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Sexual Dysfunction and HIV Infection

This review describes the prevalence and pathophysiology of sexual dysfunction among men in general and explores the modest literature on erectile dysfunction and loss of libido in HIV-positive men. The only 2 systematic studies of sexual disorders in HIV-positive women are briefly noted.

Although complaints about sexual dysfunction are common in persons with HIV infection, the epidemiology and mechanisms of sexual dysfunction in this population are poorly understood. This review describes the prevalence and pathophysiology of sexual dysfunction among men in general and explores the modest literature on erectile dysfunction and loss of libido in HIV-positive men. The only two systematic studies of sexual disorders in HIV-positive women are briefly noted. Finally, treatment options for male sexual dysfunction are described.The psychologic aspects of sexual dysfunction may take on an added dimension in patients who were infected with HIV sexually. Regardless of how they were infected, HIV-positive patients may be preoccupied with the risk of transmitting HIV to others. Although this review does not deal with psychologic issues in depth, it is important to note at the outset that psychologic issues can be a cause or an effect of sexual dysfunction, and that clinicians should therefore carefully consider referrals to therapists trained in handling sexual dysfunction.

Epidemiology and Pathophysiology of Sexual Dysfunction in Men

Male sexual function depends on complex interactions among the vascular, neurologic, and endocrine systems. The development of an erection in response to an erotic stimulus requires 1) integration of the erotic signal by nuclei in the thalamus and hypothalamus; 2) relaxation of arteriolar and sinusoidal smooth muscle in the corpora cavernosae in response to stimulation of S2-S4 parasympathetic nerve-fiber discharges and inhibition of T10-12 sympathetic nerve-fiber discharges; 3) diversion of blood from the iliac arteries into the dilated vessels of the corpora cavernosae; and 4) inhibition of penile venous return due to compression of emissary veins by the dilated corporal sinusoids. Psychologic factors and androgen hormones play an important role in sexual interest, initiative, and neuro-vascular responsiveness to erotic stimuli. The physiologic basis of male sexual function suggests 4 major pathophysiologic disturbances that may contribute to erectile dysfunction: 1) insufficient arterial blood supply to the corpora cavernosae; 2) peripheral autonomic dysfunction due to neuronal loss or disordered neurotransmitter signaling; 3) deficient androgen availability or inhibition of androgen activity; and 4) psychologic inhibition of response to erotic stimuli. The latter 2 conditions are also associated with diminished libido. Table 1 provides examples of specific diseases and medications associated with sexual dysfunction in each of these 4 pathophysiologic categories.^1,2

Aging has a powerful effect on sexual function. In the most extensive assessment of the epidemiology of male sexual dysfunction to date, the Massachusetts Male Aging Study, researchers surveyed 1290 men aged 40 to 70 years in 11 cities and towns during 1987 through 1989. Trained interviewers in the subject's home collected comprehensive information on sexual function, health status, psychologic state, medication use, and lifestyle. Complete impotence was described by 9.6% of the subjects, moderate impotence by 25.2%, and mild impotence by 17.2%, for an overall prevalence of some degree of impotence of 52%. Five percent of 40-year-old subjects suffered complete impotence, compared with 15% of 70-year-olds. After adjustment for age, impotence was also increased among men with treated diabetes mellitus, hypertension, heart disease, and high levels of anger and depression.³

Epidemiology and Pathophysiology of Sexual Dysfunction in HIV-Positive Patients before the PI Era

No large-scale epidemiologic investigations of sexual function have been performed in HIV-positive populations. Several small studies comparing sexual function in men with and without HIV infection suggest that dysfunction is more common in men with HIV. In the late 1980s, erectile capacity and libido were assessed in nearly 200 HIV-positive and HIV-negative gay or bisexual men recruited by advertisement in the New York City area for participation in a multidisciplinary study of HIV disease in the gay community. The HIV-positive and control groups were comparable with regard to age, and the HIV-positive group was characterized overall as "asymptomatic or mildly symptomatic." Nevertheless, HIV-positive men described significantly higher frequencies of "no interest in sex" and "trouble with erection" than did HIV-negative men.⁴ Findings were similar in an investigation of psychosocial problems, including sexual dysfunction, in 37 HIV-positive, largely asymptomatic men with hemophilia and 36 HIV-negative controls with hemophilia. Individuals with HIV infection reported higher rates of erectile dysfunction, loss of libido, and ejaculatory dysfunction than did controls, although only ejaculatory dysfunction reached a statistically significant difference in this small cohort.⁵

View this table: [in a new window]   Table 1. Causes of Sexual Dysfunction in HIV-Negative Men

 

The actual prevalence of sexual dysfunction in men with HIV infection has been estimated in several cohorts. In a clinic-based study of 42 male Johns Hopkins patients (mean age, 37 years) with a diagnosis of AIDS, 28 (67%) noted decreased libido and 14 (33%) described impotence.⁶ A random sample survey of 30 gay men (mean age, 35 years) receiving HIV care at a clinic in central London found similar results; half described reduced interest in sex and a third described erectile dysfunction. Individuals with symptomatic HIV disease were more likely to describe impaired libido and erectile function than individuals with asymptomatic infection.⁷ One hundred forty-nine gay men with advanced disease completed a questionnaire about sexual function during the enrollment visit for a trial of ddI therapy. Eighty-five respondents (57%) had a clinical diagnosis of AIDS and 64 (43%) had a clinical diagnosis of AIDS-related complex. A total of 77 men (53%) described ongoing difficulty in obtaining an erection, ejaculating, or both. Subjects with AIDS were significantly more likely to report sexual dysfunction than subjects with AIDS-related complex (62% vs. 42%; P< 0.02). A randomly chosen subset of 100 ddI trial enrollees also completed a general health survey that included a question about libido: 28% of respondents had completely lost interest in sex.⁸

A number of pathophysiologic disturbances probably contribute to sexual dysfunction in HIV disease (see Table 1), and the relative importance of different etiologies likely varies with stage of illness, disease complication, therapeutic intervention, age, and risk-factor group. To date, androgen deficiency is the most widely cited cause of sexual dysfunction in HIV-positive men. Early studies suggested that the prevalence of hypogonadism increased with advancing HIV-disease stage and affected approximately 50% of men with AIDS. For example, 24 of 63 (38%) ambulatory men in the Johns-Hopkins-clinic cohort had abnormally low serum testosterone levels. (Information on rate of sexual dysfunction among chemically hypogonadal subjects was not provided.) This population demonstrated a trend toward an increased rate of chemical hypogonadism with advancing clinical disease stage. Specifically, low testosterone levels were found in 1 of 16 (6%) of men with asymptomatic HIV infection, 3 of 7 (44%) men with ARC (P<.05, ARC vs. normal controls), and 20 of 40 (50%) men with AIDS (P<.001 AIDS vs. normal controls; P< 0.01, AIDS vs. asymptomatic HIV infection). In addition, serum testosterone levels were modestly but significantly correlated with total lymphocyte count (r=0.40, P<0.005). A significant association was also found between clinical disease stage (asymptomatic vs. symptomatic HIV infection vs. AIDS) and testosterone levels among 234 HIV-infected men who answered an advertisement or were referred by their primary care physician for possible participation in studies of testosterone replacement, antidepressant therapy, or both. Individuals with asymptomatic disease had significantly higher mean levels of testosterone than did individuals with symptomatic HIV infection or AIDS. Overall, this cohort had advanced immunosuppression with a mean CD4 count of 157/mm³. Nevertheless, a mild correlation between CD4 count and testosterone level was present.⁹

Studies suggest multiple mechanisms of low testosterone in men with HIV infection. Most often, hypogonadism is thought to be secondary to suppression of gonadotropin secretion by the pituitary gland⁶, a centrally mediated response common in other serious medical conditions and undernourished states. Other reported causes of hypogonadism in HIV-positive men include testicular dysfunction (e.g., interference with Leydig-cell testosterone production by antibodies, cytokines, or other active molecules)¹⁰ and testicular disease (direct involvement of the testes by HIV, opportunistic infection, or malignancy).^11,12,13,14 Finally, some drugs used to treat HIV-related complications, notably megestrol and ketaconazole, may lower serum testosterone levels.

Given the relative paucity of research on female sexual function, it comes as no surprise that very little is known about sexual dysfunction in HIV-positive women. One study of psychiatric morbidity among female U.S. military recruits with early-stage HIV infection found that 41% of the women had DSM-IIIR-defined hypoactive sexual desire disorder (HSDD).¹⁵ According to the authors, "This disorder was nearly always described in a stereotypical fashion by women months after learning of their seropositivity: gradual onset over a 2- to 4-month period of time, usually in the presence of a willing sexual partner and in the absence of comorbid medical or psychiatric conditions." A more recent, cross-sectional study explored the relation among mood disorders, sexual disorders, and endocrinologic abnormalities in 54 women with HIV infection recruited through community-based service organizations in New York City. The prevalence of affective disorders in the sample was remarkably low, perhaps because individuals with ongoing substance abuse were excluded. Although the mean CD4 count was only 158 cells/ mm³, more than 70% of participants had a Karnofsy Performance Index score above 90, suggestive of good health. Twenty-one (39%) of the women met criteria for HSDD; all reported that symptom onset occurred after they learned of their HIV-positive status. Forty-eight percent of the women had low total serum-testosterone-levels and 27% had low dehydroepiandrosterone-sulfate levels. However, in contrast to studies of HIV-negative women, androgen hormone deficiencies were not significantly associated with diminished sexual desire. Interestingly, women whose perceived risk factors for HIV infection included sexual contact were five-times more likely to be diagnosed with new onset HSDD than were women whose perceived risk factor was intravenous drug use alone.¹⁶ This finding highlights the importance of psychology in sexual function.

View this table: [in a new window]   Table 2. Relation Between PI Exposure and First Presentation with Sexual Dysfunction in Men

 

View this table: [in a new window]   Table 3. Evaluation of Male Sexual Dysfunction

 

PI Therapy and Sexual Function

Potent combination antiretroviral therapy, including 1 or 2 PIs, came into widespread use in early 1996, with approval of the first members of this drug class. Because studies conducted before the PI era suggested that the prevalence of sexual dysfunction and of chemical hypogonadism increased with stage of HIV disease, a decline in these disorders among patients treated with effective therapy might have been expected. However, in a study of 14 men with new-onset erectile dysfunction and/or loss of libido during treatment with a PI in combination with NRTIs, a possible association was found between PI therapy and sexual dysfunction. In this case series, sexual dysfunction occurred de novo during PI therapy; none of the patients had a history of sexual dysfunction, even during prior therapy with NRTIs. In addition, limited alternative explanations existed for sexual dysfunction in the men: They were young (mean age, 37 years) with well-controlled HIV disease (viral load undetectable in 11 of 14) and normal testosterone levels. Nevertheless, evidence from this case series is merely suggestive, given the high background rate of sexual dysfunction in men with HIV infection and the significant delay in onset of sexual dysfunction after PI initiation (mean, 9.4 months) in the patients described.¹⁷

To investigate the potential association between PI therapy and sexual dysfunction, we are conducting a retrospective cohort study of approximately 300 male PI recipients receiving care at a New England managed-care organization. Preliminary analysis of our data suggests that the rate of first presentation for evaluation of sexual dysfunction in this cohort is significantly higher after the initiation of PI therapy (see Table 2).¹⁸ Additional analyses that control for possible confounding by disease stage, hypogonadism, and other factors are necessary to confirm this association.

Evaluation and Treatment of Male Sexual Dysfunction

Common clues to the etiology of erectile dysfunction are outlined in Table 3. The optimal therapuetic approach to sexual dysfunction depends on the underlying cause. Androgen hormone replacement via a long-acting injectable testosterone-ester or a transdermal testosterone patch is the treatment of choice for men with impotence and loss of libido associated with hypogonadism. A recently published study examined the effectiveness of intramuscular testosterone cypionate (400 mg biweekly) in men with advanced HIV disease (mean CD4 count, 123 cells/mm³), low or low-normal serum testosterone levels (<500 ng/dl), erectile dysfunction, and diminished sexual desire. One hundred two of 112 (91%) men reported improved sexual function after 8 weeks of open-label treatment. After 12 weeks of open-label therapy, responders were randomized to receive 6 additional weeks of testosterone or placebo. Maintenance or response was seen in 78% of testosterone recipients compared to 13% of placebo recipients (P<0.001). The most common side effect in this study was irritability, which occurred in 19% of patients.¹⁹

Treatment options for men with erectile dysfunction and normal testosterone levels include penile self-injection with vasoactive agents, vacuum erection devices, and the oral medication sildenafil (Viagra®). Several placebo-controlled trials in HIV-negative populations have demonstrated that sildenafil improves both the number and duration of erections in men with erectile dysfunction due to a wide range of organic causes. Although similar efficacy trials have not been reported for men with HIV infection, the drug is widely used in HIV clinical practice. When prescribing sildenafil to patients with HIV infection, keep in mind that PIs and delavirdine inhibit the metabolism of sildenafil by the cytochrome P450 isoform CYP3a4. This inhibition increases the sildenafil area under the curve (AUC) concentration by 2- to 11-fold, depending on the antiretroviral agent used, and thereby increases the risk of sildenafil side effects such as headache, flushing, and hypotension.²⁰ The starting dose of sildenafil in individuals on concomitant PIs or delavirdine, therefore, should not exceed 25 mg, and some guidelines suggest that this 25-mg dose should not be repeated in a 48-hour period.

Conclusion

Current evidence on sexual dysfunction in HIV-positive patients is largely limited to a handful of small studies performed prior to the era of potent antiretroviral therapy. These reports suggest that the prevalence of sexual dysfunction is greater among HIV-positive men than among HIV-negative men and that the rate of sexual dysfunction may increase with advancing disease stage. To date, androgen deficiency is the most widely reported cause of male sexual dysfunction in HIV disease, and the prevalence of this disorder appears to increase with advancing disease stage. Several small studies suggest that reduced sexual desire is also common among HIV-positive women. Recent data suggest that there may be an association between PI-use and sexual dysfunction in men. In evaluating treatment options for erectile dysfunction in HIV-positive men, it is important to note that PIs and delavirdine significantly inhibit the metabolism of sildenafil. Referrals to trained therapists should be considered for both men and women.

— Amy E. Colson, MD, and Paul E. Sax, MD

Dr. Colson is an Associate Physician at Brigham and Women's Hospital and a Research Fellow at The Channing Laboratory. Dr. Sax is an Associate Editor of ACC.

Published in AIDS Clinical Care May 1, 2000

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