase-5 inhibitors to more prominently display warnings about the potential for sudden hearing loss [246]. A cross-sectional population-based study of more than 11,000 men subsequently demonstrated a higher likelihood of self-reported hearing loss associated with use of any phosphodiasterase-5 inhibitor (odds ratio: 2.23), but the association was significant only for sildenafil [247].

Use of a phosphodiesterase-5 inhibitor is contraindicated in several situations. They should not be taken by men who take organic nitrates (nitroglycerin) or nitrites (amyl nitrite) [248,249]. Vardenafil should not be used for men with a history of prolonged QT interval (or who take medication to prolong the QT interval) [230]. The use of a phosphodiesterase-5 inhibitor concomitantly with an alpha-blocker for lower urinary tract symptoms may lead to increased systemic vasodilation and hypotension [230].

Men who are being treated with a phosphodiesterase-5 inhibitor should be followed up closely to monitor efficacy and side effects. Attention to changes in health status and other medications is essential to avoid drug interactions. Clinicians should emphasize the importance of men providing information about treatment with a phosphodiesterase-5 inhibitor in case of a cardiovascular emergency [230].

Although the initial treatment option preferred by most men with erectile dysfunction is a phosphodiesterase-5 inhibiter, the AUA Panel notes that it is valid for men to begin with any type of established treatment, and recommends that patients be informed of all treatment options that are not medically contraindicated. The AUA guideline provides data on success rates, patient and partner satisfaction rates, and potential adverse effects for the following treatment options [355]:

Intracavernosal injection of a vasoactive drug is associated with the highest potential for priapism, and clinicians should ensure that men understand the correct technique and the importance of seeking medical intervention for a prolonged erection [230]. Only vacuum erection devices with a limiter (a feature that limits the amount of vacuum pressure and reduces potential for penile injury) should be recommended, whether purchased over the counter or procured by prescription [230,355]. The AUA advises that for men with erectile dysfunction, low-intensity extracorporeal shock wave therapy and intracavernosal stem cell therapy are considered investigational treatment options [355]. The risks associated with penile prostheses include mechanical failure, erosion, and infection [230]. The AUA guideline does not recommend the use of trazodone, testosterone therapy (for men with normal serum levels), or yohimbine and other herbal therapies [230].

Psychosocial therapy is an important component of treatment for erectile dysfunction. A meta-analysis showed that group psychotherapy in combination with sildenafil significantly improved erectile function and successful sexual intercourse compared with sildenafil alone [250].

There is a wide range in the reported prevalence of late-onset hypogonadism. In a population-based observational study, symptomatic androgen deficiency was found in nearly 6% of men 30 to 79 years of age, whereas in the Hypogonadism in Males (HIM) study, the prevalence was nearly 39% among men 45 years of age and older visiting primary care practices [254,255]. The prevalence increases substantially with age and is similar across racial/ethnic populations [254,255].

A diagnosis of late-onset hypogonadism requires both documentation of relevant symptoms and measurement of testosterone levels. The condition is associated with a variety of physiologic, psychologic, cognitive, and sexual symptoms; some signs and symptoms are more specific than others, and no combination of symptoms is typical (Table 11) [252,255].

Diagnosing late-onset hypogonadism (testosterone deficiency) is challenging because many signs and symptoms are associated with the normal process of aging or can be attributed to coexisting conditions. Two questionnaires that can help to identify late-onset hypogonadism are the Androgen Deficiency in Aging Males (ADAM) questionnaire and the Aging Males' Symptoms (AMS) scale [256,257,258,259,260]. The ADAM questionnaire consists of 10 questions, and the condition is defined by a positive response to two specific questions: "Do you have a decrease in libido (sex drive)?" and "Are your erections less strong?" or to any three of the other questions [256]. The AMS scale asks men to provide a score of 1 to 5 to each of 17 somatic, psychologic, and sexual symptoms. The ADAM questionnaire has been validated against testosterone levels, whereas the AMS scale was designed to evaluate the quality of life and has not been correlated to testosterone levels [261]. Both have excellent specificity but poor sensitivity [251].

In its updated practice guidelines on the treatment of androgen deficiency, the Endocrine Society recommends making a diagnosis of hypogonadism "in men with symptoms and signs of testosterone deficiency and unequivocally and consistently low serum testosterone and/or free testosterone concentrations (when indicated)" [252]. Serum testosterone level fluctuates in relation to time of day and food intake; peak concentrations occur during the morning hours. Therefore, clinicians should measure total testosterone concentrations on two separate mornings while the patient is fasting [252]. Measured levels should be interpreted with caution as not all laboratories use total testosterone assays harmonized to the national standard [355]. Intercurrent acute illness, nutritional deficiency, and certain medications (e.g., opioids, glucocorticoids) can alter the expected serum testosterone concentration. In general, a total testosterone concentration of 300 ng/dL is the cut-off level below which testosterone replacement therapy is considered for most men with suspected late-onset hypogonadism.

The increase in treatment with testosterone has been tremendous. Although there are benefits of testosterone therapy, there are also many potential risks (Table 12), and the risk-benefit ratio for men with late-onset hypogonadism has not been clearly defined [255,256,261]. Because of questions about the benefits and harms of testosterone, the Endocrine Society is specific in its recommendations for testosterone therapy (Table 13) and recommends against a general policy of offering testosterone therapy to all older men with low testosterone levels [252].

Testosterone replacement is available in several forms, including oral agents, injectable formulations, transdermal gels and patches, and buccal tablets [252,263]. In general, a decision on the type of therapy should be made according to the patient's preference, with consideration of several factors, including pharmacokinetics, cost, ease of use, and side effect profile [252,263].

Close follow-up is essential for men being treated with testosterone replacement. The clinical response and side effects should be monitored at intervals of three to six months [252]. The treatment target should be a testosterone level in the middle of the normal range [252]. Follow-up should include evaluation of the prostate, through determination of PSA levels and DRE at three to six months for men 40 years of age and older who have a baseline PSA greater than 0.6 ng/mL. In addition, a hematocrit level should be determined at three to six months and then annually; treatment should be discontinued if the hematocrit is greater than 54%.

More than half of male infertility or subfertility is potentially correctable; often, the cause is unknown. The causes, both correctable and uncorrectable, include [264,268]:

According to the AUA guidelines, evaluation of suspected male infertility should include a complete medical and reproductive history, physical examination, and one or more semen analyses [264,356]. Men with one or more abnormal semen parameters or presumed male infertility should be evaluated by a male reproductive expert. It is important not to rely solely on semen analysis, as an underlying medical or genetic cause of infertility may be missed [268]. Other tests may be necessary, depending on the findings of this initial evaluation. Clinicians should obtain hormonal evaluation including follicle-stimulating hormone (FSH) and serum testosterone for infertile men with any of the following: impaired libido, erectile dysfunction, oligozoospermia or azoospermia, atrophic testes, or evidence of hormonal abnormality on physical examination [356].

The medical history can help to detect an underlying cause of infertility. Factors that can affect fertility include [268]:

The reproductive history should address the following issues: frequency and timing of intercourse, duration of fertility effort, use of lubricants, and sexual history (including STIs) [264,267,268].

Physical examination may identify a varicocele, the most common cause of male infertility [165,182]. Other findings on physical examination that may suggest a cause of infertility include small testes (less than 4 cm in greatest dimension or less than 20 cm3), signs of ductal obstruction (induration or engorgement of the vas deferens or epididymis), and abnormal distribution of hair and fat, which may indicate endocrinopathy [268].

As noted, the semen analysis should be carried out on at least two specimens, obtained at least one month apart [264]. The specimens should be collected after two to three days of abstinence. The World Health Organization (WHO) first established reference values for semen analysis in 1987 and published its sixth update in 2021 [269]. The 2020 AUA guideline references the 2010 WHO semen parameters and lower reference limit criteria for male infertility [356]:

Initially, the updated criteria met with controversy, with some noting that the new reference values would lead to fewer men being classified as infertile based on semen analysis alone [271,272,356]. No single abnormality among sperm parameters is diagnostic of infertility; the odds ratio for infertility increases with the number of abnormal semen parameters, rising sharply with two or more abnormal parameters [356].

The National Collaborating Centre for Women's and Children's Health recommends that men be informed that there is an association between elevated scrotal temperature and reduced semen quality, but that it is uncertain whether wearing loose-fitting underwear improves fertility.

(https://www.nice.org.uk/guidance/cg156 Last Accessed: June 6, 2022)

Level of Evidence: Expert Opinion/Consensus Statement

Treatment options are available for correctable causes of infertility. Varicoceles can be repaired through open or laparoscopic surgery or by percutaneous embolization [182]. Surgical treatment leads to elimination of the varicocele in 90% of men, with improvement in the semen quality, production of testosterone, and rates of subsequent pregnancy [182,273]. For men with infertility related to obstruction, microsurgical reconstruction of the obstructed duct has led to the appearance of sperm in the ejaculate and higher rates of subsequent pregnancy [267]. Several techniques for retrieving sperm are also available. Options for reproductive assistance and adoption should be explored for men who have uncorrectable infertility. Genetic counseling should be offered to men with nonobstructive azoospermia due to primary testicular failure [267].

The prevalence of STIs according to gender vary with infection; chlamydia, HSV-2, and HPV occur more often among female than male individuals; gonorrhea occurs at similar rates among female and male individuals; and syphilis occurs more often among male than female individuals [57,277,280]. Overall, almost two-thirds of all STIs occur in individuals 15 to 24 years of age [57]. Among men, most STIs are far more prevalent in the non-Hispanic Black population than in other ethnic/racial populations and are least prevalent in the Asian population (Table 14) [57,277,281].

Chlamydia

More than 1.5 million cases of chlamydia were reported to the CDC in 2020 [57]. The 2020 rate of chlamydia infection (481.3 cases per 100,000) represents a decrease of 13% over the rate in 2019. During 2019–2020, rates of reported chlamydia decreased among both men and women. Chlamydial infection occurs more than twice as commonly in women than men, and rates are highest among adolescents and young adults.

Gonorrhea

In 2020, a total of 677,769 cases of gonorrhea were reported to the CDC, making it the second most commonly reported notifiable sexually transmitted disease in the United States [57]. Rates of gonorrhea have increased 111% since the historic low of 98.1 cases per 100,000 in 2009. In 2020, the rate of gonorrhea among men was 236.3 cases per 100,000, compared with 150 cases per 100,000 among women [57].

Syphilis

In 2000–2001, the rate of syphilis (primary and secondary) was 2.1 cases per 100,000; however, the rate has increased almost every year since that time, increasing 6.8% between 2019 and 2020 [57]. In 2020, 133,945 cases of syphilis were reported, including 41,655 cases of primary and secondary syphilis, the most infectious stages of the disease. Rates of syphilis have increased in most racial/ethnic groups, with greatest increases among non-Hispanic American Indian/Alaska Native persons and non-Hispanic persons of multiple races [57]. Young men who have sex with men are disproportionally impacted, accounting for a majority (53%) of all male syphilis cases in 2020 [57].

HSV-2

Genital herpes is a chronic, lifelong viral infection; the prevalence is unknown as the majority of persons infected have not had the condition diagnosed. Many individuals with HSV-2 have mild symptoms or unrecognized infection but shed the virus intermittently in the urogenital area. Consequently, most genital infections are transmitted by persons unaware that they have the infection. Most cases of recurrent genital herpes are caused by HSV-2, and 11.9% of persons 14 to 49 years of age in the United States are estimated to have acquired this infection [173]. In 2020, the CDC estimated the prevalence of HSV-2 at 18.6 million persons, though the actual number is likely to be considerably higher [57,173]. The seroprevalence of HSV-2 is more than twice as high among female individuals (about 34%) than among male individuals (about 15%) [57]. As with other STIs, HSV-2 infection is more common among non-Hispanic Black men than other racial/ethnic populations [57].

HPV

Data on HPV infection in men are limited. According to a data brief published by the National Center for Health Statistics (NCHS), during 2011–2014, the seroprevalence of any HPV was 7.3% among adults 18 to 69 years of age, with 11.5% among men and 3.3% among women [282]. In the HIM study, an ongoing prospective cohort study of the natural history of HPV in men (from the United States, Mexico, and Brazil), the overall prevalence of HPV infection was 65.2%, with the highest rates among White and Black men (71.5% and 66.2%, respectively) and the lowest, among Asian/Pacific Islander men (42.2%) [281,283]. An estimated 34,800 new HPV-attributable cancers occurred every year during 2012–2016; before introduction of HPV vaccines, approximately 355,000 new cases of anogenital warts occurred every year [173].

Prevention and control are keys to lowering the prevalence of STIs, and the primary preventive strategies are: risk assessment, education, and counseling; limiting the number of sexual partners; abstinence or the use of condoms and barriers; and, in the case of HPV, with vaccination [173,276]. The importance of abstaining from sexual activity should be emphasized to individuals with a confirmed STI [173].

Control of STIs involves the identification of asymptomatic individuals and of symptomatic individuals who may not seek health care; effective diagnosis and treatment; and the evaluation, treatment, and counseling of sex partners of infected individuals [173]. The CDC encourages clinicians to promote prevention with patient-centered education that focuses on risk reduction measures directed at an individual patient's personal risk [173]. Obtaining a thorough sexual history is an essential component of prevention, and the CDC suggests asking questions related to [173]:

The U.S. Preventive Services Task Force recommends behavioral counseling for all sexually active adolescents and for adults who are at increased risk for sexually transmitted infections.

(https://jamanetwork.com/journals/jama/fullarticle/2769474 Last Accessed: June 6, 2022)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

Practical strategies for risk assessment and counseling are provided in the CDC treatment guidelines document [173]. Healthcare providers should use simple, direct language when asking these questions, taking care to exhibit respect, compassion, and a nonjudgmental attitude [173]. Organizations such as the National Network of STI/HIV Prevention Training Centers, a CDC-funded group, can help providers enhance skills in counseling individuals about prevention. Resources can be found on the organization's website, available at https://www.cdc.gov/std/treatment/resources.htm.

Recommendations for screening vary according to risk and the type of STI (Table 15) [284]. The USPSTF also recommends high-intensity behavioral counseling for all sexually active adolescents and for adults at increased risk for STIs and HIV [284]. The USPSTF has not issued recommendations for screening for HPV, but beginning in 2011, the Advisory Committee on Immunization Practices (ACIP) recommended HPV vaccination for male individuals [276]. The ACIP recommends routine use of quadrivalent HPV vaccine for boys 11 or 12 years of age and for male individuals 13 to 26 years of age who have not initiated or completed the three-dose series [276,286]. The ACIP also notes that men 27 to 45 years of age may also be vaccinated if at high risk, as determined through shared decision-making [276,285,286]. In addition, hepatitis B vaccination is recommended for any patient who is being evaluated for an STI [173].

The symptoms of STIs vary and are often similar to symptoms associated with other conditions of the urogenital tract, and some infected individuals may be asymptomatic.

Infection with chlamydia is often asymptomatic [173]. Diagnosis can be made by testing of a urethral or rectal swab or a urine specimen [173]. Nucleic acid amplification tests are the most sensitive tests and can be used for urine specimens [173].

Primary syphilis usually presents as a solitary chancre that develops at the site of infection approximately three weeks after exposure to the spirochete Treponema pallidum [287]. The chancre is typically painless and must be distinguished from other genital lesions, such as genital herpes, venereal warts, chancroid, and lymphogranuloma venereum (caused by C. trachomatis) [287].

Dark-field microscopy to detect T. pallidum is the optimum method of diagnosing syphilis. Although no such detection tests are commercially available, some laboratories provide locally developed and validated polymerized chain reaction (PCR) tests for the detection of T. pallidum [173]. A presumptive diagnosis of syphilis can be made with two types of serologic tests: nontreponemal tests (Venereal Disease Research Laboratory [VDRL] and rapid plasma regain [RPR] tests) and treponemal tests (such as fluorescent treponemal antibody absorbed [FTA-ABS] tests or the T. pallidum passive particle agglutination [TP-PA] assay) [173]. The CDC notes that using only one type of serologic test is insufficient for a diagnosis [173].

Gonococcal infection, which is caused by Neisseria gonorrhoeae (a gram-negative diplococcus), can lead to either urethritis or epididymitis [288]. Urethritis is accompanied by such symptoms as purulent discharge from the penis, dysuria, or erythema at the meatus [288]. Epididymitis caused by gonococcal infection is usually associated with unilateral testicular pain and no other symptoms [288]. Disseminated infection is rare (1% to 3%) [289]. A diagnosis of gonorrhea is confirmed by Gram stain and culture of urethral discharge or swab specimen for N. gonorrhoeae, or by nucleic acid amplification testing done on a urine sample [173,288]. Both techniques have similar sensitivity and specificity [173].

The CDC recommends that all individuals who are evaluated for gonorrhea should also be evaluated for chlamydia, syphilis, and HIV infection [173]. In one study of more than 3,800 men and women, approximately 10% to 30% of individuals with gonorrhea had concomitant infection with chlamydia [290]. The typical lesions of genital HSV-2 in men appear on or around the penis and are first noted as either a single or multiple erythematosus macular lesion(s). However, these lesions are absent in many infected individuals [173]. Viral culture is the preferred test for the diagnosis of HSV-2, but it requires two to seven days for results. The sensitivity of viral culture depends on the quality of the sample and the time at which the sample is obtained; sensitivity declines as the lesion begins to heal. A PCR test is available and is suggested by the CDC for analysis of cerebrospinal fluid when central nervous system disease is suspected [173]. Type-specific serologic tests are available as laboratory assays and point-of-care tests [173]. These tests have varying degrees of sensitivity for the detection of the HSV-2 antibody (80% to 90%) and specificity of at least 96% [173].

The treatment of STIs has four main goals [173]:

The CDC has developed comprehensive guidelines for the treatment of STIs, last updated in 2021 (Table 16 and Table 17) [173]. For chlamydia, gonorrhea, or syphilis, single-dose regimens generally offer an advantage for the treatment of individuals with poor healthcare-seeking or compliance behaviors [173]. The CDC notes that for the treatment of syphilis, neither combinations of benzathine penicillin and procaine penicillin nor oral penicillin preparations are considered appropriate and emphasizes the importance of distinguishing the standard benzathine penicillin product widely used in the United States (Bicillin L-A) from the combination benzathine-procaine penicillin (Bicillin C-R); the latter is not appropriate for the treatment of syphilis [173].

In addition to antibiotic treatment, bed rest, scrotal elevation, and analgesics can help to alleviate symptoms such as fever and local inflammation, which are primarily associated with gonorrhea. Beginning treatment as early as possible decreases the likelihood of complications and spread of infection, especially in the case of syphilis [173]. To prevent the transmission of infection, a patient with a confirmed or suspected STI should be told to avoid sexual contact until therapy is completed and he (and/or his partner) no longer has symptoms [173]. The need for sexual partners to be evaluated for treatment should also be emphasized. State and local health departments may provide assistance in arranging for the evaluation and treatment of sex partners of infected men.

HSV-2

The antiviral medications used to treat HSV-2 can only partially control the signs and symptoms of infection; they cannot eradicate the virus or reduce the risk, frequency, or severity of recurrence after the treatment course has been completed [173]. Men with HSV-2 infection should be given medication for episodic treatment of recurrent infection; treatment should begin within one day after the onset of a lesion [173]. If recurrences are frequent (six or more within a year), long-term suppression therapy may be appropriate; such therapy has been shown to reduce the frequency of recurrence by 70% to 80% [173].

Peterman et al. found a 14.7% rate of reinfection among men during the first year after treatment for an STI [291]. An unexpected finding in the study was the high percentage (66%) of asymptomatic infections. The authors suggested that treated individuals be rescreened at three months. The CDC recommends follow-up with clinical examination and serologic evaluation at 6 and 12 months after treatment [173].

All states require that cases of chlamydia, gonorrhea, syphilis, HIV, and acquired immune deficiency syndrome (AIDS) be reported to local health authorities [173]. Clinicians should seek advice from state or local health departments if reporting requirements are unclear [173].

Because men are less likely to express their emotions, they may recognize and discuss only the physical symptoms of depression, making diagnosis a challenge [300,301,333]. A carefully taken history can elicit information about risk factors, which include a family history of depression, the use of some medications (beta blockers, histamine H2-receptor antagonists, benzodiazepines, and methyldopa), chronic illness or other comorbidity, lack of social support, recent life stressor, and single marital status [307,335]. Substance misuse frequently occurs concomitantly with depression, more often in men than women, but the direction of the causal relationship is not clear [300,335].

Many of the symptoms of depression reported by women are the same for men: depressed mood, changes in appetite and sleep habits, problems with concentration, and an inability to find pleasure in once pleasurable activities [300]. It has been proposed that the symptoms of depression in men represent a male depressive syndrome, characterized by such symptoms as irritability, acting-out, aggression, low tolerance of stress, low impulse control, tendency to blame others, and a greater willingness to take risk [28,300,330,333]. Men with depression may thus present with a very different symptom profile [328].

Identification of suicide risk is an essential component of the evaluation of patients with depression. Many of the risk factors for suicide are similar to those for depression; when the circumstances surrounding completed suicides were reviewed, the following were found to be factors [25]:

Clinicians should ask questions to determine the duration of symptoms and explore possible triggers of depression [328]. Because of their lack of experience with discussing emotions, many men may be uncomfortable with open-ended questions such as, "How do you feel?"; rather, discussing emotions in situational contexts can help men better express what they are feeling and why [333]. It may also be helpful to de-emphasize the negative connotation of depression and frame questions within the overall context of health and well-being [314].

The treatment approach will depend on the severity of symptoms and the patient's preference. In general, a combination of psychotherapy and pharmacologic management provides the best results for most men [328,335]. Potential psychotherapy approaches include cognitive behavior therapy and interpersonal psychotherapy [300,307,328]. First-line pharmacologic treatment involves the use of selective serotonin reuptake inhibitors, such as paroxetine, sertraline, and fluoxetine [307]. This treatment approach has efficacy rates of 30% to 70% [328]. Clinicians should emphasize the importance of taking the medication as prescribed, as it may be two to four weeks before a benefit is evident [328]. Depression that is associated with chronic illness is often seen as an inevitable consequence of the disease, but the depression should be treated. Frequently, the treatment improves the overall outcome [335].