Hypogonadism is defined as deficient or absent male gonadal function that results in insufficient testosterone secretion. Hypogonadism may be primary due to testicular failure, or secondary due to hypothalamic-pituitary axis dysfunction, resulting in the production or release of insufficient testosterone to maintain testosterone-dependent functions and systems. Hypogonadism can also result from a combination of testicular failure and hypothalamic-pituitary axis dysfunction.

Hypogonadism affects an estimated 4 to 5 million men in the United States, and although it may occur in men at any age, low testosterone levels are especially common in older males. More than 60% of men over age 65 have free testosterone levels below the normal values of men aged 30 to 35. Studies suggest that hypogonadism in adult men is often underdiagnosed and under treated. This may be because the symptoms are easily attributed to aging or other medical causes, or ignored by patients and physicians. In fact, only about 5% of hypogonadal men receive testosterone replacement. Some experts also believe that we need to reevaluate normal testosterone the levels and lower the diagnostic cutoff for hypogonadism. By doing so, many patients who we now consider to be "low- normal" would probably be considered candidates for androgen replacement.

Signs and Symptoms of Hypogonadism
Low testosterone, or male hypogonadism, is associated with a number of signs and symptoms, most notably loss of libido and erectile dysfunction (ED). Other signs of low testosterone include depressive symptoms, a decrease in cognitive abilities, irritability and lethargy or loss of energy. Deficient endogenous testosterone also has negative effects on bone mass and is a significant risk factor for osteoporosis in men. Progressive decrease in muscle mass and muscle strength and testicular dysfunction, often resulting in impaired sperm production, are also associated with low testosterone levels.

A younger patient may have pure hypogonadism as a primary event, whereas an older man may have an age-related decline in testosterone production that is a part of his ED profile. However, because both ED and loss of libido are hallmarks of hypogonadism, any patient who presents with ED should have a basic hormone profile to determine if he has low testosterone. Treatments to normalize testosterone can not only improve libido, energy level and the potential to have normal erections, but can also improve the response to sildenafil, if that is deemed appropriate treatment.


Screening for Hypogonadism
An inexpensive and reliable screening test for hypogonadism is a morning serum total testosterone level, which measures free testosterone plus protein-bound testosterone. A morning sample is recommended, because testosterone levels demonstrate a diurnal pattern in which the highest level is reached in the early morning hours. Morning testosterone values <300 ng/dL (10.4 nmol/L) suggest hypogonadism and should be confirmed by a second assay.

If a repeat assay confirms low testosterone, luteinizing hormone (LH) should be measured to determine whether the cause is primary or secondary. LH levels <2 ng/mL suggest a hypothalamic lesion (pituitary adenoma, trauma, etc), whereas LH levels >10 ng/mL indicate primary testicular failure. Levels within the normal range suggest an age-related, decreased hypothalamic response to declining testosterone levels. In addition, serum prolactin should also be measured to rule out the presence of a pituitary tumor.

At our institution we are also currently measuring dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels. Some investigators believe that replacing DHEA in patients with low libidos and normal or borderline testosterone is an important component of treatment to restore sexual desire and performance. Although controlled clinical studies are needed to confirm this approach, there is growing evidence that DHEA may play an important role in the treatment of male sexual dysfunction.

ADAM Questionnaire
In addition to laboratory tests and a careful physical examination, a brief screening instrument has also been developed to aid in the diagnosis of hypogonadism. Researchers at St. Louis University created the Androgen Deficiency in the Aging Male (ADAM) questionnaire, which has been shown to be a highly sensitive (88%) instrument but with low specificity (66%), largely due to questions that identify patients with depression. However, because many men with hypogonadism don’t seek medical attention, instruments such as the ADAM questionnaire can be a useful way to screen for clinical symptoms of androgen deficiency. Once testosterone deficiency is confirmed, we then consider testosterone replacement therapy.

Goals of Treatment
The goal of testosterone replacement therapy is to provide and maintain a normal level of testosterone, thereby restoring libido and improving erectile function; improving mood and providing a sense of well-being; decreasing fatigue; and improving lean body mass, strength and stamina. Also, because hypogonadism is the most common cause of osteoporosis in men, testosterone replacement may improve bone density to help prevent this disease and related complications.

Contraindications
Testosterone treatment may stimulate tumor growth in androgen-dependent cancers and is therefore contraindicated in men with breast or prostate cancer. Some experts believe, however, that it may be used judiciously in men who are cured of prostate cancer when the benefits clearly outweigh the risks.

It is important to stress that hormone therapy doesn’t cause prostate cancer. However, if a patient already has prostate cancer cells, it can increase the growth rate of that cancer. Thus, we need to monitor patients closely for prostate cancer. Accordingly, a thorough examination of the breast and prostate should be performed on the initial visit and at follow-up visits in patients on testosterone therapy. A digital rectal examination and baseline and follow-up measurements of PSA levels are recommended for older men at increased risk for prostate cancer.

In addition to the absolute contraindications, relative contraindications for testosterone replacement are sleep apnea and benign prostatic hypertrophy (BPH). Some experts believe that high cholesterol levels and hematologic abnormalities should also be considered relative contraindications to hormone therapy.

Treatment Options
Several treatment options exist for testosterone replacement, including oral preparations of testosterone derivatives; intramuscular injections of long-acting testosterone esters; transdermal patches applied to the scrotum or other areas of the body (eg, upper arms, legs, abdomen, or back); and a recently approved 1% testosterone gel. Each method possesses a unique profile as described below.

The classic form of androgen replacement is injection therapy using one of the long-acting testosterone preparations such as testosterone enanthate or testosterone cypionate. Both of these agents have been widely used for many years and are the most cost-effective method of male hormone replacement. However, both preparations must be administered every 2 to 4 weeks, and although they are effective, they are not physiologic. Testosterone levels surge to supranormal levels approximately 72 hours after injection and then decrease for 14 to 21 days. By day 14 post injection, serum testosterone levels are again below normal. These highs and lows in serum testosterone may produce significant mood swings with noticeable fluctuations in libido and sexual functioning.

Oral Testosterone
The oral testosterone preparations (methyl testosterones) available in the United States result in unacceptable levels of hepatotoxicity and should not be used for testosterone replacement therapy. In addition, these oral agents have erratic androgenic effects, since they increase serum levels of testosterone metabolites rather than produce true elevations in testosterone.

Patches and Gel
Transdermal testosterone patches and gel formulations provide relative convenience, as well as controlled release of testosterone that maintains serum levels within the normal range. This controlled release mimics the normal circadian patterns of testosterone secretion and provides a more physiologic approach to testosterone replacement by producing high morning levels of the hormone.

The first available testosterone patch was applied to the scrotum at bedtime. Although it effectively produced physiologic levels of testosterone, it had the disadvantage of excessively increasing dihydrotestosterone levels, raising concerns about its potential effects on the prostate. In addition, the scrotal patch required weekly scrotal shaving and was difficult for some patients to apply and maintain in place for 24 hours.

Other transdermal testosterone patches are now available. These patches are applied at night to skin on the arms, back, abdomen, upper buttocks or thighs. They effectively produce peak physiologic levels of testosterone in the morning, as measured by objective laboratory methods. However, the downside of the nonscrotal testosterone patches is that many patients experience dermatologic reactions at the patch site. Even after pretreatment with topical steroids, some patients may develop severe, unacceptable dermatitis, requiring discontinuation of treatment.

The newest method of transdermal androgen replacement is testosterone gel 1%, which is available in 2.5 and 5 g packets. Patients are instructed to apply testosterone gel 1%, preferably every morning, to clean, dry, intact skin on the shoulders, upper arms, and/or abdomen. The rise in serum testosterone produced by the gel can be closely monitored, allowing you to accurately restore the patient’s testosterone into the normal range. Whereas testosterone patches are applied at night to accommodate their slow absorption, testosterone gel is applied each morning after a shower, as it is rapidly absorbed in only 2 hours.

Erectile dysfunction (ED) is a significant and common medical problem. Recent epidemiologic studies show that about 10% of men aged 40-70 have severe or complete erectile dysfunction, defined as the total inability to achieve or maintain erections sufficient for sexual performance. An additional 25% of men in this age category have moderate or intermittent erectile difficulties. Erectile dysfunction affects an estimated 30 million men in the United States, and over 617,000 new cases are expected annually in men between the ages of 40 and 69. The disorder is highly age-dependent, as the combined prevalence of moderate to complete ED increases from approximately 22% at age 40, to 49% by age 70. Although less common in younger men, erectile dysfunction still affects 5%-10% of men below the age of 40. Findings from these studies show that ED is associated with negative effects on mood state, interpersonal functioning, and overall quality of life.

Erectile dysfunction is strongly related to both physical and psychological health. Among the major risk factors are diabetes mellitus, heart disease, hypertension and decreased HDL levels. Medications for diabetes, hypertension, cardiovascular disease and depression may also cause erectile difficulties. ED may be an important presenting symptom in many of these men. In addition, there is a higher prevalence of ED among men who have undergone radiation or surgery for prostate cancer, or who have a spinal cord injury or other neurological diseases. Life style factors, including smoking, alcohol consumption, sedentary behavior and bicycling more than 3 hours a week are additional risk factors. The psychological correlates of erectile dysfunction include anxiety, depression and anger. Despite its increasing prevalence among older men, ED is not considered a normal or inevitable part of the aging process.

Most health care providers have received little or no training in sexual medicine, nor is adequate reimbursement provided in most instances for diagnostic or treatment services. Physicians have little time available to obtain sexual histories from their patients or lack adequate training to address sexual issues and concerns. Recent studies show that the large majority of patients feel uncomfortable in discussing sexual problems with their physician, despite the prevalence and emotional distress associated with these problems. Despite the above, major changes have occurred in the physician management of ED with the advent of effective oral therapy. Many millions of patients in the U.S. have received prescriptions for sildenafil since approval of the drug in 1998. Patient education and outreach activities have increased public awareness of ED and other sexual dysfunctions. March 2003 will mark the fifth year of clinical experience with sildenafil. There have been numerous publications in peer review journal noting the safety and efficacy data of sildenafil as a treatment for men with ED. Physicians as a result are relatively comfortable prescribing sildenafil as first-line therapy for ED.

A recent study of 3291 men with ED who had used PDE 5 inhibitors, however, showed that only 51% of men with ED spoke to their physician about ED. Only 28% of them tried PDE 5 at least once. Only 14% of ED patients were still using PDE 5 inhibitors. The most common reason (42%) to avoid PDE 5 treatment for ED was concern that the treatment was dangerous. This finding emphasizes the need for continued patient and physician education, since PDE 5 oral therapy for ED has been associated with excellent safety data. The most common reasons for discontinuing use of PDE therapy was that the erection was not hard enough (34%) and the medication did not work at all (34%). In 19% of respondents, side effects were responsible for the discontinuation of treatment.

For many ED patients, sildenafil has not been the medication that has provided a safe or effective response. In the near future, two additional oral erectogenic agents will likely become available for clinical use. Vardenafil is a phosphodiesterase type 5 (PDE5) inhibitor with a pharmacokinetic profile and molecular configuration similar to that of sildenafil. Like sidenafil, vfardenafil also has selectivity to PDE 6 inhibition. Tadalafil is another PDE 5 inhibitor which has a unique chemical structure and a pharmacokinetic and pharmacodynamic profile that differs from both sildenafil and vardenafil. Tadalafil also has a selectivity to PDE 11 inhibition. The availability of these new PDE5 inhibitors will expand our treatment armamentarium for ED but also raises important questions for physicians. What criteria will be used to choose among the three PDE 5 inhibitors? How do the new PDE 5 inhibitors differ from sildenafil?

To help select the most appropriate PDE5 inhibitor for patients with ED, it is important to examine some of the distinguishing characteristics of these agents, including biochemical potency, biochemical selectivity, onset, duration of action, and safety and efficacy data. At present, there are no carefully controlled head-to-head trials with the three PDE 5 inhibitors.

Biochemical Potency
PDE 5 inhibitors are signal amplifiers. The non-adrenergic, non-cholinergic neurotransmitter nitric oxide (NO) plays a critical role in attenuating smooth muscle contraction and inducing smooth muscle relaxation and penile erection. Activation of neurogenic and endothelial nitric oxide synthases results in synthesis of NO. Released NO diffuses into smooth muscle cells and binds to the heme component of soluble guanylyl cyclase, stimulating cyclic guanosine monophosphate (cGMP) synthesis. Binding of cGMP to cGMP-dependent protein kinases (PKG) or cGMP dependent ion channels results in reduction of intracellular calcium, via calcium sequestration and extrusion, and activation of myosin light chain phosphatases causing diminution of smooth muscle contractility and enhancing penile erection. As long as sexual stimulation releases NO into the penile smooth muscle cytoplasm, PDE 5 inhibitors increase cGMP and facilitate penile smooth muscle relaxation.

Biochemical potency for a PDE 5 inhibitor is considered the efficency of prevention of cGMP hydrolysis. The enzyme PDE 5 hydrolyzes cGMP, therefore, PDE 5 inhibitors prevent c GMP hydrolysis. PDE 5 inhibitors have different "on-off" binding rates to the active sites of the PDE 5 enzyme. The PDE 5 inhibitor which has the longest dwell time is the most biochemically potent. Multiple studies by various investigators have independently shown that vardenafil is the most biochemically potent of the three PDE 5 inhibitors. Vardenafil has a more pronounced increase of cGMP in the presence of NO in intact cells compared to sildenafil at equivalent doses. The PDE 5 inhibitory effect of vardenafil is approximately 10 fold higher than sildenafil.and 12 -15 times higher than tadalafil. Vardenafil is the only PDE 5 inhibitor which is subnanomolar in dose required to block 50% of the enzyme activity. Comparative clinical studies will determine if there are any clinically appreciable differences, such as side effect profiles, between the three PDE 5 inhibitors based on biochemical potency. Vardenafil doses (5, 10 and 20 mg) are 1/5 those of sildenafil (25, 50 and 100 mg).

Biochemical specificity - Biochemical selectivity
There are at present eleven known PDE enzymes. Selectivity is an important issue, because there are as yet no pure PDE5 inhibitors. In addition to inhibiting PDE5, both sildenafil and vardenafil also produce modest PDE 6 effects at the upper limits of the dosage range, whereas these effects are absent with tadalafil. Sildenafil and vardenafil have no significant effects on PDE's 1-4 and 7-11. All efficacy and safety attributes are likely related to PDE5/6 inhibition. PDE 6 inhibition affects the cones in the retina and results in the "blue" vision experienced by some patients taking sildenafil. In contrast, only tadalafil has definite PDE11 effects at therapeutic doses, although the clincial significance of this is not yet clear. PDE11 has only recently been described and is present in the pituitary, pancreas, skeletal muscle, heart, testes, and corpus cavernosum. However, the effects on these tissues of chronic or intermittent PDE11 inhibition are not known and require further study. In preclinical studies, tadalafil caused testicular alterations in beagle dogs characterized by degeneration of germ cell line cells in the seminiferous tubules and depressed spermatogenesis. Two studies in men, who received 10mg or 20mg tadalafil daily for 6 months, showed that tadalafil had no adverse effects on human spermatogenesis or reproductive hormones. The effects, if any, of either prolonged or intermittent PDE11 inhibition by tadalafil remain unknown.

Onset of Action
The median time to maximum plasma concentration of any drug is call the Tmax. The T max for sildenafil, vardenafil and tadalafil has been reported as 0.8, 0.6 - 0.9 and 2 hours, respectively. None of the PDE5 inhibitors work immediately. Onset of action is not affected by the dose of drug. Drugs with comparable Tmax should have comparable onset of action. A recent home study with active drug, vardenafil versus placebo utilized successful intercourse as the primary efficacy parameter to assess drug onset of action. A stop watch was started at 10 minutes post administration of the study medication. At 16 minutes, vardenafil (34%) was significantly more effective than placebo (22%). A similar study showed similar data for sildenafil. In a Rigiscan-based study, tadalafil (10 mg) showed significantly different response from placebo at 45 minutes after administration.. A high fat meal delays stomach emptying, which delays absorption of the drug. Sildenafil's average onset is 30 minutes when taken on an empty stomach and about 1 hour if not. Tadalafil is reported to have lack of a food effect. This is most likely due to the drug's delayed metabolism. As a result, slow gastric emptying has less effect on the time to maximum concentration.

Duration of Action
Among the three oral agents, the most clinically significant differences are found in duration of action. The reported half-life (T 1/2) of sildenafil, vardenafil and tadalafil is 4, 4 - 6 and 17 - 21 hours, respectively. The duration of activity that is seen with sildenafil and vardenafil appears to be suited to the average couples' patterns of sexual interaction. In a recent study of sexually active men aged 40 to 69 years both with and without ED, investigators found that the average frequency of sexual intercourse was 1 episode per week and that the average time for foreplay was approximately 14 minutes; the vast majority (> 70%) of men studied reported that they had sex only once in a 24-hour period. The duration of activity that is seen with tadalafil, however, offers ED patients a new sexual paradigm. It is possible that sexual spontaneity may be enhanced by the long half life.

Safety
The safety of PDE5 inhibitors is an important concern, since many men with ED also have cardiovascular disease. A careful assessment of cardiovascular status before prescribing treatments for ED and/or advising the patient to resume sexual activity is recommended. To date, there is no evidence that any of the PDE5 inhibitors has any direct adverse cardiovascular effects. In fact, the reverse may be true, as recent studies suggest that sildenafil may delay exercise-induced ischemia and angina.

Other safety issues specific to tadalafil also need to be considered. Because of the drug's prolonged duration of action (ie, approximately 17 hours in a healthy man and up to 21 hours in an elderly patient), it will take up to 4 days for tadalafil to be completely eliminated from the body. This could potentially extend the duration of adverse effects or delay intervention with nitroglycerin during a cardiac event. In addition, because tadalafil inhibits PDE11, additional studies examining the effects of tadalafil on cardiac function are needed.

In general, the PDE5 inhibitors are well tolerated and have similar mild to moderate adverse effects profiles. In clinical trials, the most commonly reported adverse events were vasodilation, resulting in headache, nasal congestion, facial flushing, and dyspepsia. There appears to be a greater incidence of myalgia and low back pain with tadalafil, although the etiology of the myalgia remains unclear.

None of the PDE5 inhibitors has any significant drug interactions except for an absolute contraindication for the concomitant use of organic nitrates. Sildenafil and all agents in this class potentiate nitrate-induced vasodilation. In addition, they are all metabolized by the cytochrome P450 3A4 isoenzyme system, and concomitant administration of inhibitors of this pathway (eg, cimetidine, ketoconazole, erythromycin, and protease inhibitors) will prolong duration of action and raise serum concentrations of the drugs.

Clinical Efficacy
Once the safety of the drug has been established, clinical efficacy is clearly a most important factor for the clinician to consider when selecting a drug. Evidence suggests that all 3 PDE5 inhibitors improve the quality of erections and enable successful intercourse in men with ED of all etiologies, even those with severe ED. The question as to whether men with certain comorbidities (eg, diabetes, post-radical prostatectomy, and hypertension) would be more successfully treated with one particular agent awaits further study and experience. To clearly define one drug's benefit or superiority over another requires carefully designed, head-to-head studies with well-defined efficacy measures. It is hoped that more sensitive measures of drug side effects can be developed. At present, simply the presence of a side effect is recorded. In the future is hoped that data comparing the intensity and severity of the side effect will also be available.

Conclusions
New oral treatments for ED will soon be available. How physicians will choose which drug to prescribe will be much the same as electing among other classes of drugs with multiple options, such as NSAIDs, alpha-blockers, or SSRIs. The selection process will take into account physicians' previous experiences, patient satisfaction and preferences as well as the recognition that similar drugs may have significantly different effects in the same individual.