Effects of testosterone replacement therapy on sexual interest, function, and behavior in HIV+ men.

We describe the effects of testosterone replacement therapy on sexual interest, function, and behavior in men with human immunodeficiency virus (HIV) infection. Endocrine abnormalities such as low testosterone are commonly documented in patients with symptomatic HIV illness (Hellerstein, 1990; Laudat et al., 1995), as are clinical symptoms such as loss of sexual interest and erectile dysfunction (Schambelan & Grunfeld, 1994). Investigators have found sexual dysfunction to be more prevalent among HIV seropositive (IRV+) men than HIV seronegative (HIV-) controls (Catalan, Klimes, Bond, Garrod, & Rizza, 1992; Cohen, 1993; Dobs, Dempsey, Ladenson, & Polk, 1988; Meyer-Bahlberg et al., 1991), and most researchers have reported higher rates of dysfunction (Chalmers, Catalan, Nelson, & Day, 1992; Cohen, 1993; Dobs et al., 1988) and testosterone deficiency (Dobs et al., 1988; Donovan & Dluhy, 1994; Klauke et al., 1990; Wagner, Rabkin, & Rabkin, 1995) among men who are symptomatic or diagnosed with AIDS compared to asymptomatic HIV+ men. later stages of HIV illness have also been associated with reduced frequency of sexual activity with a partner, even in the context of a relationship (Rabkin, Remien, & Katoff, 1993; Wagner, Rabkin, & Rabkin, 1993). Estimates of the prevalence of testosterone deficiency in HIV+ men range from 30% to 50% (Dobs et al., 1988; Donovan & DIuhy 1994; Klauke et al., 1990; Raffi et al., 1991) in small clinical samples.

Although low testosterone may often accompany HIV infection, the nature of this relationship remains obscure. Abnormalities of endocrine function in HIV illness may stem from direct effects of the virus (either primary or secondary) or to intercurrent illnesses or medications such as ketoconazole or megestrol (Schambelan & Grunfeld, 1994). Furthermore, as Schambelan and Grunfeld noted, "the body may respond to any severe illness with changes in the rate of hormone secretion and/or clearance, even in the absence of pathological involvement of the organs that are responsible for hormone production or metabolism" (1994, P. 629). Alternatively, testosterone deficiency may be associated with wasting. Overall, its etiology remains unclear.

Outcome studies of testosterone replacement therapy for medically healthy, hypogonadal men complaining of sexual dysfunction show clear benefit (Luisi & Franchi, 1980; O'Carroll 27 & Bancroft, 1984; Salmimies, Kockett, & Pirk, 1981) and no medically serious side effects even with prolonged use. We are unaware of studies regarding efficacy or side effects of testosterone treatment in medically ill patients whose low testosterone appears associated with their illness.

In 1993 we began an ongoing clinical trial of testosterone replacement therapy for HIV+ men with low CD4 cell counts and low levels of serum testosterone who complain of diminished sexual interest and/or sexual dysfunction. In this report we address the following questions: Is testosterone replacement therapy effective in ameliorating diminished sexual interest and sexual dysfunction? Are testosterone injections tolerated in terms of side effects? How is sexual behavior influenced by treatment? Is response maintained over time? Findings from an initial study of 81 patients have been reported (Rabkin, Rabkin & Wagner, 1995), with emphasis on effects of treatment on depressed mood, low energy, and poor appetite. That sample included 31 men who participated only in an open pilot study, as well as 50 men who are included in the current report.

Methods

Participants and Study Inclusion Criteria

Eligibility criteria included CD4 cell count under 400 cells/cu.mm., serum testosterone levels under 400 ng/dl. (laboratory reference range at the time the study began was 360 to 990 ng./dl.), and significant diminution of sexual desire and/or sexual dysfunction. Low mood, low energy, low appetite, and weight loss were common ancillary problems but were not required for study entry. Patients had to be sufficiently ambulatory to come for biweekly visits, be in treatment for their HIV illness, and have their HIV physician agree to their participation. Exclusion criteria included current or recent substance dependence, psychotic symptoms, significant suicidal risk, severe cognitive impairment, and unstable medical conditions. Those with major depression were offered antidepressant medication and advised to try that treatment before starting the testosterone study. Men over age 55 were required to have negative prostatespecific antigen test findings. The first 80 eligible men to give written informed consent and begin treatment were included in the analyses for this report.

Measures

Demographic variables. Variables assessed included age, ethnicity, education level, employment status, and relationship status.

Clinical Global Impression Scale (CGI). This clinician-rated measure is widely used in clinical trials as an outcome measure of response to treatment The seven-point scale was used to rate response to treatment with regard to sexual interest and sexual functioning. Ratings reflect level of improvement in the prior two weeks, since last injection), in comparison to baseline severity. Scores of one ("very much improved") and two ("much improved", indicate a treatment responder, whereas scores of three ("minimally improved") to seven ("severely worse") indicate treatment nonresponders. This scale was completed at each study occasion by the study psychiatrist.

Reynolds Sexual Functioning Inventory--Revised (Reynolds et al., 1988). We used 10 items of this 21-item scale designed to assess male sexual functioning, including erectile functioning, sexual interest, and sexual satisfaction. The response format varies, with some items scored with a five- or six-point scale (e.g., strength of sexual interest, satisfaction with one's sex life), whereas others have a six-point scale based on frequency of the event being rated (e.g., oral sex, ability to regain full erection after becoming flaccid). The scale's authors report satisfactory test-retest reliability, construct validity, and concurrent validity. This scale was administered at baseline and Week 12 of the study.

Visual analog scales. Ten-point visual analog scales (a straight line, usually 100 mm in length, with anchor descriptives provided only at the endpoints) were used to assess sexual interest and strength of spontaneous morning and daytime erections. These scales were completed at every study visit.

Sexual activities inventory. A self-report measure was developed to assess sexual behavior during the prior month, including number of partners, types of sexual activity (oral, anal, vaginal), and number of occasions of unprotected sex (no use of condom) of each type of activity. Respondents were also asked to report their perception of risk for their partner(s) becoming HIV infected via their sexual activity with them. This inventory was administered at baseline and Week 12 of the study.

Side effects assessment. Patients were asked by the study psychiatrist if they had experienced any of 10 potential testosterone side effects. The 10 side effects consisted of low energy, irritability, acne, tension, being uncharacteristically bossy, feeling "high," hair loss, testicular atrophy, decreased amount of ejaculate, and breast tenderness. The presence of side effects was assessed at every study occasion.

Follow-up phone interview. A structured interview was developed as a follow-up phone interview to assess whether treatment had continued, if response had been maintained, and if side effects were present. Responders to treatment who had intended to continue treatment were contacted at least three months following study completion to administer this brief interview.

Blood values. Laboratory tests at baseline, performed by Metpath Laboratories (Teterboro, NJ), included CBD chemscreen, T-cell subsets, [beta.sub.2] microglobulin, and serum testosterone. Testosterone levels were tested every other week, in the interim weeks between injections. T-cell subsets and [beta.sub.2] microglobulin were repeated at Week 12 (end of study).

Several psychiatric measures were also administered, with findings reported elsewhere (Rabkin, Wagner, & Rabkin, in press) in a report focusing on the treatment's antidepressant effects.

Procedures

Potential study participants were briefly screened over the phone to assess preliminary eligibility. Those who appeared to be eligible were scheduled for a more extensive screening evaluation by a trained psychologist, as well as laboratory blood work. After eligibility was established, an appointment was made with the study psychiatrist for a final evaluation. At this appointment, the patient read and signed the consent form and began treatment. All men were treated for eight weeks with biweekly intramuscular injections of testosterone and visits with the study psychiatrist to discuss treatment progress. Starting dose was 200 mg., increasing at Week 2 to 400 mg. biweekly in the absence of adverse reactions or testosterone serum levels exceeding twice the upper limit of the laboratory reference range. Responders were maintained on testosterone for at least four more weeks and were then randomized to testosterone or placebo (at the same dose as at Week 12) for six weeks or until relapse (discontinuation phase), with the treatment being unknown to both the patient and study psychiatrist (double-blind). Patients who remained on testosterone treatment following completion of the study protocol were contacted by phone for a follow-up interview at least three months following study completion.

Results

Independent t-tests (2-tailed) and univariate analysis of variance models were used to assess differences between groups (e.g., responders versus nonresponders) with regard to continuous variables, whereas Chi-square analyses were used to assess group differences with regard to categorical variables. Paired t-tests (2-tailed) were used to assess change over time. For analyses of change from baseline to Week 12, Week 8 data were carried forward to Week 12 for those who ended treatment at Week 8.

Sample Description

Demographics. Mean age was 41 (range: 28-62), 20% were Hispanic or Black, 90% had attended at least some college courses, 40% were in a relationship, 38% were employed, and 51% were on disability. Most men were identified as gay or bisexual. Two men had a history of intravenous drug abuse.

Baseline medical status. As a group, the men had relatively advanced IRV illness, with 84% meeting 1993 CDC criteria for an AIDS diagnosis. The mean length of time between testing HIV+ and study entry was 5 years (range: 3 months to 11 years). Mean CD4 cell count was 104 cells/cu.mm (SD = 110, range: 3-408). Fifty percent had baseline CD4 cell counts under 50 cells/cu.mm. The mean [beta.sub.2] microglobulin was 3.5 mg./L. (SD = 1.3, range: 1.7-7.1). The laboratory reference range for [beta.sub.2] microglobulin is 0.7 to 3.4 mg./L., with higher numbers representing greater viral activity. The mean number of HIV medications was five, with 58% taking an antiretroviral at study baseline.

Presenting Sexual Problems

Four men reported no loss of sexual interest but only sexual dysfunction problems, and 12 reported loss of sexual interest and no sexual dysfunction problems. The other 64 men complained of both diminished sexual interest and sexual dysfunction. Only eight men complained exclusively of sexual problems: the others had at least one ancillary problem (i.e., depressed mood, low energy, weight loss, poor appetite).

Clinical Outcomes

Dropouts. Of the 80 men who entered the study, 73 completed at least 8 weeks of treatment. There were seven dropouts (9%): Two men discontinued treatment because of side effects (discussed later), two were unable to adhere to a regular appointment schedule, and three had prolonged hospitalizations for AIDS-related conditions.

Changes in sexual interest and functioning. Of the 73 completers of the open treatment phase, 67 (92%) were rated as clearcut responders by the study psychiatrist and the patient. This rating takes into account the patient's response with regard to both Sexual interest and sexual functioning. When we examined these areas Separately. 57 (83%) of the 69 completers who complained of diminished sexual interest at baseline reported much improvement, and 43 (69%) of the 62 completers who had initial complaints of sexual dysfunction reported much improvement. Of the four men who complained only of sexual dysfunction, two were rated as responders, and two were rated as nonresponders. Concurrent use of medications associated with lowered testosterone levels (e.g., ketoconazole, megesterol, cimetidine) was not associated with treatment outcome. The mean testosterone level at baseline was 302 ng./dl., increasing to 1162 ng./dl. after 4 biweekly injections. Degree of testosterone deficiency at baseline was not associated with response (t = 1.9, df = 71, p = NS). Self-ratings of sexual interest, erectile functioning, and satisfaction with one's sex life revealed significant improvement, with all statistically significant tests having strong effect sizes (see Tables 1 and 2).

Table 1

Change in Self-Ratings of Erectile Functioning
Among Study Completers

Variable                           Baseline           Week 12

Strength of morning
  erections(*)                1.8 [+ or -] 1.4     4.8 [+ or -] 2.9
Strength of spontaneous
  day-time erections(*)       1.2 [+ or -] 0.6     3.3 [+ or -] 2.5
In sex with partner,
  frequency of ejaculation
  without full erection(**)   0.8 [+ or -] 1.0     1.1 [+ or -] 1.4
Strength of erection
  during masturbation(***)    3.0 [+ or -] 2.2     5.1 [+ or -] 1.6
Strength of erection
  during oral sex(***)        2.8 [+ or -] 2.3     4.7 [+ or -] 1.9
Strength of erection
  during anal sex(***)        2.6 [+ or -] 2.4     5.1 [+ or -] 2.0
Ability to regain
  erection when lost(****)    3.2 [+ or -] 2.2     2.6 [+ or -] 1.6

Variable                                   t        P
Strength of morning
  erections(*)                            -7.3      .000
Strength of spontaneous
  day-time erections(*)                   -6.6      .000
In sex with partner,
  frequency of ejaculation
  without full erection(**)               -1.2       NS
Strength of erection
  during masturbation(***)                -4.9      .000
Strength of erection
  during oral sex(***)                    -3.2      .004
Strength of erection
  during anal sex(***)                    -3.3      .004
Ability to regain
  erection when lost(****)                 1.6       NS

(*) Strength of morning and daytime erections are based on a 10-point visual analog scale, with higher numbers representing greater strength.

(**) Based on report of activity in month prior to assessment for those who had sex partners; response code: 0 = never ejaculated without full erection; 1 = seldom, 25% of the time; 2 sometimes, 50%; 3 = usually, 75%; 4 = always ejaculated without full erection; 5 = have been unable to ejaculate during sex with a partner.

(***) Based on report of activity in month prior to assessment for those who had engaged in the activity; response code: 1 = no erection; 2 = barely noticeable enlargement; 3 = slight elevation from body; 4 = moderate elevation; 5 = definite elevation, but too soft for penetration without manual assistance; 6 = full erection, sufficient for penetration.

(****) Based on report of activity in month prior to assessment for those who had engaged in sexual activity; response code: 1 = have not lost erections; 2 = always able to regain erection; 3 = usually, 75% of the time; 4 = sometimes, 50%; 5 = seldom, < 25%; 6 = never able to regain erection.

Table 2

Change in Self-Ratings of Sexual Interest, Satisfaction, and
Behavior Among Study Completers

Variable                         Baseline             Week 12

Sexual interest(*)            2.2 [+ or -] 1.9     6.0 [+ or -] 2.5
Satisfaction with
  one's sex life(**)          6.0 [+ or -] 1.4     3.6 [+ or -] 2.0
Mean frequency of
  masturbation(***)           1.5 [+ or -] 1.4     3.5 [+ or -] 1.6
Mean frequency of
  oral sex(***)               0.6 [+ or -] 0.9     1.1 [+ or -] 1.5
Mean frequency of
  anal sex(***)               0.2 [+ or -] 0.5     0.8 [+ or -] 1.2
Mean number of
  partners in past
  month                       0.9 [+ or -] 1.3     1.6 [+ or -] 2.0

Variable                             t           p

Sexual interest(*)                 -9.4        .000
Satisfaction with
  one's sex life(**)                7.4        .000
Mean frequency of
  masturbation(***)                -7.1        .000
Mean frequency of
  oral sex(***)                    -3.4        .002
Mean frequency of
  anal sex(***)                    -3.5        .002
Mean number of
  partners in past
  month                            -3.0        .005

(*) Strength of sexual interest is based on a 10-point visual analog scale, with higher numbers representing greater strength.

(**) A six-point scale was used, with lower scores representing greater satisfaction.

(***) Means are based on report of activity in month prior to assessment; response code: 0 = not at all: 1 = once; 2 = 2 or 3 times; 3 = once a week; 4 = 2 or 3 times per week: 5 = once a day; 6 = more than once a day.

Fifty-seven men entered the double-blind discontinuation phase and were randomized either to placebo or to continue on testosterone. The other 11 responders in the initial treatment phase did not enter the discontinuation phase: 4 were moving to other cities, 2 were removed from the study because of protocol violations, 1 discontinued treatment because of side effects (hair loss), 1 was too ill physically, 1 continued to feel depressed, 1 refused to enter the discontinuation phase, and 1 was receiving an irregular dose schedule. Fifty-three men completed the discontinuation phase, with four dropping out for AIDS-related reasons (three died, and one was hospitalized). Twenty-five of 27 patients randomized to placebo injections completed the double-blind phase, of whom 5 maintained their response (20%) with regard to sexual interest and/or functioning, and 20 relapsed. Twenty-eight of 30 patients randomized to continue on active testosterone completed the double-blind phase, of whom 21 (75%) maintained their response and 7 relapsed (this difference was statistically significant-Chi-square 16.0, 1 df, p [is less than] .000).

Changes in sexual behavior. The majority (62%) of completers of the initial treatment phase were sexually abstinent in the month prior to study baseline, and nearly half (45%) were abstinent in the month prior to Week 12. Of the 28 men who were sexually active in the month prior to baseline, 2 reported sexual activity only with women (both reported having only 1 partner), and 26 reported sexual activity with only men. For those who reported sex with men at baseline, the mean number of partners over the past month was 2 (SD = 2), with a range of 1 to 10 partners and a mode of 1 partner. Only 1 of the 36 men who were sexually active in the month prior to Week 12 reported having a female partner (he reported only 1 partner); of the 35 who reported sex with men, the mean number of partners was 2.3 (SD = 1.6), with a range of 1 to 6 partners, and a mode of 1 partner. Frequency of masturbation, as well as oral and anal sex with partners, increased significantly for those who continued treatment at least through Week 12 (see Table 2).

Sexual risk behavior: Oral sex. Twenty-two men reported practicing oral sex at baseline, with 13 reportedly not using condoms on at least one occasion (12 reported unprotected insertive oral sex). Twenty men reported practicing oral sex at Week 12, with 14 reportedly not using condoms on at least one occasion (12 men reported unprotected insertive oral sex). Two men who reported unprotected oral sex at baseline rated their sexual activity as risky for their partner(s); all 14 men who reported unprotected oral sex at Week 12 rated their sexual activity as posing no risk to their partner(s). We did not ask about the rationale for such judgments; hence, it is unknown whether such beliefs were based on logic (e.g., partner was HIV+) or misconception e.g., lack of ejaculation).

Sexual risk behavior: Anal and vaginal sex. Eleven men reported practicing anal sex in the month prior to baseline, of whom three reported not using condoms on at least one occasion 1 one reported unprotected insertive anal sex). At Week 12, 17 men reported practicing anal sex during the prior month, of whom 6 (including one who reported such activity at baseline as well) reported not using condoms on at least I occasion (3 men reported unprotected insertive anal sex). At both baseline and Week 12, one patient reported vaginal intercourse with the use of condoms on each occasion during the month prior to both assessments.

All those who reported unprotected anal sex at baseline and/or Week 12 rated their sexual activity as posing no risk to their partner(s). Of the eight men who reported unprotected anal sex at either baseline or Week 12, four were in relationships at baseline: two men had HIV+ partners, one had an HIV- partner, and one was in a relationship with a man who was untested. Retrospectively, we attempted to contact these eight men to ask them about the circumstances surrounding their participation in unprotected anal sex and why they had perceived their partner(s) to be at no risk for HIV transmission. Of the six men who we contacted (two men were unable to be contacted because of disconnected phones and no forwarding addresses), all claimed to have good memory of the related events: Four men reported that their partner(s) was also HIV+; one reported that his partner was HIV-, but that penetration was withdrawn before ejaculation took place; and one reported that his partner's status was unknown, but that he perceived the activity to be of low risk because the patient assumed the receptive role. None of these men was willingly and knowingly tying to infect his partner(s), nor did it appear that they were engaging in high-risk sex with indifference or hostility.

Side Effects

Two men discontinued the first phase of the study because of side effects: irritability and hair loss. Other treatment-emergent (absent at baseline but present at some point during the study) side effects that were reported, but did not lead to study discontinuation, included truncal acne, fatigue, tension, uncharacteristic assertiveness, feeling "high," decreased ejaculate, testicular atrophy, gynecomastia, and in one instance, undesired weight gain. Irritability was the most commonly cited treatment-emergent side effect, with 22 men reporting its presence at least once. The side effects that were reported for at least two consecutive biweekly assessments were irritability, fatigue, acne, tension, and uncharacteristic assertiveness; however, only irritability was reported on three or more consecutive study occasions (six or more weeks). In most cases, treatment-emergent side effects diminished without a change in dosage. For example, six of the eight patients who reported irritability on consecutive occasions experienced an amelioration in this symptom without a change in dose; dosage was reduced for the other two patients to alleviate the adverse reaction and then elevated once the side effect was no longer present, and without its re-emergence. For the one patient who experienced gynecomastia, nolvadex (an anti-estrogen) was added to his treatment, with good results. Overall, these data suggest that side effects of testosterone replacement therapy are mild, transient, and reversible with lowering or discontinuation of dose.

Long-term Follow Up

Of the 39 men who met criteria for the follow-up interview, 22 were interviewed. Of the remaining 17, 9 were inaccessible (e.g., phone disconnected, moved out of New York City area), 3 had died, 2 were in the hospital, 2 discontinued when the study ended because of hair loss, and 1 was not willing to participate in the interview.

Interviews took place an average of 20 weeks (range was 13 to 35 weeks) following discharge from the study and an average of 44 weeks 1 range was 29 to 61 weeks) after onset of treatment. Of the 22 who were interviewed, 19 (86%) had continued to receive testosterone replacement therapy. Ten of the 19 men were self-injecting, and the others had a physician or nurse administer the treatment. The majority of the men were receiving 400 mg. intramuscular injections biweekly: however, the dosage range was 50 mg. to 400 mg., and many were taking weekly injections. All but 1 of the 19 still on treatment reported no difficulty in getting access to treatment.

Among the three men who were not receiving treatment at the time of the interview, two had continued treatment following discharge but then stopped (one experienced intolerable pain from the injections following a hair-follicle infection, and the other felt less effect after he started self-injecting). The one man who did not continue treatment following discharge had become increasingly ill and went to live with his family The latter patient reported problems with diminished sexual interest and erectile dysfunction, whereas the former two patients denied such problems at the time of the interview.

Maintenance of effect. Fifteen of the 19 (79%) men still on treatment reported no current problems with sexual interest or sexual functioning. Of the four who reported problems, one reported lower sexual interest, two reported some difficulty with erectile functioning, and the other reported a drop in both sexual interest and functioning. Five of the 19 men reported an easier time with finding sexual partners, which they attributed to increased self-confidence as a result of treatment Three men reported no change in this area, whereas the remaining 11 men were in relationships or had no problems in finding partners from the outset of treatment

Side effects following extended treatment. Eight of the 19 (42%) men still on treatment reported noticeable side effects (often more than one side effect) resulting from extended treatment. Four men reported testicular atrophy and/or decreased ejaculate, two men reported hair loss, one reported a noticeable increase of acne, one reported fatigue for the first two days following injection, and one reported increased aggression and irritability. All those who reported side effects continued the treatment, believing that the benefits of treatment outweighed its costs.

For a few patients who experienced testicular atrophy and/or decreased ejaculate, we added human chorionic gonadotropin (hCG) as an adjunct to testosterone and lowered the amount of testosterone administered. A trial-and-error approach has led to our using 200 mgs. of testosterone and 2000 i.u. of hCG once a week with these patients. We have found improvement in these symptoms, and the patients have continued in treatment.

Discussion

In this study of 80 men with clinically deficient or borderline serum testosterone levels, relatively advanced HIV illness, and subjective complaints of diminished sexual interest and/or sexual dysfunction, testosterone replacement therapy was effective and well tolerated. Significant improvements were found in sexual interest and function, even in the presence of active HIV illness and among men taking medications associated with lowered testosterone levels.

Progressive HIV illness entails many kinds of losses. Restoration of sexual desire and/or functioning can help enhance overall outlook and quality of life. Several men, including those who remained abstinent despite a desire to increase their sexual activity with partners, spoke of a vitality and a "sexual self" that had returned to their lives. Study completers reported a significant increase in their sexual activity, both with partners and in solitary masturbation.

Data from the follow-up interviews suggest that extended use of testosterone is well tolerated and that response to treatment is maintained. The occurrence of side effects, in particular, testicular atrophy and decreased ejaculate (long-term use of testosterone inhibits pituitary secretion of gonadotropins), seems more likely with extended treatment. However, such adverse reactions appear to be minor and tolerable, given the patients' decisions to continue treatment.

This study has several limitations; hence, caution is warranted when interpreting our findings. We relied on self-reports to measure changes in sexual desire and erectile functioning; we are hoping to add an objective physiological measurement such as nocturnal penile tumescence (NPT) to our future research of this treatment further to validate our findings. Measuring effect on immune status is difficult when 50% of the men have CD4 cell counts under 50 cells/cu.mm. at study baseline. Also, our clinical trial did not include a placebo control group for the first 12 weeks of treatment. We recently changed the study design so that a 6-week double-blind, placebo-controlled phase precedes 12 weeks of open (active medication) treatment.

Several questions remain unanswered concerning the treatment applications of testosterone replacement. Our sample was comprised of men with testosterone levels below 400 ng./dl. and CD4 cell counts below 400 cells/cu.mm. Would the treatment be just as effective for HIV+ men with "normal" testosterone levels? We have begun a pilot study involving HIV+ men with low CD4 counts and low to mid-normal testosterone levels (401 to 650 ng./dl.) and have observed results similar to those reported here. What about HIV+ men with low testosterone levels but relatively intact immune function? Given the findings from studies of medically healthy men, one would expect that HIV+ men with higher CD4 counts would also benefit from treatment. The primary concern with long-term testosterone replacement therapy is the possibility of exacerbating incipient prostatic: cancer as men get older. However, when life expectancy is uncertain, but limited, the potential benefits of testosterone on mental health, quality of life, and nutritional status appear to outweigh such possible health risks. Further research is needed to begin to understand the full gamut of possibilities for testosterone replacement therapy.

Although the majority (92%) of our sample reported no unprotected anal or vaginal intercourse either before or after treatment, the finding that eight men reported unprotected anal sex alerted us to the need to implement additional safeguards into the ongoing study protocol. From the outset of the study we offered group and individual counseling sessions with a certified sex therapist for those patients who expressed a desire to discuss safer sex negotiation or sexual issues in general. We recently added systematic, individual safer sex counseling for all patients throughout the study (baseline and Weeks 2, 8, and 12), during which we inquire about condom use and address areas of concern involving the risk of transmission to partners. We have also added the self-report of "unprotected anal or vaginal sex with an HIV- or unknown HIV status partner in the three months prior to baseline" to our study exclusion criteria. Unprotected oral sex was not added to this criterion, given the unclear and debatable risk associated with such behavior. For example, in Canada and some European countries, oral sex is regarded as permissible within the boundaries of "safer" sex.

We do not discontinue treatment for patients who report unprotected anal or vaginal sex with partners who are not HIV+ once they are in treatment. Such a policy would require us to inform potential patients in the consent form that if such information emerged during the study that their participation would be discontinued. We believe that this would greatly inhibit the reporting of unprotected sex and would thus prevent us from providing needed counseling. The validity of our data concerning sexual practices would be diminished as well.

Testosterone replacement therapy for HIV+ men may raise questions from a public health perspective. Some are opposed to testosterone treatment because it may enhance the sexual desire and function of persons who have the potential to transmit HIV. Although extreme, a logical extension of this view is that any treatment for persons living with HIV increases societal risk, because the longer they live, the longer they pose a potential threat to the community as disease vectors. Our ethical responsibility to prevent harm to our patients or others as a result of treatment is a top priority in our research, and we share the concern about enhanced risk for transmission, which is why we have implemented the safeguards as stated previously.

These findings suggest that testosterone replacement therapy should be considered for men with relatively advanced HIV illness who complain of sexual problems and who have deficient or borderline serum testosterone levels. Although we are strong advocates of the treatment, we do urge clinicians who provide testosterone to their patients to use caution when considering whether a patient is appropriate for the treatment by assessing the patient's recent history of sexual risk behavior and counseling patients about potential risks to sexual partners when appropriate. The treatment is inexpensive and is easily provided in a primary care setting, although some climes and physicians are reluctant to prescribe steroids because of their classification as a controlled substance. The resulting clinical changes are much appreciated in terms of quality of life.

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Manuscript accepted April 24, 1996

Grant support for this study was provided by National Institute of Mental Health (NIMH), grant no. 5 R01 MH52037 (Dr J. Rabkin, Principal Investigator).

Address correspondence to Glenn Wagner, Ph.D., New York State Psychiatric Institute, Unit 35, 722 West 168 Street, New York, NY 10032. Phone: [phone]. Fax: [phone].