Hosam Kamel MD
Laurie Dornbrand MD
Life expectancy today is 74 years for men and 80 years for women, a remarkable rise in longevity from 100 years ago, when men lived an average of 48 years and women an average of 51 years. Men aged 65 currently have a life expectancy of another 16 years compared with another 19 years for women. In the past 10 years, life expectancy at birth has increased more for males than females, narrowing the gender gap in longevity. It has been postulated that the improvement in longevity can be ascribed to advances in medicine, healthier lifestyles, improved access to health care, and generally better health before age 65.
HYPOGONADISM & HORMONAL CHANGES OF THE AGING MALE
ESSENTIALS OF DIAGNOSIS
Many but not all males undergo hormonal changes with age. Controversy exists regarding the terminology of male hormone change with age (eg, male menopause, andropause, male climacteric) and its clinical meaning. What is clear is that testosterone and the more clinically relevant forms bioavailable testosterone and free testosterone decline with age. Free testosterone measures the non-sex hormone-binding globulin (SHBG) non-albumin-bound testosterone, whereas bioavailable testosterone measures the non-SHBG-bound fraction (testosterone that is both free and albumin bound). The circadian rhythm of both free and bioavailable testosterone is blunted with age. Between the ages of 50 and 70, ~50% of healthy males will have bioavailable testosterone concentrations below the lowest level seen in men aged 20–40.
The decline in testosterone seen with aging appears to be due to secondary (hypogonadotropic) hypogonadism rather than primary hypogonadism. Low androgen in aging males often fails to produce an associated increase in luteinizing hormone (LH), suggesting an age-associated hypothalamic pituitary dysfunction. It appears likely that deficits reside at the hypothalamic/pituitary level, with an alteration in gonadotropin-releasing hormone (GnRH) secretory function, a decreased stimulation of LH, and delayed feedback by testosterone.
Signs and symptoms of testosterone deficiency may include decrease in libido, decreased strength and muscle mass, osteoporosis, anemia, and fatigue (Table 36-1).
A validated questionnaire as a hypogonadism screening tool has been developed.
Total testosterone levels may be normal in androgen-deficient elderly men because SHGB increases with aging. Therefore, free or bioavailable testosterone measurements are preferred. However, as an initial screen, a total testosterone level of < 200 can also be considered as diagnostic of hypogonadism. If the result is in the borderline range, either free or bioavailable testosterone should be measured. LH levels are not helpful in diagnosing hypogonadism in older men: A low value does not contradict the diagnosis.
Treatment with testosterone has been shown to result in a marked improvement in libido. In addition, feelings of well-being and improvement in mood can occur
with testosterone replacement in hypogonadal men. Improvement in muscle strength, bone mass, and erectile function appears variable.
Table 36-1. Signs & symptoms of gonadal deficiency in men.
Testosterone is usually administered via intramuscular injection or as transdermal patches. Oral testosterone is relatively contraindicated, as no 17β testosterone is available in the United States, and 17α compounds are associated with hepatotoxicity. Intramuscular injections of either testosterone enanthate or cypionate have an onset of action of 2–3 days and a duration of efficacy of ~2 weeks. A therapeutic response is sometimes seen after the second or third injection, even if there has been no response initially; thus, a series of 3 injections 2–3 weeks apart constitutes a reasonable therapeutic trial. Typical dosage regimens of testosterone injections are 200–300 mg intramuscularly every 2–4 weeks. Doses and dosing intervals are adjusted based on the extent and duration of the effect; it is not necessary to monitor testosterone levels. If treatment is successful and therapy is continued, the patient or partner may be taught to self-administer the injections.
Typical transdermal dosage regimens are 2.5–10 mg administered daily, usually adjusted in 2.5-mg increments. As with injections, they are titrated to effect, not serum level; however, as with injections, supraphysiological levels of bioavailable testosterone are not recommended. The scrotal patch (Testoderm) has been associated with skin irritation and adherence problems; because of the latter, shaving of scrotal hair is recommended. The nonscrotal patch (Androderm) is applied to truncal skin and has less associated skin irritation. Testosterone gel (Androgel) is applied to truncal skin (shoulders and abdomen). Skin-to-skin transfer to a partner is possible, so wearing a shirt over the application site is recommended during intimate contact.
Testosterone therapy is contraindicated in men with known or suspected prostate cancer. A baseline prostate-specific antigen (PSA) should be obtained before starting treatment; rectal exam and prostate symptom assessment are also recommended. Men with elevated PSA levels or abnormal prostate exams should be referred for urological clearance before considering treatment. Because testosterone stimulates red blood cell production, a baseline hemoglobin (Hgb) or hematocrit (Hct) should also be obtained. PSA and Hgb or Hct levels should be checked after 3 mo of treatment. However, polycythemia is dependent on neither dose nor duration of administration. PSA should be monitored at 6-mo intervals thereafter, as should hematocrit in men with values at the upper limit of normal. PSA increases of > 1.4 ng/mL between 2 measurements is cause for urological evaluation. Hct levels > 52 should prompt modification of the regimen.
Morley JE et al: Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000;49:1239. [PMID: 11016912]
MALE SEXUAL FUNCTION & DYSFUNCTION
Sexual behavior and interest continue into old age, although the proportion of sexually active persons declines. Of community-dwelling elders older than 70, ~30% report recent sexual intercourse. As in all age groups, there is marked individual variation in sexual interest and capacity. Apart from the increased prevalence of medical illnesses that impair sexual function, impediments to sexual activity in older adults may include social factors, such as unavailability of a sexually functional partner, and negative attitudes toward sexuality and aging.
Individuals who stay sexually active are less likely to report changes in function and may note less intense changes compared with those whose activity has been minimal or interrupted. This may in part reflect gradual adaptation to normal physiological changes, such as the need for increased time and stimulation to achieve erection, decreased firmness of erections, and increased sensitivity to drugs, such as alcohol, which impair sexual responsiveness.
ESSENTIALS OF DIAGNOSIS
Erectile dysfunction (ED) is the most common sexual dysfunction in men. Although this problem is often referred to as impotence, the latter term is imprecise and pejorative and thus preferably avoided. About 70% of men have ED by age 70, usually as the result of vascular disease. Vascular causes include atherogenic arterial disease (impaired inflow), venous disease (impaired outflow), or a combination of these. Other causes are listed in Table 36-2.
The goals of assessment are to identify the type and extent of dysfunction and contributing medical causes.
Chronic medical conditions, particularly diabetes and vascular and neurological disease, as well as prior surgical procedures in the abdominal-pelvic region should be identified. A complete list of medications should be obtained: Antihypertensive agents, including diuretics, and psychotropic medication are the drugs most likely to cause ED, but many other agents may beassociated, including alcohol and drugs of abuse. Patients should be asked to describe the onset of symptoms, the relationship of symptoms to events or medications, whether erections occur under any circumstances, such as with manual stimulation or spontaneously, and the estimated firmness of the best erections obtainable. Libido is typically unaffected; loss of libido raises the index of suspicion for hypogonadism as well as for pharmacological or psychological precipitants. The ability to have orgasms and to ejaculate is frequently preserved in men with ED; the absence of ejaculation suggests a neurogenic cause.
Vascular examination should include measurement of blood pressure, assessment of peripheral pulses, and auscultation for abdominal and inguinal bruits. Neurological exam should include deep tendon reflexes and motor-sensory exam of the legs. Integrity of the sacral plexus is assessed by perianal sensation (S2-S4), sphincter tone (S4-S5), and bulbocavernosus reflex, a contraction of the anal sphincter when the glans penis is squeezed (S2-S4). Secondary sexual characteristics (beard, body hair, and testicular size and consistency) as well as gynecomastia should be noted, but these are less sensitive indicators of hypogonadism in older men.
Testosterone should be tested in men with ED, although the diagnosis of hypogonadism in unlikely in a man with normal libido. Because of the strong association between diabetes and ED, and because ED can be the presenting complaint in type 2 diabetes mellitus, a fasting glucose level or HgbA1Cshould be obtained. Thyroid function tests and other baseline lab studies, such as complete blood cell count and chemistry panel with liver function tests should be performed if they have not already been done in the course of other medical care. When the index of suspicion is high, a prolactin level may be helpful but should not be ordered routinely.
Table 36-2. Causes of erectile dysfunction.
Vascular studies, ranging from Doppler measurement of penile pulsation to more sophisticated assessments of flow, are useful principally when surgical interventions are being considered. Nocturnal penile tumescence testing does not add significant information to that available from the history and physical exam.
A single cause for ED, such as a medication or hypogonadism, is identified in only a minority of older men. When a drug has been identified as the potential cause of ED, a period of 4–6 weeks off the agent may be necessary to detect improvement. In many situations, however, it is not practical to discontinue or change the offending medications. A trial of testosterone in hypogonadal men may be warranted if there are no contraindications. However, when the cause is multifactorial, testosterone treatment or adjusting medications alone may not be adequate to correct the problem.
The goal of treatment should be a satisfactory sexual experience rather than simply a firm erection. Choice among the available treatment options is influenced by patient and partner preferences. When possible, the patient's partner should be included in treatment decisions to clarify expectations and avoid misinformation.
Sildenafil has the longest safety record of these drugs and is preferred for that reason. Side effects are dose related and include headache, flushing, dyspepsia, and transient visual changes. It is available in 25-, 50-, and 100-mg tablets, and a starting dose of 25 mg is recommended in older men. Sildenafil should be taken 1–2 h prior to sexual activity and has a duration of action of about 4 hours. Absorption is slowed if the pill is consumed in proximity to a high-fat meal.
Vardenafil is available in 2.5-, 5-, 10- and 20-mg tablets and is similar in price, onset, and duration of action of sildenafil. Tadalafil is available in 5-, 10-, and 20-mg tablets, has a slower onset of action (~ 45 min) and a longer duration of action (~ 36 h) than the other two agents. High fat meals do not impact its absorption.
Patients should understand that these medications potentiate rather than produce erections; achieving an erection will still require sexual stimulation. The price of these pills is about 10 per dose; the tablets may be broken to reduce the cost per dose.
Vacuum tumescence devices are highly effective in ED of almost all causes and have few side effects and contraindications. Erections are induced by negative pressure, which enhances the flow of blood into the penis. This is attained by placing a plastic tube over the penis, obtaining a seal, and creating a vacuum with a hand or battery-operated pump. The erection is maintained by a latex constriction ring, which is slid off the tube onto the penis and may be left in place for up to 30 min. Men with Peyronie's disease may have difficulty fitting a cylinder over the penile curvature, and caution is recommended in those taking coumadin, although serious bruising is rarely a problem. The erections achieved are
not completely the same as a natural erection; patients and partners may describe a cold blue penis and hinge effect (the penis pivoting from the base). An unexpected benefit in a small proportion of men is the spontaneous return of natural erections after a period of using the device. Although this phenomenon has not been studied, it is theorized that the repeated stimulation increases regional vascularity.
Patient reluctance to use a mechanical device may be difficult to overcome. However, a skillful orientation to the use of the vacuum device enhances the chance of success. The cost of a set ranges from $150–400; a substantial proportion is reimbursed by Medicare. It is highly recommended that devices be dispensed from companies with strong customer support and preferably with available clinical instruction in using the system.
Patient preference should dictate the therapeutic option chosen. Penile prosthetic devices are usually used as a last resort. Options include malleable, hinged, rigid, or inflatable devices. Ideally, the potential burdens and benefits of each option should be discussed extensively with a physician with expertise in the area before a decision is made.
Fink HA et al: Sildenafil for male erectile dysfunction: a systematic review and meta-analysis. Arch Intern Med 2002;162:1349. [PMID: 12076233] (This update concluded that sildenafil is safe and effective and is not associated with adverse cardiovascular outcomes in men who are not taking nitrates.)
Goldstein I et al: Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998;338:1397. [PMID: 9580646] (Sildenafil was safe and effective in a variety of causes of erectile dysfunction.)
Lue TF: Erectile dysfunction. N Engl J Med 2000;342:1802. [PMID: 10853004] (A thorough review of pathophysiology and treatment of erectile dysfunction.)
Ejaculation, the forceful emission of semen from the urethra, is distinct from orgasm, although the 2 processes typically occur together. The volume of ejaculate is decreased in normal aging, as are duration and intensity of orgasmic contractions.
Retrograde or absent ejaculation occurs in older men as a result of incomplete closure of the bladder neck during ejaculation. This condition may result from transurethral prostatectomy (TURP) or bladder neck incisions, diabetic autonomic neuropathy, α-blocker therapy for prostatism, as well as spinal cord injuries. Cloudiness of the first voided urine after ejaculation helps establish the diagnosis; microscopic examination of the urine for spermatozoa can be performed but is rarely necessary. Unless fertility is an issue, which is not often the case for an older man, treatment to reverse retrograde ejaculation is rarely pursued, and reassurance may be the only treatment necessary. Premature ejaculation is the most common ejaculatory dysfunction in younger men but is unusual in the elderly.
Delayed or absent orgasm may be a side effect of antidepressant medications, notably the selective serotonin reuptake inhibitor (SSRI) class. Clinical surveys suggest that these effects are more common than is reported in the drug literature. Antidepressants with the lowest prevalence of side effects are reportedly bupropion (Wellbutrin), nefazodone (Serzone), and possibly mirtazepine (Remeron). Reasonable approaches to managing anti-depressant-induced sexual dysfunction are to reduce the drug dosage, wait for adaptation, and consider interrupting drug treatment or switching to a drug with presumed lower incidence of dysfunction. A number of pharmacological antidotes have been used, including sildenafil, buspirone, and psychostimulants, based largely on case reports rather than controlled studies.
BENIGN PROSTATIC HYPERPLASIA
ESSENTIALS OF DIAGNOSIS
The incidence of benign prostatic hyperplasia (BPH) increases in men after age 40. Approximately 50% of men between the ages of 51 and 60 in the United States have BPH. By the age of 80, the prevalence is 80%. Both genetic and environmental factors have been implicated in the development of BPH.
Men with BPH often present with lower urinary tract symptoms, including increased urinary frequency, urgency, nocturia, intermittent urination, incomplete bladder emptying, straining on micturition, and weak urinary
stream. Such symptoms may be caused by conditions other than BPH (eg, lower urinary tract infection, bladder cancer, bladder stone, or prostate cancer). Thus, initial assessment of a patient presenting with lower urinary tract symptoms should focus on ensuring that these symptoms are due to BPH and not other causes.
Assessment of the degree of the symptoms of BPH and their impact on the quality of life is easily achieved using a symptom score sheet developed by the American Urologic Association (AUA; Table 36-3). In this assessment tool, each symptom is assigned a score. Based on the total score, symptom severity is described as mild, moderate, or severe. This symptom score is not specific for BPH and thus should be corroborated with other signs from the history and physical.
A comprehensive medical history and a focused clinical examination combined with targeted tests enable an accurate diagnosis of BPH in the majority of cases.
The digital rectal examination (DRE) is an important component of the physical examination of a man presenting with lower urinary symptoms. During this examination, prostate size, shape and consistency should be evaluated. The prostate gland in an individual with BPH is usually smooth, symmetrically enlarged, and rubbery in consistency, and the central sulcus can often be felt. A tender, firm prostate usually indicates prostatitis, whereas a hard, nodular prostate with loss of the central sulcus should raise the suspicion of prostate cancer (see Chapter 30 for a discussion of prostate cancer). However, it is the posterior portion that can be palpated. Urinalysis and a kidney function test should also be performed in men presenting with lower urinary symptoms. PSA testing is optional and depends on patient preferences and goals of care. Current recommendations include DRE and PSA assessment in men older than 50 with a life expectancy > 10 years. Risks and benefits of screening should be discussed.
Treatment depends on severity of symptoms and patient preferences. Patients with mild symptoms (AUA scores
< 8) usually do well with watchful waiting. Those with moderate to severe symptoms (AUA scores ≥ 8) should be counseled on the benefits and risks of watchful waiting, medical therapy, and surgery. Patients with moderate to severe symptoms may require additional testing, including urinary flow rates, postvoid residual urine, and ultrasonography. Men who have refractory urinary retention, recurrent urinary tract infection, recurrent or gross hematuria, bladder stones, or renal insufficiency related to BPH should be counseled to receive a more acute form of intervention such as surgery.
Table 36-3. Symptom score sheet to assess BPH symptoms.
The α1-receptors are situated on smooth muscle cells in prostatic stroma and capsule as well as in the urethra and bladder neck. Norepinephrine binds to the α1-receptors and stimulates smooth muscle contraction, resulting in urinary outflow obstruction. Prazosin, a selective α1-receptor blocker, was found to improve symptom scores and urine flow rates and decrease postvoid residual volume in patients with BPH. Other selective α1-receptor blockers include doxazosin and terazosin. More recently, so-called uroselective inhibitors of the α1A-adrenoreceptors (eg, tamsulosin) have been developed and are useful in men with lower blood pressure, orthostasis, or other cardiovascular side effects. The α-adrenergic receptor blockers have been shown to improve symptom scores and flow rates. These drugs have a rapid onset of action, with symptom improvement that may begin rapidly, and achieve full therapeutic benefit by 3 mo. Side effects of α-adrenergic receptor blockers were reported in 10–15% of cases and include orthostatic hypotension, fatigue, dizziness, headaches, falls, and, less frequently, asthenia, palpitations, and gastrointestinal disturbances such as nausea, vomiting, diarrhea, and constipation. Although the hypotensive effect of α1-blockers may be desirable in some hypertensive patients with BPH, α-blockers are not associated with the beneficial cardiovascular effects seen with other antihypertensive classes and should not be considered as the most appropriate antihypertensive therapy. Dosages are as follows: prazocin, 1–5 mg orally twice daily; terazocin, 1–10 mg orally every day; doxazocin, 1–8 mg orally every day; and tamsulosin, .4-.8 mg orally every day. One should start with the lowest possible dose and increase slowly until the patient is satisfied or the maximum dose is reached. The physician should warn the patient about the potential of orthostatic hypotension, particularly with any increase in dose.
Finasteride, a drug that inhibits the 5 α-reductase enzyme, has been shown to reduce urinary retention and need for invasive therapy in men with BPH and demonstrated prostate enlargement. Combination therapy with an α-blocker and finasteride reduces the risk of overall clinical progression of BPH when compared to either therapy alone. Finasteride may decrease overall prostate cancer while increasing the risk of high-grade prostate cancer. Other side effects of finasteride include decreased libido and erectile dysfunction. Because of the potential risk associated with its use, physicians should counsel men about potential risks and benefits before beginning finasteride therapy. The dose is 5 mg orally daily.
Saw palmetto and other herbal supplements are commonly used by men as treatments for BPH. Data suggest that saw palmetto can improve symptoms but has no effect on urinary flow rates or quality of life. Side effects may include gastrointestinal distress, and decreased libido.
Surgical options include TURP, transurethral incision of the prostate (TUIP), and open prostatectomy. TURP achieves ≥ 75% chance of symptom improvement and ~85% reduction in symptom score. Complications include bleeding requiring transfusion in 8% of cases, urethral strictures and bladder neck stenoses requiring surgery in 5% of cases, and rarely the development of transurethral syndrome, which results from the absorption of irrigating fluid via the prostatic veins, resulting in hyponatremia and volume overload. In addition, 65% of men will have retrograde ejaculation after TURP. TURP does not, however, affect potency. Open prostatectomy is used when the prostate is too large for endoscopic removal or in the presence of other comorbid urological conditions, but it has a higher complication rate than TURP. TUIP is an option for some men with small prostates and moderate to severe symptoms and is associated with fewer complications than TURP. Other techniques include transurethral vaporization of the prostate, laser ablation, transurethral microwave thermotherapy, transurethral needle ablation, and balloon dilation.
McConnell JD et al: The long-term effect of doxazocin, finasteride, and combinatin therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387. (This 4.5 year trial found that combination therapy with doxazocin and finasteride reduced the risk of overall clinical progression of BPH more than did treatment with either drug alone.)
AUA Practice Guidelines Committee: AUA Guideline on management of benign prostatic hyperplasia (2003). Diagnosis and treatment recommendations. J Urol 2003;170:530. (Reviews evaluation and treatment of BPH based on current evidence.)
Thompson IM et al: The influence of finasteride on the devleopment of prostate cancer. N Engl J Med 2003;349:215. [PMID:12824459] (This randomized trial suggested that finasteride prevents the appearance of prostate cancer, but increases risk of high grade prostate cancer. Men taking finasteride had fewer urinary problems but higher rates of sexual side effects than the placebo group.)