Erectile dysfunction in men with HIV-1: effect of hypogonadism and antiretroviral therapy.
Erectile dysfunction (ED) is the inability to attain or maintain an erection sufficient for sexual intercourse. It is more common amongst men with HIV-1 (receiving antiretroviral therapy or not) than HIV-1-negative men [1,2]: 74% of HIV-1-positive men report ED . However, the overall prevalence of ED in HIV-1-positive men is unknown. This is due to differences in studies, such as ED case definitions, sample sizes, and study designs. Moreover, whilst age and CD4+ count are usually considered, co-morbid conditions such as AIDS-defining illnesses, cardiovascular disease and psychological conditions, are more difficult to adjust for. HIV-1-positive men with ED rate their quality of life as lower than men with normal erectile function . Diagnosing and treating ED has benefits at two levels: the individual, by strengthening sexual relationships and self-esteem, and the population, by potentially facilitating more consistent condom usage ('safer sex culture') in men who might otherwise not use condoms because of ED. The causes of ED affect all men regardless of HIV-1 serostatus; however, hypogonadism and antiretroviral therapy (ART) are associated with ED in HIV-1-positive men and these are the subject of this review.
Hypogonadism is not a common cause of erectile dysfunction (>95% patients have normal testosterone levels) , but is the commonest endocrinopathy and cause of sexual dysfunction in HIV-1-positive men . Serum testosterone levels decrease with progressive HIV-1 disease [7, 8]. Before ART, up to 50% of men with AIDS were affected, 33% of whom reported impotence and 67% low libido . In the ART era, 20-25% of HIV-1-positive men are hypogonadic--still higher than the prevalence in the general male population . The reduction in prevalence is largely due to the reduction in morbidity and mortality associated with ART.
Hypogonadism in HIV-1 patients is probably caused by chronic pyrexia, stress, malnutrition and weight loss . HIV-1 wasting syndrome is associated with low total and free testosterone levels compared to men with similar CD4+ counts but no wasting . Hypothalamic-pituitary dysfunction, prolactinaemia  and increased sex hormone binding globulin (SHBG)  may also be associated with hypogonadism in HIV-1 wasting . Drugs to treat HIV-1-related diseases may be implicated, for example ketaconazole . The testes themselves are targeted by HIV-1: testicular destruction by HIV-1-associated infections (e.g. toxoplasmosis, Mycobacterium avium intracellulare, cytomegalovirus) , cytokine-induced Leydig cell impairment , and rarely testicular carcinoma  occur.
The diagnosis of hypogonadism relies on clinical features of androgen deficiency and subnormal serum testosterone levels. Symptoms include fatigue, weight loss, low libido and depression. Signs include gynaecomastia, alopecia, wasting and testicular atrophy. Symptoms are difficult to differentiate from HIV-1 infection per se and the laboratory diagnosis of hypogonadism is complex. Testosterone is 98-99% bound to serum proteins (-58% bound to SHBG and -40% bound to albumin) but only the free fraction (1-2%) is pharmacologically active. Total testosterone (i.e. bound and free fractions) displays diurnal secretion, being highest at 8-9am and decreasing during the day. Total testosterone, measured in the morning, is a cheap assay but does not account for relative changes in protein binding, for example in patients with hypoalbuminaemia. Also, the concentration of SHBG is higher in HIV-1 infection : total testosterone level may fall but the free fraction may remain constant in some men. There are also physiological changes in testosterone production that may complicate the diagnosis. Testosterone decreases with age, with 40% of men over 60 years of age having < 12nmol/1 and 20% <10.4 nmol/1. SHBG, however, decreases with age, and therefore it is not clear if older men are really hypogonadal. In order to overcome the limitations of using total testosterone alone, it is recommended that the free androgen index and SHBG level be measured in clinically compatible cases where total testosterone levels are normal or borderline . Free testosterone is preferable, but equilibrium dialysis is expensive and not a routine test.
The definition of a subnormal total testosterone level is controversial: <300ng/dl (two standard deviations from the mean testosterone level in young men) is frequently used ; but this cannot be applied to older men (in whom total testosterone is known to fall) and HIV-1-infected men. Moreover, a total testosterone level should not be interpreted separately from clinical features of androgen deficiency. A low level should be repeated, and if it persists, an endocrinologist should be consulted to exclude primary (testicular) or secondary (hypothalamus-pituitary) hypogonadism. Follicle-stimulating hormone and luteinising hormone will be high in primary disease and low-normal in secondary disease. Prolactin, thyroid-stimulating hormone and cortisol may be abnormal in secondary disease and an MRI scan of the pituitary fossa is indicated.
Testosterone supplementation should be considered for symptomatic hypogonadism with documented laboratory evidence of androgen deficiency. Testosterone supplementation increases libido and sexual function , nocturnal penile tumescence and sleep-related erections in men without HIV-1 . The effect on sexual function in HIV-1-positive men is not widely studied. Testosterone has been used for the treatment of AIDS-related cachexia on the basis of low serum testosterone  and dehydroepiandrosterone  in HIV-1-positive men with wasting syndrome. Whilst low libido is frequently improved by adequate dosage [22-25], testosterone supplementation appears to be less effective in correcting ED in HIV-1-infected men , although a trial of testosterone supplementation may be clinically beneficial in some men. Testosterone may be given by oral, intramuscular and transdermal routes (reviewed elsewhere) [5,17]. Oral preparations are less effective than intramuscular and transdermal formulations [26,27] and are potentially hepatotoxic (e.g. hepatitis, hepatoma, carcinoma) . Intramuscular injections do not mirror the diurnal variation of testosterone levels and result in an initial surge of hormone. Transdermal preparations mirror diurnal variations of testosterone  and are convenient for patients.
Adverse effects of testosterone supplementation include salt and water retention, gynaecomastia, prostatic neoplasia, poyycythaemia, sleep apnoea, testicular atrophy and acne. Oral formulations are associated with hepatotoxicity , for example increased alkaline phosphatase and conjugated bilirubin. Oxandrolone appears to be the least hepatotoxic oral form . The effect of testosterone on the immune system is ill-defined. Natural killer cell activity is augmented by testosterone supplementation but serum immunoglobulin levels are decreased ; other data suggest that testosterone has no effect on viral load or CD4 count . There is one case report of Kaposi's sarcoma (KS) in an HIV-1-negative patient being treated with exogenous testosterone for aplastic anaemia . The tumour regressed when the androgen was stopped. In HIV-1 infection, testosterone levels may be higher  or lower  in men with KS than in men without KS. There are no large prospective studies to clarify any association between testosterone and KS.
The dosage of testosterone required to reverse the clinical features of androgen deficiency varies between individuals. Patients with a clinical response to testosterone supplementation can be maintained on the current dosage without the need for a testosterone assay . For patients with minimal or no response, a serum testosterone level is indicated and an increased dose considered . All patients should be monitored for the development of poylcythaemia, hepatotoxicity and changes in digital rectal examination and prostate-specific antigen for prostatic carcinoma.
Before ART, the prevalence of ED amongst HIV-1-positive men was estimated to be 53-67% [1, 4, 38, 39]. In a case-control study comparing HIV-1-positive and -negative gay men , 75% of seropositive subjects reported low libido compared with 31% of seronegative men (P<0.05). In the same study, 30% of HIV-1-positive haemophiliacs reported premature ejaculation compared with 4% of seronegative controls (P<0.05). Age was excluded as a confounder because most subjects were aged in the mid-30s. Pre-ART studies, however, had limitations. No large-scale prevalence studies were conducted. CD4+ cell count and viral load were inconsistently reported, the instruments for self-assessment and case definitions for ED differed between studies, and co morbid conditions were frequently neglected.
ART has decreased the morbidity and mortality from HIV-1/AIDS and, consequently, improved sexual health. ART per se, however, is associated with ED. Studies of ED during ART have been improved by using the validated Index of Erectile Function Questionnaire, a multi-dimensional self-report instrument for the evaluation of male sexual function [40,41] developed approximately when protease inhibitors (PIs) became available. None the less, differences in study type and size, adjustment for confounders and ART regimens remain (Table 1). How does one differentiate androgen deficiency (being common in HIV-1 infection) from ART as the primary cause of ED? Patients on ART may have normal serum testosterone [2,42] but subnormal levels of luteinising and follicle-stimulating hormones . This at least suggests that ED in men taking ART is not due to disturbances at the hypothalamo-pituitary level.
In a study of non PI-based ART , the prevalence of ED in men receiving ART cf. no ART is 26% and 25%, respectively. ED is more prevalent with PI-based regimens (27.5%) cf. non-PI regimens (19.5%) in a study of 189 asymptomatic HIV-1 seropositive men . Data indicate that Pis--particularly indinavir [44, 45], ritonavir [45, 46] and saquinavir --are associated with ED. There was no association between PI use and ED in one study , but the duration of ART is not stated here and might bias the results if patients receive ART for only a short time. The mechanism by which PIs cause ED is unknown; however, raised oestradiol levels may result from the altered hepatic metabolism of oestrogens by PIs [46, 47]. Increased oestradiol directly opposes androgenic effects .
ED becomes more common as patients advance to AIDS , with up to 62% of sufferers compared with 42% of HIV-1-positive men (P=0.02) in one study . Difficulty in maintaining an erection and achieving ejaculation are the most frequent self-reported problems in AIDS sufferers . In a study of 78 HIV-1 seropositive men an association was noted between CD4 <200 cells/[micro]l, ED and low libido (P=0.02) . Of 60 men receiving ART, half had undetectable viral load. It is not specified which patients with viral suppression had low CD4 counts--which would better define any association between viral load, CD4 count and ED. The results are also limited because no details of ART regimens and physical health (including hypogonadism and AIDS-defining illness) are given. The study highlights why there is no easily discernible relationship between plasma HIV-1 load, CD4 count and ED in the literature .
MANAGEMENT PRINCIPLES FOR ERECTILE DYSFUNCTION
ED is becoming a more acceptable and potentially better managed health issue, particularly with the advent of the phosphodiesterase-5 inhibitors and more open dialogue about men's health. Specific guidelines for the management of ED  apply to all men. However, HIV-1 per se, HIV-1-related chronic illness, drug interactions with ART and side effects from ART are associated with ED and require attention. In the pre-ART era when patients were ill and dying, sexual function was overshadowed. Now that ART has given patients better health, prognosis and treatment optimism, sexual health has also improved. At the same time, there appears to have been a parallel increase in unprotected anal intercourse and STI rates amongst homosexually active men in large Western cities. With this in mind, should HIV-1-positive men be treated for ED?
There is a fear that restoring sexual function may facilitate more unprotected anal intercourse; this has been borne out to some degree in a study of 429 HIV-1-seropositive men . The prevalence of unprotected anal intercourse with any partners in the previous 3 months was significantly higher in users of sildenafil (60%) when compared with non-users (29%) (P<0.001). Sildenafil users (38%) were also more likely to have unprotected sex with men of unknown HIV-1 status or known seronegative men, than men not using sildenafil (17%) (P<0.01). Another study suggests that the high incidence of HIV-1 and STIs emerging in men aged 50 years and over may be due to sildenafil use in combination with a general lack of HIV-1/STI knowledge .
Most people would find it unacceptable and draconian to suggest that HIV-1-positive men abstain from sex altogether. Similarly, withholding treatment for ED on the presumption that the patient might have unprotected intercourse seems unreasonable. Clinicians should pay particular attention to the following issues when counselling HIV-1-positive patients with (or without) ED [53, 54]:
(1) Uphold the principles of medical ethics, that is respect for autonomy (self-determination and freedom), justice (rights and responsibilities, both personal and public health) and beneficence (doing well by the patient);
(2) Recognise 'the physician's confidence in his or her own ability to judge whether particular patients are likely to be responsible with a newly erect penis';
(3) Impart safer sex information to maximise a patient's sexual health (e.g. prevent STIs, HIV-1 superinfection) and that of his sexual partner(s); and
(4) Understand and reinforce the jurisdiction-specific legalities around the duty to disclose serostatus (e.g. public health acts).
The discussion should be documented carefully in the case notes. A thorough sexual history may identify sexual partners who may be at risk of infection and appropriate contact tracing should be undertaken. Safer sex and disclosure of serostatus should be covered during pre-test counselling for HIV-1 and again following an HIV-1 diagnosis. It seems, however, that these issues are rarely mentioned during subsequent consultations with HIV-1 positive patients. In a multicentre study, 29% of 389 HIV-1 infected patients reported that no clinician had ever talked with them about safer sex . Clinicians are even less likely to discuss disclosure of serostatus than safer sex practices because they may feel ill-equipped to tackle the topic . Referral to a counsellor or sex therapist may be appropriate.
Hypogonadism is a significant factor associated with ED in men with HIV-1. Where possible a clinical diagnosis should be supplemented by laboratory evidence of subnormal testosterone. Primary and secondary causes should be excluded before using testosterone supplementation. The patient should be carefully monitored for adverse effects. PIs are strongly associated with ED. Any adverse effect of ART on ED would also appear to be determined by duration of therapy. Prospective studies are needed to exclude CD4 count as a confounding factor. Apart from addressing the concerns of the patient, identifying and managing ED, with appropriate counselling, may facilitate more consistent condom use amongst HIV-1-positive men and their sexual partners.
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Correspondence to: Derek J Chan, Head of Division, Sexual Health Medicine, Albion Street Centre, 150-154 Albion Street, Surry Hills, NSW2010, Australia. Email: email@example.com
Table 1. Studies of ED prevalence in the ART era Reference Study Sample Age CD4+ type size (years) count (n) (cells/ [micro]l)  Cross 189 36.80 450 sectional (mean) (mean)  Cross 156 40.50 415 sectional (median) (median)  Cross 334 36 431 sectional (median) (median)  Case HIV+: 73 HIV+: 40.5 N/S control HIV-: 100 HIV-: 35.2 (median) (45] Cross 904 39 Most 200 sectional (mean) to 500  Retrospective 254 37 Most 20 (median) to 199  Cross 14 37.40 374 sectional (mean) (mean)  Cross 78 N/S Most 301 sectional to 500+ Reference ART class ED prevalence (or commonest drug)  86% on ART 27.5% in PI users N/S 19.5% overall 3.5% in untreated  All on ART 111/156(71%) * 58% using Pis (N/S) suffered sexual * 42% using non-Pis dysfunction (N/S) 91/111 (86%) suffered ED  95% on ART 80% in PI users * 75% using Pis 10% overall (IDV, NFV) * 25% using NRTls (ZDV, 3TC, d4T) [+ or -] NNRTI  64% on ART 26% in ART users * NRTls (N/5) 25% in HlV+ * NNRTls (NVP) (no ART) 10% in HIV-- (45] All on ART 31% in PI users, cf * 75% using Pis 12% PI-na<ve (IDV, NFV) (OR=2.56, 95% * NRTls and NNRTls (N/S) CI, 1.33-5.03)  All on ART 44% in PI users, cf * 62% using IDV 27% in non-PI users (and SOV,NFV) (P<0.05) * NRTls (ZDV, 3TC, d4T) * NNRTls (N/S)  All on ART 100% * 92% using Pis (IDV) * NRTls (d4T, 3TC)  78% on ART (regimen 51% lost erection N/S) with condom 38% had difficulty keeping erection 33% had difficulty attaining erection N/S, not specified; PI, protease inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; IDV, indinavir; NFV, nelfinavir; SOV, saquinavir; ZDV, zidovudine; 3TC, lamivudine; d4T, stavudine; NVP, nevirapine.