Erectile Dysfunction Articles

Antidepressants

Many patients suffering from mood disorders have sexual difficulties. Studies suggest that at least half of patients will have some aspect of sexual functioning affected. Loss of interest and social withdrawal may have profound influences on the ability to maintain intimate relationships. Although loss of interest in sex is probably the most common aspect of sexual dysfunction, depressive disorders may also affect arousal, and orgasm, the same three parameters that many antidepressants affect. Mood disorders may lead to loss of interest in sex, emotional withdrawal from a love interest, and subsequent performance anxiety about having sex. Hence, unless clinicians take detailed sexual histories at the start of antidepressant treatment, and ideally before mental disorders begin, separating the sexual difficulties of the mood disorder from those induced by the antidepressant is difficult, if not impossible. In addition to loss of desire, arousal or orgasm dysfunction associated with a depressive disorder, patients may also have pre-existing sexual problems (e.g. premature ejaculation or anorgasmia) and medical problems (e.g. diabetes, peripheral vascular disease, or ischemic heart disease) that may compromise sexual functioning. Even though patients may have multiple factors contributing to sexual dysfunction, patients appear reluctant to volunteer sexual information to clinicians, and physicians may be reluctant to ask about sexual matters. Not surprisingly, studies find that patients are far more likely to report sexual difficulties when they are directly queried rather than when the clinicians give them the chance for an unprompted response.

Until recent years, studies of antidepressants did not specifically address sexual side effects and relied completely on self-report. This led to low reported rates of sexual dysfunction. For example, the initial PDR rate for fluoxetine-associated sexual effects was 1.9%, though many studies later found rates to be between 30–40% of patients.

Serotonin Reuptake Inhibitors

The selective serotonin reuptake inhibitors (SSRIs) are a group of antidepressants that increase the availability of serotonin in the synapse via inhibition of the serotonin transporter. For this review, SSRIs will refer to the usual medication grouping (fluoxetine, citalopram, escitalopram, paroxetine, sertraline, and fluvoxamine) as well as the two drugs that inhibit serotonin and norepinephrine reuptake (venlafaxine and duloxetine).
Although serotonin’s effects on sexual behavior are complex and not fully elucidated in animal models, in general, increased synaptic serotonin has an inhibitory effect on sexual functioning. The individual SSRI agents vary slightly in their pharmacologic profiles, with a range of potency at the serotonin transporter, and some have effects on other receptor sites that may influence sexual functioning. For example, fluoxetine mildly inhibits norepinephrine reuptake, while sertraline modestly blocks reuptake of dopamine. Paroxetine, perhaps the most problematic of the SSRIs for sexual function, slightly blocks postsynaptic dopamine type 2 receptors and also inhibits nitric oxide oxidase activity, thereby affecting sexual function by multiple mechanisms.

Even though the SSRIs have a clear reputation for affecting sexual functioning, there are relatively few placebo-controlled prospective studies carefully evaluating sexual effects of the SSRIs. Because sexual problems are common in the general population as well as in depressed individuals, it remains somewhat difficult to fully ascribe the sexual effects associated with depression treatment solely to antidepressants. Moreover, different rating scales are used in the studies, and there are no prospective randomized placebo-controlled studies comparing all of the SSRIs.

Nonetheless, the limited number of prospective studies investigating individual SSRI drugs in depressed patients suggests that the SSRI antidepressants are generally similar in their propensity to affect sexual function. There is no evidence that one SSRI is superior to another. Although all aspects of sexual functioning are affected, including libido, arousal and orgasm, there is some suggestion that delayed orgasm is the most commonly affected sexual parameter. In many studies, however, the magnitude of change is relatively small and it is difficult to determine the clinical relevance of the sexual change and to dissect the drug effect from the depression effect on sexual function.

In the last 5 years, a few studies have been specifically performed to evaluate sexual function with antidepressants. There have been a number of pharmaceutical company studies sponsored by manufacturers of mirtazapine or bupropion, attempting to show their relative benefit for sexual side effects compared with SSRI antidepressants. These studies have shown some advantages, but they are not overwhelming. Studies that specifically evaluated sexual function are reviewed below.

In a short-term study comparing venlafaxine (mean dose 150mg) with bupropion (mean dose 300mg) for depression (n = 328), sexual function was rated over the course of the study with a validated rating scale. In the depressed patients with so called normal sexual functioning at the start of antidepressant treatment (n = 251), the authors found that patients treated with venlafaxine fared less well than those treated with bupropion in all aspects of sexual functioning. This difference between treatments was statistically significant, but the change in magnitude was quite small (three points, with a baseline score over 42 for women and 48 for men), making it difficult to determine if the change was clinically significant. Moreover, the change on individual items (pleasure, desire, arousal and orgasm) was less than a point. Although the authors, funded by the manufacturers of bupropion, concluded that bupropion ‘had a significantly more favorable sexual side effect profile’ than venlafaxine, the data suggest a small advantage. The study’s findings were limited by the lack of a placebo comparison group.

In a study (n = 345) comparing sertraline with mirtazapine for rate of onset of antidepressant effect, sexual effects of mirtazapine and sertraline were also studied prospectively. This was a usual clinical trial sample that excluded patients with systemic medical conditions, many of which also affect sexual functioning. As with the bupropion and venlafaxine study listed above, the difference between the two groups with regard to sexual functioning was quite small. The study found no overall differences between groups on depression symptoms, and very minor, though statistically significant changes on a sexual rating scale. Interestingly, there is some evidence of improvement in sexual functioning over the course of the study in both groups, with somewhat higher rates attaining normal sexual function in the mirtazapine group than the sertraline group. Without a placebo comparison group, a limited number of conclusions can be drawn, though it appears that in this sample of patients the sexual side effects were relatively modest. The authors, funded by the manufacturer of mirtazapine, however, concluded that ‘mirtazapine had a greater effect than sertraline on sexual functioning’.

In a placebo-controlled study (n = 456) evaluating bupropion and fluoxetine for depression, patients were specifically questioned whether several parameters of sexual functioning (orgasm, desire, or arousal) were present or absent, and if the sexual parameter was rated as ‘better’, ‘no change’ or ‘worse’ than baseline. Hence, this study primarily measured if a problem was present or absent and did not measure severity on a graded rating scale. Over the course of the study, the percent of patients with sexual desire problems did not change in the fluoxetine or placebo groups, though the problematic percent dropped in the bupropion group (25–10%). Sexual arousal, however, worsened in approximately 10% in the fluoxetine and placebo groups and was no different from bupropion. Only in orgasm dysfunction was there a clear difference between fluoxetine, placebo, and bupropion. For orgasm dysfunction, approximately 30% of the fluoxetine patients reported orgasm difficulty; while only 10% of placebo- and bupropion-treated patients experienced this problem. This study, more than others, demonstrated that orgasm is the principal sexual function affected by fluoxetine.

A careful study evaluating bupropion and sertraline (again, without a placebo group)  funded by the manufactures of bupropion, took into account sexual functioning problems at the start of antidepressant treatment. The authors found that sertraline was associated with more sexual problems than bupropion. At the start of the study, however, 43% of patients in both groups were not satisfied with their sexual functioning. Following treatment, the percent of sertraline-treated patients that were unsatisfied did not change, but the bupropion treated patients fared better, with only 21% reporting that they were unsatisfied. Both groups improved similarly with respect to depression. Comparing groups according to rates of dissatisfaction is somewhat difficult to appreciate, but overall, it is reasonable to conclude that bupropion helped reverse sexual dysfunction as depression remitted, but sertraline did not improve sexual functioning as patients’ mood increased. Additionally, orgasm dysfunction (defined as delay and/or failure) was far more common with sertraline than bupropion (52 vs. 8%), but the magnitude of this dysfunction was not delineated. That is, it was not reported how many of the patients had orgasm failure and how many were only delayed. In some cases, particularly for men, delay in orgasm would not be of serious consequence. Thus, although the difference between the two drugs appears impressive, it is not certain that the difference was of meaningful clinical significance.

In a study comparing fluoxetine (n = 150) with reboxetine (n =150) and placebo (n = 150) in depressed patients, overall sexual satisfaction was relatively low at the start of treatment (mean score approximately 35 on a visual analogue scale from 0 to 100), and following treatment there was a relatively small increase (7 points) in sexual satisfaction in the placebo group compared to a small decrease (4 points) in the fluoxetine group. Although this difference was statistically significant, the clinical relevance is marginal, and, overall, patients were still rating their overall sexual satisfaction score at a low level. Fluoxetine was similar to placebo on several dichotomous items regarding sexual functioning, though fluoxetine-treated patients were more likely than placebo-treated patients to endorse that ‘more stimulation was needed to attain an erection than usual’ (42 vs. 21%).

Finally, in a pooled analysis of 1,477 patients enrolled in studies sponsored by the manufacturer of duloxetine that compared duloxetine (40–120mg/day) with paroxetine (20mg/day) and placebo, investigators found that paroxetine was associated with sexual dysfunction more frequently than duloxetine or placebo. Of note, 59% of the patients reported significant sexual dysfunction at the start of drug treatment as measured by a brief questionnaire. Among 475 patients who completed baseline and endpoint rating scales and ‘did not report significant sexual difficulties with sex drive, arousal, or orgasm at baseline’, there were considerable treatment-emergent sexual adverse effects following treatment. The definition of sexual dysfunction was quite wide, ranging from patients with ‘somewhat difficult troubles’ to ‘inability to get aroused or have orgasm’. The incidence of newly acquired sexual dysfunction was as follows:

• paroxetine 61%,
• duloxetine 46%,
• placebo 29%.

This suggests that although duloxetine may be somewhat less problematic than paroxetine, there remains considerable risk for sexual dysfunction, albeit for a range of impairment. For the patients who developed more severe sexual dysfunction (rated as ‘very difficult’ to ‘never have orgasm or arousal’) there were differences only in the orgasm dimension. The presence of serious orgasm difficulties following treatment were as follows: paroxetine 20%, duloxetine 16%, placebo 9%. Both drugs led to serious orgasm difficulties more than placebo and there were no differences between the two antidepressants for this more serious adverse effect. In all, it appears that duloxetine frequently caused minor sexual problems, at slightly higher rates than paroxetine, but duloxetine w as j ust as l ikely to c ause s ignificant o rgasm difficulties as l ow-dose paroxetine.

Sexual dysfunction is common in the general population and even more common in the mentally or medically ill.

– Because mentally ill patients are often prescribed psychotropics, many of which are well known to affect sexual functioning, a patient’s preexisting sexual difficulties are often compounded, and these adverse effects may contribute to psychological difficulties or medication discontinuation.

– Because psychotropics may ameliorate seriously debilitating illnesses, such as depressive disorders or schizophrenia, stopping medication may have profound negative effects, such as job loss or marital disruption.

It is therefore critical to understand the effects of psychotropics on sexual function in the mentally ill and to make use of this information in prescribing patients psychotropics.

Although some aspects of psychotropic-associated sexual dysfunction are understood, unfortunately many are not. Clinical trials evaluating sexual function often exclude patients with systemic medical problems or multiple medications that could affect sexual functioning. Parsing the effect of the mental illness and the psychotropics on sexual function is also not well established and may be impossible. Sexual functioning or sexual well-being is complex, with multiple contributing psychological, interpersonal, and medical factors. For example, serotonin reuptake antidepressants are frequently prescribed for depressed patients with coronary artery disease following myocardial infarction or cardiac surgery. With so many possible contributors to sexual dysfunction (e.g. peripheral vascular disease, cardiac medications, depression, marital problems, antidepressant use), isolating the effect of one variable, such as a single psychotropic, is unrealistic. Hence, the state of the art is derived from patients with uncomplicated disorders, usually taking just one medication.

Furthermore, because sexual function or dysfunction is difficult to measure, the meaning of the findings is sometimes difficult to interpret. A person’s description of sexual functioning is likely affected by perception of social norms and may have a common variation influenced by relationships and cultural factors. Rating scales may be inefficient in detecting subtle differences that are highly subjective. Although there are numerous rating scales, usually with expanded items related to sexual interest, genital arousal, orgasm, and overall satisfaction, none is uniformly employed, thereby making comparisons between drugs difficult. Even the so-called validated rating instruments, when used in clinical trials of psychotropics, produce findings with small changes of marginal importance, such as mild delay in orgasm, a sometimes welcome effect for men. When changes in sexual functioning are in the mild range, the findings are of questionable clinical validity because it is difficult to know if these changes are related to the normal fluctuation of sexual function, the illness being treated, or the effects of drugs. Thus, only categorical findings (e.g. inability to attain orgasm) or truly measured effects (e.g. minutes to reach orgasm) may have true face validity.

Clinical trials specifically addressing sexual functioning rarely have a placebo control group. Hence, little is known about the sexual effects of the antidepressants compared with placebo. Placebo-controlled studies may not force questions about sexual functioning, but often rely on spontaneous reports, which are well known to be less forthcoming than direct inquiry. Most large studies are drug company-sponsored, and those specifically addressing sexual functioning are often sponsored by the company whose drug is suspected to have fewer sexual side effects. These studies may report small differences that are statistically significant, but of uncertain clinical difference, and these studies ordinarily do not include a placebo group.

Most importantly, studies generally do not address premorbid sexual functioning. Because it is well known that mental illnesses affect sexual functioning and disrupt interpersonal relationships, it is very difficult to ascribe sexual difficulties to illness or the drug. These two factors, of course, are not the only contributors to sexual functioning, for systemic illness and substance abuse also accompany patients with mental illness and further complicate the conundrum. An ideal study to address the effects of drugs on sexual functioning would measure sexual functioning in physically healthy patients before the illness started and then prospectively follow the changes in sexual functioning following the start of the drug. In addition, a control sample would be needed to determine how much variability could be attributed to the natural course of being in drug treatment for a mental illness.
Cross-sectional comparison studies of psychotropics avoid the issue of the effects of disease and drug. In these studies, it is impossible to determine if it is the drug or the disease that is responsible for a person’s sexual dysfunction. Without randomization or a comparison sample taking placebo, it is impossible to know the contributions of a drug to a person’s reported sexual problems. In the cross-sectional design, isolating the effects of a drug on sexual functioning is nearly impossible because preexisting conditions could certainly be culpable for the current difficulties, even though attempts are made to retrospectively isolate the drug effect from long-standing psychological factors, the effects of psychiatric illness, occult substance abuse, or undiagnosed medical conditions.

With these limitations in mind, this chapter will review the clinical effects of psychotropics on sexual functioning and what, if anything, can be done to treat adverse effects associated with psychotropic medications. Emphasis will be placed on those randomized, placebo-controlled clinical trials in which sexual functioning was specifically evaluated with a rating instrument. Because these are relatively few, other comparison and naturalistic clinical trials will also be addressed. Most psychotropic studies evaluating sexual dysfunction concern antidepressants, though there is a reasonable body of evidence regarding antipsychotics, and a much smaller literature about mood stabilizers, and anxiolytics.

The effects of antidepressants, antipsychotics, mood stabilizers and anxiolytics on sexual functioning will be reviewed. When possible, the types of sexual dysfunction (e.g. desire, arousal, or orgasm) induced by the drug will be described. Additionally, treatments to alleviate psychotropic-associated sexual dysfunction will be detailed, but there is, unfortunately, precious little controlled data about how to effectively treat drug-induced sexual problems. Until effective psychotropic medications are discovered that do not affect sexual functioning, coping with these vexing problems remains a challenge.

Physical Examination

Generally, the distribution of body hair, adipose tissue and muscle bulk should be recorded. All men should have blood pressure, heart rate, waist circumference and weight measured. Any evidence of abdominal masses can be recorded. All patients should have a focused physical examination of the genitals. This is essential if there is a rapid onset of pain, deviation of the penis during tumescence, symptoms of hypogonadism or other urological symptoms in the past or current. The genitalia should be inspected and the general size, shape and characteristics of the penis and testicles should be noted. When evidence of fibrosis of the penis (Peyronie’s disease) or problems with the foreskin including phimosis and paraphimosis observed, these should be recorded. Testicular size, consistency and presence should be noted. Specific neurological examination includes the glandular pudendal reflex and the cremasteric reflex as well as general sensation in the perineal area. Where there are genitourinary or protracted secondary ejaculatory symptoms digital prostate examination is advised.

Laboratory Investigations

All patients should be screened for fasting blood glucose to exclude diabetes mellitus. A total testosterone level should be measured between 8:00 am and 10:00 am, and if this is low it should be repeated alongside measures of FSH and LH. A reasonable estimate of free and bioavailable testosterone levels can be calculated from total testosterone, sex hormone-binding globulin and albumin levels. The serum prolactin should be measured in all cases and if raised should be repeated in a fasting state and cannulated. A fasting lipid profile is useful to assess total cholesterol and HDL levels. Where urological symptoms are evident a PSA level should be measured. If there are concurrent problems of sexual desire then thyroxine/TSH should be measured.

Additional Investigations

The use of intra-cavernosal injection of alprostadil, into the corpus cavernosum of the penis to augment penile response either in clinic or during either RigiScan investigation or ultrasound investigation is well reported. The specific use of specialist investigations varies between departments and clinical need. Specialist units may use devices such as the RigiScan which allows both real time (provocative) and night time/sleep (nocturnal) recordings or ultrasound recordings for confirming the diagnosis and extent of primarily vascular disease. However its value in discriminating between neurological and psychogenic disease is also worth of note. Where there are suggestions of veno-occlusive disorder, ultrasonography followed by, if necessary, cavernosometry or cavernosography is appropriate. Where patients have symptoms suggestive of significant psychological contribution nocturnal penile tumescence and/or provocative RigiScan may be useful to confirm normal function. The normal parameters would be a minimum of 3 erections per night on at least one of three nights. Each erection should last at least 10 min with change in girth at both the base and the tip and with greater than 60% rigidity at the tip.

Measurement Tools

Validated questionnaires including the International Index of Erection Function (IIEF) and the validated shorter version the Sexual Health Invention for Men (SHIM) can assess sexual function domains as well as the impact of interventions and treatments. They do not replace a through history or medical examination. The use of the self-administered IIEF questionnaire is the basic tool used in assessing and monitoring treatment in erectile function. It is simple for patients to complete and is sensitive and specific in detecting treatment-related changes in ED. Fifteen questions deal with erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction. The ability to maintain erections during sexual intercourse is the best discriminator between men with and without ED. The score of 21 has a sensitivity of 98% and specificity of 88%. Scores of 22 and above indicate normal ED.

Aetiology

A number of medical conditions are known to be associated and instrumental in bringing about ED. The commonest group of conditions are those affecting the cardiovascular system and particularly the peripheral vessels. Peripheral vascular disease, hypertension and diabetes mellitus are common conditions in the community and commonly associated with ED. Despite this there has been, until recently, very little research undertaken to establish the relative risk of sexual problems associated with these conditions, predictors and response to intervention and the impact and consequences of the disease state and any treatments provided. ED and heart disease have both common and shared risk factors. These have been described as diabetes mellitus, hypertension, dyslipidaemia and smoking cigarettes.

Oxidative stress and damage brings about endothelial dysfunction. Patients with cardiovascular disease and diabetes mellitus share a common factor of endothelial dysfunction. This has been shown to occur prior to the formation of atherosclerotic plaques and provides the link between vascular disease and ED. Patients with no apparent cardiovascular disease or diabetes mellitus have also been found to have impaired endothelial function where there is ED.

Hence, it is recognised that ED can act as a sentinel for many underlying medical states but the stigma associated with ED leads to only a minority of cases being brought to the attention of medical professionals. ED is considered to be a harbinger of cardiovascular events in some men and so prompt investigation and intervention for cardiovascular risk factors is imperative. Montorsi et al. provide illustrative representation to show the importance of ED as a predictor for subsequent coronary artery disease. The relative arterial diameters illustrate how a 50% reduction in penile artery flow brings about ED long before similar symptoms emerge from coronary artery symptoms.

Symptoms of depression may be the consequences or aetiology of ED. Many common factors may be etiologically responsible for both depression and ED. The prevalence of depression in men with ED was 25% when compared with men without ED in whom it was 13%. A separate survey of over quarter of a million men with ED found the prevalence of depression to be 11.1%.

Other conditions which should be excluded include late-onset hypogonadism, Peyronie’s disease and prostatic disease.
The interplay between psychological factors as a consequence and reaction to any physical disease state deserves considerable attention. For example around 1 in 3 patients following a myocardial infarction suffer with symptoms of anxiety and depression. Anxiety and depression have been noted to be major contributors in both the aetiology and maintenance of ED. The psychological impact of incapacity and disability, ongoing circulatory dysfunction with heart failure and the consequences of drug treatment for both cardiovascular diseases as well as for depression can all have a compounding and negative impact on a person’s wellbeing, quality of life and erectile function.

Communicating with Patients

For those who have the sequelae of cardiovascular disease, such as a myocardial infarction, communication between physicians and patients remains limited. The whole issue of communication and discussion around themes of sexuality with patients remains unclear, although the evidence would suggest that increasingly patients expect to be able to receive clear and accurate information from their physicians, even if it is them who have to raise the subject.

A postal questionnaire sent to doctors, nurses, physiotherapists and occupational therapists investigated views about acute and rehabilitation settings and discussing sexual issues with patients. 90% of respondents agreed that the sexual issue should be addressed, although 68% admitted to never initiating discussion, 26% initiated only a few times and only 6% initiated on a regular basis.

The reasons given as barriers to communication were:

• lack of training (76%),
• lack of time (67%)
• embarrassment (50%).

Additional attention barriers were:

• patient age (61%),
• physical status (54%),
• gender (52%)
• marital status (42%).

Only 14% reported significant training with the other 86% having either no training (46%) or only minimal (40%).

There are certain groups of men whose needs are often neglected including the older man who may be more reluctant to disclose sexual symptoms to a physician. Similar issues of poor training and fear of raising the subject have been described by Humphrey and Nazareth and Rele and Wylie. Humphrey and Nazareth noted personal embarrassment, inadequate skills and knowledge and a fear that ‘a flood gate’ might be opened were described.

Gott et al. undertook in depth semi-structured interviews of 22 GPs and 35 practice nurses. The barriers they described were ‘opening up a can of worms’ that would have to have been followed through, fear of patients believing that the clinicians may be sexualising the consultation, middle age and older patients who may be more easily offended and sensitive to such issues, those from ethnic minorities who may not openly discuss such issues, religious beliefs and fear of possible prejudice of non-heterosexual patients as well as a general uncertainty of knowing which terms to use, were all cited as key barriers.

Disorders of sexual desire are frequently encountered in psychiatric practice. These disorders may be part of the presentation of common psychiatric disorders such as depression and anxiety disorders, a drug side effect, secondary to relationship discord or idiopathic. Understanding the etiology of problems of low sexual desire is also complicated because of the interplay of biological, psychological and interpersonal influences. Because these disorders can have a multitude of etiologies, diagnosis is often complicated and most often imprecise. Because sexuality is such an important part of one’s self-identity and plays a significant role in intimate relationships, low sexual desire can have a multitude of unfortunate consequences and obviously should be a focus of psychiatric interventions.

The goal of this chapter is to review current evidence concerning the diagnosis, epidemiology, etiology and treatment of hypoactive sexual desire disorders. Masters and Johnson and the DSM-IV-TR regard male and female sexual disorders as symmetrical.

However, there appear to be sex differences in the strength of sexual desire, its covariates, its sequencing in the sexual response cycle, and its response to relationship discord. In this chapter, female disorders of desire will be considered separately from male disorders of desire as they may represent different diagnostic entities.

Male Hypoactive Sexual Desire Disorder

In the DSM-IV-TR, the same criteria apply to the diagnosis of male and female hypoactive sexual desire disorder. There have been no publications addressing whether male criteria should be modified.

Epidemiology
Epidemiological studies have found that the prevalence of complaints of low sexual desire is lower in men than women.

– In the Global Study of Sexual Attitudes and Behavior, 17.6 % of men in Canada, the United States, Australia, New Zealand, and South Africa complained of lack of sexual interest. However, only 2.7% complained of this as a frequent problem.

– Lack of interest in sex was associated with older age, poor health, and depression. Similarly, in a national probability sample of sexual behavior in the United Kingdom, 17% of men complained of low sexual desire in the preceding year. However, only 1.8% complained of this problem lasting for at least 6 months.

Psychological Treatment of Male Sexual Desire Disorder
As noted in the ‘Epidemiology’ section, male sexual desire disorder is far less common than female sexual desire disorder and less has been written concerning the psychological treatment of such disorders in men. Most of the treatment approaches involve helping the individual develop sensory awareness and to identify erotic cues in his environment, desensitization of anxiety-evoking stimuli, cognitive restructuring and couple psychotherapy. Some therapists recommend a psychotherapeutic approach concentrating on transferential relationships and internalization of past exciting and rejecting objects. To the authors knowledge, there is minimal empirical support for any of these approaches.

Pharmacotherapy
Pharmacological approaches mainly concern the treatment of psychiatric conditions known to be associated with low sexual desire such as depression, anxiety disorders and psychotic disorders. Depression has been well established as a cause of low sexual desire and its successful treatment can lead to the restoration of libido.

Unfortunately, some of the pharmacological interventions for depression are themselves associated with sexual dysfunction, especially anorgasmia and to a lesser extent low desire. This can be minimized by the use of antidepressants such as bupropion or nefazodone that are rarely associated with sexual dysfunction. There is also some evidence that duloxetine may be associated with a lower incidence of sexual dysfunction than the selective serotonin reuptake inhibitors. If an SSRI is required, there is some evidence that antidotes may preserve libido.

It is also well known that many psychotic disorders, especially schizophrenia, may be associated with decreased libido. Again, successful treatment of the psychosis may help to restore libido but many antipsychotic drugs may have sexual side effects. The available evidence suggests that prolactin-sparing antipsychotic agents may have lower incidence of sexual dysfunction. Also, use of dopamine agonists such as bromocriptine and cabergoline may help lessen the side effect burden of these agents.

One study of couples with low sexual desire found that bupropion had a prosexual effect. This study has not been replicated.

Endocrinological Therapy
Endocrinological therapy mainly consists of treating endocrine disorders associated with hypoactive sexual desire disorder. These primarily include hypothyroidism, hyperprolactinemia and hypogonadism. Hypothyroidism has been found to be associated with lower sexual libido and restoration of a euthyroid state has been associated with an improvement in libido. Low sexual desire along with fatigue can be presenting symptoms of hyperprolactinemia. Hyperprolactinemia is important to detect as it may be the result of a pituitary tumor. Pituitary microadenomas may respond to bromocriptine or cabergoline therapy.

Much of the evidence concerning the relationship of androgen levels to libido has been derived from studies of patients who are androgen deficient as the result of disease states. In hypogonadal states, most men report a marked decrease in libido that is restored by androgen replacement therapy. In patients who have been castrated, the usual sequence is first a decrease in libido followed in several weeks by a loss in the ability to ejaculate. Similar effects have been observed in men receiving antiandrogen therapy. Laboratory studies have suggested that hypogonadism is associated with decreased nocturnal erections and decreased sexual fantasies. The relationship between androgen levels and libido within the normal range is unclear. Most evidence suggests that a minimal level of androgen, perhaps slightly above the lower limit of normal is necessary to support normal sexual function and that increases in androgen above this level have negligible effects on libido in most men. However, there is reason to believe that the threshold for the biological effects of androgen in older men might be higher than in younger men. In these cases, one might attempt to achieve slightly higher serum androgen levels than one would in younger men.

Current recommendations are to attempt to restore serum testosterone to midnormal range. A variety of therapeutic approaches are possible. These include 75–100mg testosterone enanthate or cyprioate administered weekly, one to two 5mg testosterone patches nightly, 5–10mg of testosterone gel applied daily, or 30mg bioadhesive buccal testosterone tablet applied every 12 h. Follow-up care should include routine PSA, hematocrit and serum testosterone levels.

Potential side effects of testosterone replacement therapy include prostatic hypertrophy, increased erythropoiesis, worsened sleep apnea, gynecomastia, and fluid retention possibly worsening hypertension and cardiac failure.
The effect of androgen on male libido decreases with age as the result of decreased testicular function, decreased activity of the hypothalamic pituitary axis, an increase in serum hormone-binding globulin decreasing the amount of bioavailable testosterone, and possibly decreased sensitivity of the testosterone receptor. The term andropause has been used to describe a syndrome consisting of low libido, osteoporosis, decreased muscle mass, decreased energy and other signs of aging.

Differential Diagnosis
The major issue in the treatment of male hypoactive sexual desire disorder is a differential diagnosis between etiologies that are predominantly psychogenic versus those which are predominantly biogenic. Lifelong problems with desire tend to be situational and are presumed to be predominantly psychogenic where acquired global problems may be psychogenic, mixed or organic in etiology. One first attempts to identify treatable causes of low desire such as depression and drug side effects. Most other known causes of biogenic hypoactive sexual desire disorder in males are endocrinological. Common causes include hypogonadism, hyperprolactinemia, and thyroid abnormalities. These disorders tend to be gradual in onset in global. However, a global presentation may appear situational to an unskilled clinician. For example, a man might report low libido with a regular partner yet report increased libido with a novel partner. For these reasons, routine laboratory examinations are recommended in men complaining of acquired, global hypoactive sexual desire disorder.

Typically, these laboratory examinations would include thyroid indices, serum prolactin, and serum testosterone. If available, serum free testosterone is preferred. A blood draw before 10:00 AM is recommended as testosterone secretion has diurnal variation. Serum free testosterone is recommended as approximately 80% of circulating testosterone is bound to serum hormone-binding globulin and considered not to be bioavailable. Approximately, 2% occurs as free testosterone and about 20% is loosely bound to albumin.

Laboratory Assays

Although laboratory assays are occasionally definitive in determining the etiologic picture (e.g. hyperprolactinemia associated with a pituitary adenoma), for the most part they rule biologic factors in or out of the diagnostic equation. The critical question with laboratory assays often comes down to cost/benefit in the broadest sense of that concept. That is to say, what is the incremental value of adding a particular test to the laboratory request, and the probability that it will identify a significant causal agent. This increment must be weighed against the cost in time and energy required to obtain and interpret the test result, and the dollar cost associated with the assay.

Often, clinicians are discouraged from ordering any but the most basic laboratory tests because published data based on the general population show that the ‘hit rate’ or probability of a positive is relatively small. It is important to remember, however, that by virtue of their presenting complaint, sexually dysfunctional patients no longer represent the ‘general’ population, but are now members of a specific subset of individuals where the probability (i.e. the ‘base rate’) of a sexually-related biological derangement is much higher. This is particularly true if the individual under evaluation is over 50 years of age.

One can find almost as many different lists of recommended laboratory tests as there are experts. Some of this variation is a result of the recommending expert’s particular specialty, and the nature of the patients seen in his/her practice. Also, the patient’s gender obviously plays a role in the specific labs requested, as does the patient’s presenting complaint, its duration (lifelong vs. acquired) and its specificity (situational vs. generalized). In some cases, there is little to be gained from laboratory assays, for example when a woman experiences low sexual desire with her husband, but no problems with her lover. Such manifestly interpersonal etiologies tend to be rare, however, and often difficult to ascertain.

The list outlined in table is a relatively generic inventory of laboratory assays that can be utilized in both male and female patients to determine if any ‘first line’ (relative to sexual functioning) biological functions appear abnormal. I have divided tests into ‘recommended’ and ‘optional’, very much based on what we do in our Center. It is obvious that many more assays could be added, a few subtracted, and others shifted from the ‘recommended’ to the ‘optional’ list and vice versa. Usually, laboratory tests do not provide a definitive etiology for a disorder, rather they more often give us a signal of where to look further.

Assimilation and Integration of the Data

The clinical evaluation process essentially represents an iterative progression with everincreasing quantities of data concerning the patient’s presenting complaint, sexual, medical and interpersonal histories, and summary of current assessments. The clinician’s principal task is to assimilate these data and integrate the multiple elements into a cohesive assessment and explanation of the nature of the patient’s sexual dysfunction and its probable cause(s). There are a number of important issues that should be kept in mind during this process.

– First, the evaluation should be perceived by the clinician, and explained to the patient, as being a programmatic endeavor; it is not a one-shot, all or none process, but rather a complementary series of assessments that will hopefully result in a comprehensive understanding of the patient’s problem, and an optimum approach to treatment. This being the case, whenever possible the patient’s partner should be involved in the evaluation so that he/she can provide verification and corroboration of the facts of the case, and at the time of treatment recommendations or referral also help confirm the whys and wherefores of the clinician’s recommendations.

– Second, in the current era of patient-based medicine it is important that the patient (and the patient’s partner whenever possible) be perceived and treated as important decision makers in the evaluation and treatment process. The clinician should be careful not to assume an authoritarian posture, but rather take on the role of an expert guide, informing, educating, and sharing knowledge and experience with the patient, and ultimately sharing details concerning accepting a referral or initiating a particular treatment regimen. Since education represents a critical aspect of the evaluation process, the patient should be exposed to the data comprising the various clinical assessments, and the processes whereby these data impact on the clinician’s decision making and recommendations regarding the case.

Data from the patient’s psychometric assessment, clinical interview and laboratory assays should be shared with the patient in an effort to have him/her understand the basis for the conclusions that the clinician has reached. These data and their assimilation by the provider will form the platform for the clinician’s treatment recommendations. Since the patient should be an active participant in decisions to accept or reject specific treatment recommendations, it is essential that the patient understand the nature of the data the clinician has used in his decision-making.

In many cases, it is possible that the primary care provider can initiate and maintain effective treatment for the patient’s sexual dysfunction, but this is not always the case. Underlying complex cardiovascular or endocrine conditions, male or female disorders requiring surgery for optimal resolution, and psychiatric or interpersonal conflicts that demand specialized treatment knowledge, all represent situations where a referral should be made. If referral turns out to be the case, it is important that the primary care provider maintain communication both with the patient about how treatment has progressed, and the specialist to promote an integrated treatment program.

Optimal treatment is the ultimate goal of the clinical evaluation process, whether it is delivered by the primary care clinician or a specialized health care provider. The more relevant information that can be brought to bear in the evaluation process, the greater likelihood that the most appropriate treatment of the problem will be achieved.

Clinical Interview

Clinical interview is the second major source of information available to us in doing clinical evaluations of sexual functioning. The clinical interview is extremely important in both research and clinical contexts; however, interviews are conducted in a somewhat different manner in research trials versus clinical practice.

Clinical Research Interview

In research trials, the ‘interview’ is actually almost always a series of interviews usually done by different members of the research team to establish and verify the patients’ status and whether or not they qualify for the study being conducted. An initial screening interview, typically done by phone, frequently serves as a gross filter to establish certain patient characteristics. Age, gender, education, marital status, length of relationship, inclusion criteria, the absence of exclusionary characteristics, and whether or not the patient meets other study requisites are usually reviewed during the screening interview. Subsequent in-person interviews verify the data determined from the screening interview, and in addition, establish certain patient physical parameters, such as height, weight, BMI, blood pressure, medical history, drug history, and current health status. Usually, a sexual medicine expert then does a diagnostic interview to establish and verify that the patient is suffering from the index condition, and is free of any comorbid manifestations that might disqualify him/her from the study. Laboratory specimens are also collected at this time to be evaluated as further evidence of inclusion/exclusion qualifications for the patient. Essentially, the research interview is conducted with the purpose of establishing that the patient is suffering from the condition which represents the index diagnosis in the study, meets all other study criteria, and is free of any history or current condition that would prohibit him/her from study participation.

Clinical Practice Interview

As alluded to earlier, in clinical practice the patient presents without any previous screening information, unless he or she is a regular patient of the health care provider, who has previous knowledge of the condition in question. In clinical practice, for all intents and purposes, the clinical evaluation never disqualifies the patient from participating in treatment, unless in completing the evaluation the provider discovers a more s erious c ondition ( e.g. a cute h ypertension, g ynecological c ancer) t hat tak es precedence over the sexual problem, and requires a more immediate intervention. Basically, the evaluation is designed to provide an ever-widening circle of accumulating evidence on health-related factors that, either in consort or independently, may be viable etiologic factors regarding the patient’s current condition.

It is at least worth mentioning here that not all sexual problems meet the criteria for sexual dysfunctions; sometimes patients experience sexual tribulations that do not qualify for formal diagnosis, but are better characterized as sexual difficulties. As examples, disagreements among partners concerning how often to have intercourse (given a reasonable normative range), or when during the day to have sex, or what positions or sexual activities to try, do not truly qualify as dysfunctions, but are much more productively treated as difficulties. They reflect inclinations concerning sexual activities that are not rooted in pathophysiology or psychopathology, but rather in differing personal preferences. There is little value in invoking a medical model to try to address such issues, since usually they can be resolved through negotiation between the partners involved. Occasionally, a provider can provide useful information or education in such instances, but the concept of treatment is not appropriate.

Returning to the sphere of true clinical disorders, it is important to remember that etiologic factors arising from numerous biological, psychological, interpersonal and cultural origins can be operational in cases of sexual dysfunction. It is also appears that these agents do not operate independently or in a mutually exclusive manner. Rather, various etiological mechanisms tend to operate co-inductively, so that multiple factors usually contribute to any particular case of sexual dysfunction. A female sexual pain disorder, with its basis in menopause-induced changes, can give rise to a perception of ‘withholding’ on the part of the male partner, which if communicated, can induce anger and guilt in the female patient associated with the idea that she has failed to be ‘a good lover’. ED, with origins in vascular endothelial lesions will often present with a secondary (ego-protective) manifestation of sexual disinterest, which can be interpreted by the female partner as evidence of a loss of affection and interest in her as a sexual partner. The important concern to be exercised here is that even if one can accurately identify a primary etiologic agent in a particular case, it does not eliminate the possibility of corollary factors that need to be addressed.

In figure, I have taken the liberty of condensing the myriad of potential sources that can have an etiological bearing on sexual functioning into three broad classes: biological, psychological, and interpersonal. In doing so, I am aware that influences from other spheres beyond these three can act causally relative to sexual dysfunction; however, I believe the majority of causal agents are subsumed under these three broad categories, and that more esoteric influences account for only a small proportion of the prevalence of sexual dysfunctions.

The first broad category outlined in figure is biological. There exist an extremely large number of diseases, disorders and biological derangements that can act to produce sexual dysfunction. Causal agents range from endocrinopathies such as hyperprolactinemia, and age-related hypogonadism, through numerous chronic illnesses like diabetes and cardiovascular disorders, to medical conditions that directly affect the genital organs. In addition, a vast array of pharmacologic agents, with SSRI antidepressants and antihypertensives heading the list, possess the capacity to inhibit normal sexual functioning at every stage of the sexual response cycle. As an example of the potential magnitude of medication-induced dysfunction, it is well established that the SSRI antidepressants have a prevalence of sexual dysfunction associated with them of 35–65%. This is why it is extremely important, whenever possible, to conduct a thorough physical examination and review of systems, and take a careful history of medication use with particular attention to the temporal relationship between medication initiation and the onset of sexual symptoms. When they are present, biological etiologies tend to be primary in nature because they assault and undermine the fundamental biological matrix essential for the adequate performance of sexual behaviors. As I have emphasized, however, they are often not the sole etiological agent acting in a particular case.

The second class of etiological precursors identified tend to be classified as psychological in nature. The ubiquitous experience of stress, if it is of sufficient magnitude or duration, clinical depression, and other psychiatric disorders, are all associated with the presence of sexual dysfunction, with clinical depression having an established prevalence rate of 40–50%. An individual does not have to be afflicted with a formal psychiatric disorder, however, for psychological factors to play a disruptive role in his/her sexual function. Any strong negative affect state, e.g. anxiety, guilt, hostility can be extremely disruptive to effective and satisfying sexual function. Sex works best in a relaxed state of mind, and negative emotions have the effect of distracting the individual from appropriate sexual cognitions, and disrupting the smooth progression of sexual arousal from early initial levels through high plateau and eventual orgasm. Often, such negative emotions are associated with chronic self-concept problems, where the individual has heightened concern about some aspect of his or her physical or psychological person. Such conflicts can range widely, from concerns regarding physical adequacy and attractiveness (e.g. body image), to intrapsychic conflicts about fear of disease or pregnancy. The goal in the clinical interview is to ascertain that such conflicts exist, with the treatment of such problems often accomplished through referral to a specialist.

The final broad class of potential etiologic agents in sexual dysfunction I have labeled interpersonal, because, for the most part, they arise from conflicted interactions within the individual’s interpersonal relationships. It goes without saying, that such conflicts usually give rise to strong negative emotions. Marital conflict represents a more or less generic label for any of the hundreds, if not thousands, of controversies that couples find themselves engaged in from time to time. Usually, it is not the substantive aspect of the argument that interferes with sexual intimacy, but rather the negative emotions that the partners harbor or direct at each other. At other times it is the specific conflicted issue that holds the disruptive potential. Conflicts revolving around extra-marital liaisons, or sexual disinterest arising from homosexual preferences are just two specific examples. In addition, childrearing can at times fall disproportionately to one or another parent, producing considerable dismay and resentment. Clinicians should also be sensitive to the possibility that partner sexual dysfunctions exist, which are not addressed by the patient, often out of embarrassment, or a misconstrued belief that the partner’s dysfunction actually represents disinterest in them as a sexual partner.

In the clinical context, an ‘evaluation’ typically refers to an appraisal or assessment of some domain(s) of an individual’s health status. In the case of the current discourse, the domain of interest is the individual’s sexual functioning. Evaluation may be defined as, ‘a specified set of operations designed to examine and determine the state of an individual’s health status, usually, with the purpose of defining a benchmark, making an assessment of morbidity (i.e. a diagnosis), or establishing a need for, or the optimal course of, a therapeutic intervention’.

Sexual dysfunction is a highly prevalent condition, with prevalence showing a definite relationship to age and health status for both men and women. From the outset, however, I believe it is important to make a distinction between ‘clinical’ and ‘research’ evaluations of sexual dysfunction. This distinction is important because while there is definite overlap between the methods of assessment used in these two evaluation contexts, their perspectives, purposes and goals are often quite dissimilar.

My major reason for highlighting this distinction between research and clinical evaluations is that traditionally, often via a somewhat opaque translational process, the results derived from clinical research are regularly incorporated into, and frequently become the basis for, standard clinical practice. This being the case, I believe it is important to understand the nature and scope of the differences between research and clinical evaluative processes.

Research evaluations tend to be focused on defining the presence or absence and relative severity or status of a specified index condition in the patient. The condition and its treatment are usually the major focus of the research program. Typically, a comprehensive baseline screening process rules out patients with comorbid conditions, prohibitive medications, laboratory values outside the normal range, a medical history of certain conditions (e.g. cancer, psychiatric disorders) and undesired physical, relational, or demographic status (e.g. BMI greater than 35, impaired personal relationship, age greater than 70). Research evaluations, initiated at ‘baseline’ continue to be done systematically throughout the course of the research study, although the baseline and ‘final visit’ assessments are usually the most comprehensive. Evaluations for any treatment-emergent adverse events are added once treatment has been initiated. Research evaluations are typically very much bound by the context of the index condition and its treatment. Other aspects of the patient’s sexual functioning, medical, and psychological status are addressed only insomuch as they may have a measurable effect on the research condition of note. The research sexual evaluation should be appreciated as a much more narrowly focused assessment, with a very highly defined sample of patients, compared to clinical sexual evaluations.

Clinical sexual evaluations on the other hand, while also focused on the nature and scope of an individual’s sexual morbidity, do so within a much broader overall health context. Patients are not dismissed from the evaluation because of medical, psychological, or relational complexities, but rather these events must be taken into account and factored into the clinical evaluation and recommendations for treatment. This being the case, clinical evaluations sometimes involve assessments in greater depth than research evaluations, although the sequential follow-up evaluations built into typical research protocols are usually not part of the patient’s appraisal. The principal goal of most clinical evaluations is to determine the patient’s diagnosis, and an optimum treatment regimen. By contrast, the patient’s diagnosis is usually specified a priori in operational research protocols, which also specify the nature and magnitude of any treatments. Although many of the same operations comprise both research and clinical evaluations, the logistic and operational features of the assessments, and their primary goals, are usually quite distinct. In research evaluations, the patient’s status is specified a priori to a high degree. Diagnosis is indicated by the protocol, and the ultimate purpose of evaluation is usually to determine the efficacy and safety of a specified treatment, also established a priori, in treating patients with that diagnosis. In clinical evaluations we are usually working with patients de novo. Nothing is specified o r k nown a p riori except t he p resenting complaint, and a t the very l east, a focused review of systems within the medical history must be done as well as obtaining a comprehensive sexual history.

Regardless of whether our evaluation occurs within the clinical or research context, there are basically three fundamental sources of data from which we can draw our conclusions: psychometric assessment, clinical interview, laboratory assays. Most data in our evaluations derive from the first two sources, with occasional insights or clarification drawn from laboratory test results.

PDEs are intracellular enzymes that are of critical importance for regulating the levels of cyclic nucleotides (cAMP and cGMP) in the cell. They constitute a large superfamily, are highly regulated by several signaling pathways, exert their inhibitory activity mainly via hydrolysis of the 5′-nucleoside monophosphate (but may also function as a means of sequestration of cGMP), and are targeted by many drugs.

DESCRIPTION, CLASSIFICATION, AND NOMENCLATURE

The PDE superfamily contains two classes, but all mammalian PDEs are contained in Class I. Class I contains 11 families and 21 subfamilies, each from separate genes, among which there are more than 59 variations/isoforms. The individual PDEs are differentiated by their substrate selectivities (cGMP and/or cAMP), mechanisms of regulation, tissue distribution, inhibitor selectivity, and subcellular localization.
PDE5 was first purified two decades ago by Francis et al. This group has undertaken much of the subsequent work on this enzyme and has published several excellent reviews. Their working model of PDE5 illustrates the dimeric structure common to all mammalian PDEs.

SUBSTRATE SELECTIVITY

Certain PDEs are specific for cGMP (PDEs 5, 6, and 9), and others are specific for cAMP (PDEs 4, 7, and 8); both cAMP and cGMP are substrates for the “dual-specificity” PDEs (PDEs 1, 2, 3, 10, and 11), as measured in vitro. PDE5 is a cGMP-binding, cGMPspecific PDE that is particularly abundant in smooth muscle. The PDE5 catalytic site has a significantly higher affinity for cGMP (Km approximately 1–5 M) than for cAMP (Km approximately 300 µM), but cAMP can be hydrolyzed if the concentration is artificially maintained high enough and it is the only in vitro substrate available. However, under normal physiological conditions, only cGMP is hydrolyzed by PDE5. PDE11 is the most similar to PDE5 based on amino acid sequence analysis (50% identity in the catalytic domain. However, PDE5 is cGMP-binding and cGMP-specific, whereas PDE11 is a dual-specificity PDE. Three splice variants of the PDE5A family have been identified. PDE5A1, PDE5A2, and PDE5A3 have similar cGMP catalytic activities, with binding rate constants for the catalytic site of 6.2, 5.75, and 6.06 µM, respectively. MECHANISMS OF REGULATION Various mechanisms regulate PDE activity, and most of these are known to be active with PDE5. As theorized by Corbin and Francis, several specific mechanisms appear to interact in a complex manner to regulate PDE5 through negative feedback:

• increased intracellular cGMP concentration stimulates increased cGMP catalysis by PDE5 because of mass action (increased substrate availability);
• binding of cGMP at the PDE5 catalytic site enhances cGMP binding at PDE5 allosteric sites, inducing a conformational change in PDE5;
• cGMP binding at PDE5 allosteric binding sites increases phosphorylation of PDE5 by PKG,
• further increases in cGMP catalysis.

Compartmentalization between cells can physically segregate different cyclic nucleotide signaling pathways and prevent crosstalk, for example, between PDE3, which is expressed within the cardiac myocyte, and PDE5, which is not. Furthermore, compartmentalization within the cell can also serve to limit crosstalk between signaling pathways involving PDEs, as has been recently and well characterized for PDE4.

TISSUE DISTRIBUTION AND INTRACELLULAR LOCALIZATION

Intracellular localization of PDEs can affect their ability to influence or be influenced by other components of cyclic nucleotide signaling pathways and, therefore, can determine the physiological and functional role of a PDE. Some PDEs are localized primarily in either the particulate fraction or the cytoplasmic fraction of the cell, whereas others are distributed more evenly in both compartments which is determined by the isoform in question. Certain PDEs appear to be expressed selectively in different tissues, and PDE5 is relatively less widely distributed compared with many other PDEs. PDE5 is abundant in vascular smooth muscle of all tissues, including penis and lung. It is also present in platelets and visceral smooth muscle. Recent PDE localization studies using immunohistochemistry have confirmed that PDE5 is highly expressed in vascular medial smooth muscle and smooth muscle bundles). Among cardiovascular tissues, PDE5 activity was found in the saphenous vein, the mesenteric artery and coronary vascular smooth muscle tissue but not in the cardiac ventricle or cardiac myocytes. Two PDE5 isoforms, PDE5A1 and PDE5A2, have been isolated from penile and nonpenile tissues, whereas PDE5A3 has been reported to be detected only in tissues with substantial amounts of smooth muscle. Parums et al., using a specific polyclonal antibody against PDE5 and immunohistochemistry techniques, have not been able to detect PDE5 in human cardiac myocytes. However, there have been reports of PDE5 in cardiac myocytes in the dog. Senzaki et al. used chemifluorescent immunohistochemistry to demonstrate PDE5A expression in both the vasculature and myocytes of normal and failing dog hearts, but the possibility of a false positive signal caused by epifluorescence in cardiac tissue cannot be discounted.

INHIBITOR SELECTIVITY

Competitive inhibitors of PDE are analogs of cyclic nucleotides that bind to the substrate-binding site and directly decrease the rate of substrate catalysis. Noncompetitive inhibitors bind to different, nonactive sites and, therefore, indirectly decrease the rate of substrate catalysis, perhaps by effecting conformational changes in the PDE molecule. Inhibitors do not interact with the cGMP-binding allosteric sites. Some nonselective PDE inhibitors, for example, zaprinast, may exhibit inhibitory effects on multiple PDE families, but others are quite selective for a specific PDE. Selectivity is dependent on how the inhibitor molecule fits into the catalytic site of the PDE enzyme molecule, which will vary between PDE families and will be dependent upon inhibitor structure. Therefore, structurally related molecules generally will have similar selectivity profiles, for example, sildenafil and vardenafil, which are potent PDE5 inhibitors with moderate selectivity over PDE6. In contrast, structurally unrelated molecules may have different selectivity profiles. For example, although sildenafil and tadalafil are both potent PDE5 inhibitors, only tadalafil has moderate selectivity over PDE11. The specific role that PDE5 plays in controlling vascular smooth muscle relaxation in the corpus cavernosum of the penis has now become apparent with the demonstration that sildenafil selectively increases penile levels of cGMP.

Nitric Oxide

Organic nitrates have been a mainstay in the symptomatic management of coronary artery disease (CAD) since Brunton and Murrell used them to relieve angina in Britain in the mid-1800s. The organic nitrates mediate hemodynamic and antianginal actions via vasodilation of capacitance veins and conductive arteries. However, a century passed before it was determined that NO, liberated after denitration of the organic nitrate prodrug, was the active moiety in organic nitrates.

ENDOGENOUS SYNTHESIS

From the 1980s onward, the endothelium began to be recognized not simply as a passive internal lining of blood vessels but for its active ability to modulate the tone of the adjacent smooth muscle by secreting a chemical signal. The chemical factor was known originally as endothelium-derived relaxing factor because of its source and vascular smooth muscle relaxation activity, but in 1987 it was recognized that NO and endothelium-derived relaxing factor were one and the same entity.

NO is produced by the catalytic actions of NO synthase (NOS) on the substrate L-arginine. There are three types of NOS: two calciumdependent, low-output enzymes (type I or neurogenic [nNOS] and type III or endothelial, constitutive [eNOS]) and a calcium-independent, high-output enzyme (type II or inducible. All three isoforms have been found in vascular smooth muscle cells, depending on the blood vessel type. In the corpus cavernosum of the human penis, the cavernous nerves express nNOS, and eNOS and iNOS are present in smooth muscle cells and endothelial cells.

PHYSIOLOGICAL EFFECTS

NO diffuses rapidly across cell membranes. Some of the many biochemically transformed species of NO are highly reactive and include transition metals such as hemoglobin (Fe2+)–NO and oxygen superoxide, which produces the potent and toxic oxidant peroxynitrite. However, most of the nonlytic effects of NO are mediated by cGMP. In the NO/cGMP signaling pathway, released NO helps to regulate blood flow and blood pressure through actions on vascular smooth muscle; it is also involved in inhibition of platelet aggregation and adhesion and probably in inhibition of vascular smooth muscle proliferation.

The use of NOS antagonists, such as N-monomethyl-L-arginine, helps to elucidate some of the physiological effects of NO. Inhibition of NO synthesis with an NOS antagonist increases total peripheral resistance and mean arterial pressure and decreases heart rate and cardiac index. Interestingly, in earlier studies using animal models, small doses of NOS inhibitors inhibited erections.

Guanylyl Cyclases

Guanylyl cyclases are a family of membrane-bound or soluble enzymes that catalyze the conversion of GTP to cGMP. They respond to diverse signals, including peptide ligands and changes in intracellular calcium concentrations. However, NO is the chief activator of sGC. sGC is found in the cytoplasm of almost all mammalian cells, and NO binds directly to the heme group of sGC to form a ferrous-nitrosyl-heme complex. cGMP and pyrophosphate are the sole products of catalysis of GTP.

Cyclic Guanosine Monophosphate

CELL SIGNALING

cGMP interacts with cGMP-dependent protein kinases (PKGs), cGMP-regulated ion channels, and cGMP-regulated PDEs. Increased availability of intracellular cGMP has different physiological and functional outcomes depending on the type, combination, and intracellular localization of cGMP targets and on the cGMPmetabolizing activity of PDEs. This complex interaction of cellular processes involves multiple intracellular signaling pathways, “crosstalk” between pathways, and feedback loops, which gives rise to a great diversity of responses that can be cell and tissue specific. cGMP signaling to protein kinases and ion channels is discussed below, and the interaction of cGMP with PDEs is discussed in “Substrate Selectivity.”

Protein kinases catalyze the phosphorylation of target proteins, and PKG is the principal mediator of cGMP signals. Phosphorylation has been demonstrated in vitro for many proteins, but only a few have been recognized clearly as physiological substrates, indicating the importance of intracellular localization or compartmentalization.

The principal family of cyclic nucleotide-gated ion channels regulates the influx of Ca2+ and Na+ into cells. All are regulated by intracellular and/or extracellular Ca2+ and are activated by both cGMP and cAMP, although certain isotypes are more sensitive to one or the other of the cyclic nucleotides. Cyclic nucleotide-gated ion channels are involved in the physiology of vascular smooth muscle relaxation. They are also the means by which cGMP regulates retinal phototransduction in rod and cone photoreceptors and by which cGMP and cAMP regulate olfaction.

PHYSIOLOGICAL EFFECTS

Intracellular levels of cGMP affect numerous cellular functions, including extent of smooth muscle relaxation, intestinal fluid and electrolyte homeostasis, initiation of visual signal phototransduction, neutrophil degranulation, and inhibition of platelet aggregation. Regulation of vascular smooth muscle motility is a major function of cGMP generated via the NO/cGMP signaling pathway.
cGMP mediates vascular smooth muscle relaxation via reduction of, and desensitization to, intracellular Ca2+. Reduction of intracellular Ca2+ is mediated by PKG phosphorylation of proteins associated with Ca2+-gated channels. Desensitization of the contractile apparatus to Ca2+ is effected via cGMP-dependent protein kinase I α, which interacts with myosin light chain phosphatase to dephosphorylate myosin light chain.