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Christoph Mayr and U. Fritz Bredeek

In the "Multinational Survey of Aging Males' (MSAM), the 14,254 interviewed men age 40 to 70, voiced continuous interest in sexual activity: 83 % rated sexual desire and interest as an important to very important component of their lifes. The mean number of sexual intercourse was 5.8 per month in that age group. On the other hand studies have shown that erectile dysfunction has serious impacts on the overall quality of life (Feldman 1994).

Various factors affect sexual function and overall satisfaction not at least age (Feldman 1994). HIV infection may lead to sexual dysfunction because of well known interactions between the immune system and the reproductive, endocrine and the neuroendocrine systems. The impact of the knowledge of HIV infection on the psyche cannot be underestimated, and furthermore long-term highly active antiretroviral therapy (HAART) might additionally have negative psychological effects on sexual health. Lipodystrophy Syndrome can be caused by HAART,which shares some characteristics of the classic metabolic syndrome, for instance the increased insulin resistance, excess weight, dyslipidemia or hypertension. The clear association between metabolic syndrome and erectile dysfunction (ED) makes ED a predictive marker for the metabolic syndrome (Shabsigh in 2005).

Still, many questions remain regarding the causes of sexual dysfunction in HIV and its treatment.

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Definitions Erectile dysfunction or Impotentia coeundi is defined as the "constant or repeated appearance of an inability to attain or maintain an erection sufficient for satisfactory sexual intercourse," (NIH 1993). The diagnosis requires a minimum of 6 months of ongoing problems with 70% or more of the attempts for sexual intercourse unsuccessful. Important is the differentiation between ED and libido disturbance, defined as a decreased or entirely absent sexual drive or desire, and ejaculation disturbance, with its main signs of Ejaculatio praecox or tarda. Etiology of sexual dysfunction in HIV/AIDS Causes of sexual dysfunction (SD) are plentifold. A paradigm shift has taken place since 1980: Improved diagnostic tests and increasing knowledge of the aging processes in men have led to the conslusion that 80% of ED have some organic component and 50% are exclusively organic in nature. A truely only psychological cause is responsible for just 20% of cases (NIH in 1993). A disease-specific peculiarity of HIV is the fact that the probability of a SD is not only increased by the chronic illness but also by comorbidities associated with HIV, i.e. the aging patient population, psychosocial stressors and the need for polypharmacy (Crum 2005). Age The most important biological cause of ED is age. ED exists in variable degrees, from light (17 %) to moderate (17-34 %) to complete (5-15 %) in 52 % of all men aged 40 to 70 years (Feldman 1994). The overall prevalence of ED ranges from 7 % in men aged 18-29 years (Braun 2000) to 85 % in men aged 76-85 years. Both the increased lifespan and the higher quality of life in HIV patients have an increasing influence on the incidence of SD. Changes that occur with age, like the declining testosterone production, decreasing sensitivity of the erectile tissues secondary to decreasing neural or hormonal activity and vascular problems are further boosted in the context of HIV infection and its therapy. Risk factors: diseases and comorbidities Important ED risk factors coexist frequently in HIV patients, including excessive alcohol consumption, smoking and other recreational drug use; metabolic disorders (hyperlipidemia, diabetes mellitus); and cardiovascular disease, with hypertension being of particular importance. Pathophysiologically, most cases of ED are caused by neuronal (polyneuropathy) and vascular (micro- and macroangiopathy) changes; however, ED can also be an early sign of a metabolic syndrome. Other possible risk factors are endocrine disorders, various neurological problems (i.e. disc prolapse) or infectious diseases. Frequent causes of ED in young men are chronic kidney or liver dysfunction (hepatitis, cirrhosis). Psychosocial problems, relationship conflicts and psychiatric illnesses (e.g., depression) are frequently related to sexual dysfunction. As a consequence, HIV patients have an increased risk for erectile dysfunction. Table 1: Substances/Substance classes which may cause Erectile Dysfunction Alcohol Nicotine Antihypertensives Antidepressants Diuretics Antirheumatics (NSAR) Lipid lowering agents H2-Antagonists, proton pump inhibitors Anticonvulsants Tranquilizers Opiates Gestagens/estrogens Chemotherapeutics, HAART Amphetamines, hallucinogens Medications Many drugs have a negative impact on sexual function, mainly on libido and the arousability. Table 1 lists an overview of relevant drug classes in this context. Antiretroviral medications are also associated with SD; and both duration and combination of therapies have an accelerating effect. In a standardized survey on 78 HIV-infected men who have sex with men (MSM), conducted by Cove in London in 2004, 69 % reported on at least one occasion dysfunction and 38 % indicated ED. All antiretroviral drugs can decrease sexual function. Some studies (Colson 2002, Schrooten 2001, Martinez 1999) mention Protease Inhibitors (PI's) to be the main culprit, but this was unble to be confirmed by Lallemand, 2002. Furthermore, our own studies suggest that combinations of NRTIs and PIs may cause this problem equally. Ongoing research An increased prevalence of SD, up to 50%, was observed in HIV-infected men in the early 1990s (Tindall 1994). Similar results were seen in HIV-positive women (Goggin 1998). A clear increase in prevalence of both libido loss (48%) and ED (25%) was seen by Lamba in 2004 in HIV positive MSM on HAART, compared to HIV positive MSM not on HAART (both at 26%) or HIV negative MSM (2% and 10% respectively). A European study (Schrooten 2001) on 904 HIV-infected men and women showed that libido loss and ED is significantly more common in patients on a PI containing HAART regimen compared to patients not taking PIs (40% vs. 16% for LL and 34% vs. 12% for ED, respectively). In a multivariate analysis, the following factors were identified for libido loss: Current or past use of a PI, symptomatic HIV infection, age, and MSM. Additionally, taking tranquilizers was found to be an independent risk factor for ED. The impact of PIs in SD was also seen by Collazos (2002) in a prospective study of 189 patients. No correlation could be found between measured sex hormone levels and incidence of SD. Interestingly, in subjects taking a PI-containing regimen, testosterone levels were significantly higher compared to NNRTI-containing regimens in which 17ß-estradiol levels were significantly elevated. In a standardized questionnaire of 156 MSM, no role for PIs as the cause of SD could be ascertained (Lallemand 2002). 71% of the participants indicated signs of SD since initiation of ART; however, in therapy stratified groups (PI: 71%, without PI: 65%, no PI in the last 4 weeks: 74%) there were no significant differences seen between patients taking or not taking a PI. 18% of the participants had already suffered from SD before the diagnosis of HIV infection, and 33% before the initiation of ART. The impact of psychological factors is highlighted by one study, in which the rate of HIV-positive MSM with ED rose from 38 to 51% with the use of condoms (Cove in 2004). More recent research impressively underscores the positive effect of testosterone substitution in HIV-infected hypogonadotropic men (Rabkin 2000, Grinspoon 1998). Testosterone deficiency can cause weight loss, loss of muscle mass, osteopenia, and depression (Grinspoon 1996, Huang 2001). Diagnosis of sexual dysfunction A diagnostic work-up for the causes of SD is required before therapy. This includes a complete anamnesis with emphasis on sexual, social and family history as well as social (recreational drug use) and familiar risk factors (i.e. diabetes mellitus), and a complete medication history. A thorough physical examination is obligatory. A diagnostic test of the morning blood level of testosterone is of central importance to determine the testicular endocrine function. The calculated index of free testosterone is the recommended parameter to follow, since this index reflects the real biological activity of testosterone. The direct determination of free testosterone by the lab has been identified as being unreliable (www.issam.ch). Table 2: Laboratory diagnostics for erectile dysfunction Special hormone diagnostics General work-up Testosterone (free circulating testosterone) CBC Luteotropic hormone Glucose, HbA1c Follicular stimulating hormone Lipid panel Poss. LHRH Poss. HCG possible: TSH Poss. Prolactin, PSA Urine analysis Low testosterone level requires maesurement of LH and FSH. Further work-up may require an LH or FSH stimulating test, usually handled by an endocrinologist, to exclude secondary hypogonadism. NPT (nocturne penile tumescence measurement) is considered minimally invasive and measures nocturnal erections. 3-6 erections per night of at least 70 % rigidity, lasting 10 minutes, are considered normal values. The question of morning erections can serve as critical criterion for the sexual anamnesis. Further andrological diagnostics include sonography of the scrotum and, if the mammary glands are enlarged or involvement of the hypophysis is suspected (i.e. by an increased prolactin or estrogen level), an MRI of the Sella turcica is indicated. Other diagnostic tests used for the vascular work-up include Doppler sonography of the penis and pharmacocavernosography; and for the neuro-physiological work-up a Cavernosum EMG, vibrometry, sphincter- and N. pudendus-EMG. These are rarely necessary and left to the urologist. Therapy for sexual dysfunction General overview Phosphodiesterase 5 inhibitors (PDE-5 inhibitors: sildenafil, vardenafil, tadalafil) have substantially improved the therapy of ED. They are simple to take, effective and, in general, relatively well tolerated. However, with the exception of a few private insurance companies, PDE-5 inhibitors are not covered by insurance plans. and so must be paid for by the patients themselves. With the introduction of PDE-5 inhibitors, intra-cavernous erectile tissue injection or the intra-urethral application of vasoactive prostaglandins has clearly receded into the background. Today, surgical interventions, such as penile vein surgery, revascularization surgery or prosthodontics, also no longer play a role. For HIV physicians the interactions between PDE-5 inhibitors and HAART (particularly protease inhibitors and the NNRTI delavirdine) are important factors. Through the inhibition of the cytochrome p450 enzyme system (CYP3A4) plasma levels of PDE-5 inhibitors are increased. This needs to be discussed with the patient. In particular, for patients using a boosted PI regimen PDE-5 inhibitors need to be started at a lower dose. We specifically recommend a mini test dose at the beginning (e.g., 1/4 of a tablet of sildenafil 50 mg) and increase according to the success and side effects. Our experience indicates that a significant proportion of patients have the desired success with such a low dose. However, some patients do not achieve any effect with these low dosages (HIV infection of several years, multimorbidity, and psychological overlap). In these patients, the approved maximum dose should not be exceeded. Simultaneous administration of nitrate containing medications or substances containing nitrites ("poppers"!) is contraindicated since it may cause therapy-resistant hypotension. Sexual activity is physically tiring and can be a strain on the cardiovascular system. If it is not clear whether a patient has an underlying cardiovascular problem, it is advised to screen for it before prescribing ED drugs. This is particular true if unstable angina is suspected. Apomorphine is a centrally effective dopamine receptor agonist. It is less effective and so less important in the treatment of ED, but should be considered in patients with contraindications to PDE-5 inhibitors (APO-go ampullae, max. 100 mg s.c.). Apomorphine seems to be particularly helpful in psychogenic ED and light organic ED. Miscellaneous herbal substances (Yohimbine, Maca, Turnera diffusa) might have a positive effect on sexual function. However, systematic studies have not been performed. These substances have few side effects, but monitoring for possible interactions with HAART is advisable. For psychosocial problems, relationship conflicts or depressive disorders, psychotherapeutic support and if necessary a sexual-medical discussion are advised. PDE-5 inhibitors Sildenafil (Viagra™) Sildenafil was licensed in the USA in 1998, and shortly afterwards in Europe, as the first PDE-5 inhibitor. Sildenafil is available in dosages of 25, 50 and 100 mg. The first effects are seen between 12 and 40 mins (mean 25 mins) after taking the medication. This can be delayed if a fatty meal or alcohol is consumed simultaneously. The maximum plasma concentration is reached after approx. one hour, the clinical time of effectivity lies within approx. 8 - 12 hours. The response rate is dependent on the etiology of ED, but varies between 43 and 83%. The most frequent side effects seen are headaches (11%), flushes (11%), dyspepsia (3%), dizziness (3%), rhinitis (2%) and color blindness (1%). Because of synergistic effects of PDE-5 inhibitors with nitrates and NO-donators (e.g. molsidomin) the simultaneous consumption of those two substance classes can lead to vasodilatation and therefore to severe hypotension. The combination is absolutely contraindicated. Clarification with the patient is needed, since the use of amyl nitrates ("poppers"), or similar substances used as sexual stimulants, is prevalent in some of the groups more affected by the HIV epidemic (i.e. the gay scene). Epidemiologic studies have so far not shown a statistically increased likelihood of angina pectoris, myocardial infarct or deaths under sildenafil use. Vardenafil (Levitra™) Vardenafil was licensed in 2003. Phosphodiesterase 5 or the hydrolysis from cGMP is restrained approx. tenfold greater than by sildenafil, but the bioavailability, at 15%, is low. Vardenafil is available in a dosage of 10 and 20 mg. First effects are seen approx. 15 to 30 mins after taking the medication; maximum plasma concentrations are reached after 60 mins. The clinical effect can last up to 12 hours. Randomized, placebo-controlled studies, evaluating satisfaction with the amount of erection, showed a response rate of between 48 and 80%. The response rate for successful sexual intercourse with ejaculation was approx. 75 %. Vardenafil is well tolerated by patients on antihypertensive therapy and is effective in these patients. The same contraindication for the combination with nitrates and NO-donators exists. Adverse events include - as with sildenafil - headache (10-21%), erythema (5-13%), dyspepsia (1-6%) and rhinitis (9-17%). Tadalafil (Cialis™) Tadalafil was licensed in 2003. Dosages of 10 and 20 mg are available. Compared to other PDE-5 inhibitors the maximum plasma concentration is reached at 2 hours, the first effect is noticeable after 15 to 20 minutes. Since the plasma half-life is approx. 17.5 hours, the medication is effective up to 36 hours after intake. Personal observations point to the fact that these circumstances promote the popularity of tadalafil in the gay scene ("weekend pill"). Headache (7-21%), dyspepsia and heartburn (1-17%), myalgia (3-7%), back pains (4-9%), rhinitis (5%) and flushes (1-5%) are the most frequently observed side effects. Clinical influences on the cardiovascular system could not be observed; an increased incidence of myocardial infarction was not seen in any study. Recent studies with MSM suggest a connection between the intake of drugs, the intake of PDE-5 inhibitors and sexual risk behavior (Swearingen 2005, Jackson 2005, Spindler 2006). Testosterone Substitution therapy is indicated for a deficiency of testosterone with clinical symptoms. Options include intramuscular injections (testosterone depot 250 mg i.m. with an interval of 14 to 21 days) and application in the form of a gel (e.g., testogel 25 mg/50 mg daily). Oral substitution is possible (e.g., andriol testocaps), but has not proved itself in clinical everyday life. The depot injection of 1,000 mg testosteroneundecanoat (Nebido™) has recently been recommended in intervals of 3 months with an increasing dose 6 weeks after the initial one. Advantages of the depot injection lies in the more even serum concentrations of testosterone. In times of limited recourses, it is advisable to document the testosterone deficit and the appropriate clinical symptoms precisely. It has been pointed out that testosterone injections may promote growth of a carcinoma in situ of the prostate. Yearly PSA measurement during therapy, and a baseline physical examination before starting substitution is recommended, although this may not be covered by health insurance plans. Moreover, with a positive family anamnesis, a urological consultation is advisable before the beginning of the substitution. Hair loss, skin irritation (with the gel!), increase in serum liver enzymes, the lipid panel and the e-phoresis, as well as water retention in tissues, have been described as relevant side effects. References 1. Braun M, Wassmer G, Klotz T et al. Epidemiology of erectile dysfunction: results of the ŽCologne Male SurveyŽ. International Journal of Impotence Research 2000; 12: 305-11. http://amedeo.com/lit.php?id=11416833 2. Collazos J, Martinez E, Mayo J et al. Sexual Dysfunction in HIV-infected Patients Treated with highly active antiretroviral therapy. JAIDS 2002; 31:322-26. http://www.medscape.com/viewarticle/449091 3. Colson AE, Keller MJ, Sax PE at al. Male sexual dysfunction associated with antiretroviral therapy. J Acquir. Im. Defic. Syndr. 2002; 30:27-32. http://amedeo.com/lit.php?id=12048360 4. Cove J, Petrak J. Factors associated with sexual problems in HIV-positive gay men. Int. J. STD & AIDS 2004; 15: 732-6. http://amedeo.com/lit.php?id=15537458 5. Crum NF, Furtek KJ, Olson PE et al. A Review of Hypogonadism and Erektile Dysfunction Among HIV-Infected Men During the Pre- and Post-HAART Eras: Diagnosis, Pathogenesis, and Management. AIDS Patient Care STDS 2005; 19:655-71. http://amedeo.com/lit.php?id=16232050 6. Feldman HA, Goldstein I, Hatzichritou DG et al. Impotence and itŽs medical and psychosozial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151: 54-61. http://amedeo.com/lit.php?id=8254833 7. Goggin K,.. et al. The relationship of mood, endocrine, and sexual disorders in HIV+ women: an exploratory study. Psychosom Med 1998; 60:11-6. http://amedeo.com/lit.php?id=9492233 8. Grinspoon S, Corcoran C, Askari H et al. Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998; 129:18-26. http://amedeo.com/lit.php?id=9652995 9. Huang JS, Wilkie SJ, Sullivan MP et al. Reduced bone density in androgen-deficient women with acquired immune deficiency syndrome wasting. J Clin Endocrinol Metab. 2001; 86:3533-9. http://amedeo.com/lit.php?id=11502775 10. Jackson G. PDE 5 inhibitors and HIV risk: current concepts and controversies. http://amedeo.com/lit.php?id=16236072 11. Lallemand F, Salhi Y, Linard F et al. Sexual dysfunction in 156 ambulatory HIV-infected men receiving highly active antiretroviral therapy combinations with and without protease inhibitors. JAIDS 2002; 30: 187-90. http://amedeo.com/lit.php?id=12045681 12. Lamba H, Goldmeier D, Mackie NE, Scullard G et al. Antiretroviral therapy is associated with sexual dysfunction and with increased serum oestradiol levels in men. Int J STD AIDS 2004; 15:234-7. http://amedeo.com/lit.php?id=15075015 13. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993;270:83-90. http://amedeo.com/lit.php?id=8510302 14. Schrooten W, Colebunders R, Youle M, et al. Sexual dysfunction associated with protease inhibitor containing highly active antiretroviral treatment. AIDS 2004; 15:1019-23. http://amedeo.com/lit.php?id=11399984 15. Shabsigh R et al. Erectile dysfunction as a predictor for metabolic syndrome. Results from the Massachusetts male aging study (MMAS). Abstract 1236, 100. Annual meeting of the Am. Urol. Association 2005, San Antonio 16. Spindler H, et al.Use of Viagra and crystal methamphetamin and high risc sexual behaviour. XVI IAC, Toronto 2006, #MOPE0342 17. Swearingen SG, Klausner JD. Sildenafil use, sexual risk behavior, and risk for sexually transmitted diseases, including HIV infection. Am J Med 2005; 118:569-70 http://amedeo.com/lit.php?id=15922685 18. Tindall B, Forde S, Goldstein D et al. Sexual dysfunction in advanced HIV disease. Aids Care 1994; 6:105-7. http://amedeo.com/lit.php?id=8186272