tt Address reprint requests to: Department of Medicine, University of Mississippi, 2500. North State Street, Jackson, MS 39216. Supported in partby: Grant Nos.
EFFECT OF WEIGHT LOSS ON THIAZIDE PRODUCED ERECTILE PROBLEMS IN MEN* HERBERT G. LANGFORD, M.D. *tt, ROBIN W. ROCKHOLD, Ph.D.*, SYLVIA WASSERTHEIL-SMOLLER, Ph.D.t, ALBERT OBERMAN, M.D.4, BARRY R. DAVIS, M.D., Ph.D.**, and M. DONALD BLAUFOX, M.D., Ph.D.t THE TAIM INVESTIGATIVE GROUP
INTRODUCTION Problems with erectile performance and libido in the treated hypertensive man are said to be a frequent and often unrecognized cause of poor compliance with therapy. However, obtaining and interpreting valid data on the frequency and severity of sexual problems in hypertensive males is complicated by several facts: 1) decreasing function with age; 2) as Bansal pointed out recently, hypertensive individuals without therapy report increased sexual dysfunction (1); 3) eliciting the frequency of sexual dysfunction is highly sensitive to the mode of gathering the information. Data are now adequate to conclude that sexual dysfunction in the male is a frequent consequence of antihypertensive drugs. The Medical Research Council reported that 20% of participants randomized to a thiazide drug, albeit at a very high dose, reported difficulty, and 13% randomized to Propranolol reported difficulty (2). Both of these figures were significantly higher than the percent receiving placebo. This information was obtained by questionnaire, though it was a single-blind study. Bulpitt reported on the frequency of sexual dysfunction found in the hypertensive clinic, as evaluated by a self-administered questionnaire (3). He found an enormous frequency of dysfunction, as illustrated by the statement "only 36% of the patients taking Methyldopa, plus or minus diuretics, complained of impotence." * Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi (H.G.L., R.W.R.) t The Department of Nuclear Medicine (M.D.B.); and Epidemiology and Social Medicine (S.W.S), Albert Einstein College of Medicine, Bronx, New York. t Division of General and Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.O.). ** The Coordinating Center for Clinical Trials, University of Texas School of Public Health, Houston, Texas (B.R.D) tt Address reprint requests to: Department of Medicine, University of Mississippi, 2500 North State Street, Jackson, MS 39216 Supported in part by: Grant Nos. HL-30171, HL-24369, HL-30163, HL-41445 From the National Heart, Lung and Blood Institute, National Institutes of Health US Department of Health and Human Services
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DRUGS AND ERECTILE DYSFUNCTION
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The high percent of dysfunction has been observed in trials where the information was obtained by questionnaire. A V.A. trial reported that only 3% of individuals on thiazide diuretics had difficulty (4). However, this information was obtained by direct questioning by a nurse, often of a different race as well as a different sex. The dose of the drug being studies is also probably very important in the frequency of difficulty. In the study of Propranolol therapy, the average dose for those with complete erectile failure was 143 mg/day, the participants reporting decreased sexual functioning were taking 124 mg/day, and those with no sexual complaints were taking a mean daily dose of 83 mg/day. The threshold effect for the difficulty was felt to be between 160-180 mg/day (5). No reports are available on the interaction of diet and the effect of drugs on sexual performance. We report on the interaction of diet and drugs on the report of sexual performance from a multi-center trial aimed at determining optimum therapy for mild hypertension. DESIGN AND METHODS The clinical data are derived from the Trial of Antihypertensive Interventions and Management (TAIM). TAIM is a study to determine optimal management of mild hypertensive individuals. Patients with diastolic blood pressures between 90-99 mmHg were randomized into one of three diet groups (no diet change, weight loss, and a low sodiumhigh potassium diet), and one of three drug groups (placebo, 25 mg Chlorthalidone, or 50 mg Atenolol). Questionnaires were administered at baseline and at six months. The patient data that we report is from the
questionnaire. Preliminary rat data was also obtained. Sexually mature male rats were obtained and screened for appropriate male penile reflexes and copulatory behavior. Penile reflexes were evaluated prior to drug therapy, and at seven days following daily injection intraperineally of vehicle, Clonidine (25 mg/kg) or Hydrochlorthiazide (10 or 50 mg/kg). Copulatory tests were performed in the same rats following nine days of drug treatment (n = 6 rats). RESULTS Figure 1 shows the changes in reported ability to have erections. The chlorthalidone group, with usual diet, reported a 28.3% frequency of worsening erection, and a 6.5% frequency of improved erection. Those randomized to chlorthalidone and weight loss reported a 13.5% frequency of worsening erection, and a 21.6% improved erection, significantly different by Anova. Figure 2 shows significant depression of the penile reflex score in the Hydrochlorothiazide and Clonidine treated rats, compared to the control
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137D.10 **
-
Drug Effects On Penile Reflexes And Copulatory Function Penile Reflex Score
Vehicle
Pre-Drug
7 Day
(control)
Treatment
Vehicle
Copulatory Score
3.17 N.S. 3.20 %0.34 %O0.37 0 2.83 ** %0.31
Clonidine HCTZ (10 mg/kg) HCTZ (50 mg/kg)
2.67
%0.33
3.33 %0.33
**
1.67 0.21 0.80 0.49
3.0 %O 0++ -
1.33"'
%0.42
0.20"
%0.20
Hct 43.3 %0.8 43.3 %0.6 42.0 %0.8 43.9 %0.6
Body Weight 413
%17
383 %18 382 %7 357 %5
FIG. 1.
Percent Of Male Participants Reporting Worsening Or Improvement In Problems With Erection At 6 Months+ N in each drug group 30
X 0 20
ffi
E
-
(34) (45) (47)
(47) (35) (42)
(35) (41) (54)
M Placebo
U Chlorthalidone * Atenolol
1 10
0 a
-10
* -20 .Ou
Usual Diet Na Reduction Weight Loss (1) Chi-Square comparing worsening among the 3 drug groups on Usual diet * 103, df.a2, P-.009 * percent of those reporting no change are omitted from this graph FIG. 2.
rats. Similarly, copulatory score was also reduced by treatment, with a zero score for the Clonidine treated group, 0.20 score for the 50 mg/kg HCTZ treated rat, and a 1.33 score, still significantly reduced, for the 10 mg/kg treated rats.
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DISCUSSION The results confirm the frequency of decreased erectile performance produced by a thiazide-type diuretic in men. Moreover, they show that the same phenomenon occurs in rats. It seems unlikely, therefore, that psychological factors are the main cause of the phenomenon in men. We have not presented the data on women, but there does not seem to be a decrease in sexual functioning in women produced by Chlorthalidone. The mechanism by which thiazide-type diuretics produce erectile dysfunction is unknown. My colleague, Dr. Rockhold, has postulated that sodium depletion produces increased central alpha 2 adrenergic function, which depresses erectile competence. The associated hypokalemia perhaps could affect vascular contractility. There is no reason to think that the thiazide diuretics should affect sex related hormones. However, we are measuring basal and six-months levels of testosterone, estrodiol and prolactin. Even if the levels are not changed by therapy, it may be that the baseline levels will affect the frequency that this complaint occurs. As we cannot explain the mechanism by which the thiazides produce erectile dysfunction, we are unable to explain how weight loss reduces the frequency of this complaint. Obesity is associated with decreased testosterone and increased estrodiol levels, and there is some evidence that hypertension has a similar association, even when the amunt of obesity is taken into account. Perhaps the weight loss improves the testosterone-estrodiol balance enough for the individuals to function adequately, without affecting the basic mechanism of the thiazide effect. Understanding the mechanism of thiazide-produced erectile dysfunction is extremely important, as thiazide diuretics remains one of the most useful classes of antihypertensive drugs. Almost all hypertensive patients need to lose weight. Although we do not known how weight loss helps thiazide-produced erectile dysfunction, the knowledge of the favorable effect of weight loss on this key function should be a strong incentive towards reducing weight.
SUMMARY Thiazide-type diuretics frequently produce erectile dysfunction in men on a regular diet. However, men on a weight-loss diet have much less erectile dysfunction. Thiazide-type diuretics also produce erectile dysfunction in rats and interfere with normal copulation. The mechanism of the dysfunction and the favorable response to weight loss is unknown. REFERENCES 1. Bansal, S. Sexual dysfunction in hypertensive men. Hypertension 1988; 12: 1. 2. Report of Medical Research Council Working Party on Mild to Moderate Hypertension.
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Adverse reaction to bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981; 2: 539. 3. Bulpitt, C.J. and Dollory, C.T. Side-effects of hypotensive agents evaluated by a selfadministered questionnaire. Brit Med J 1973; 3: 485. 4. Veterans Administration Cooperative Group. Study on Antihypertensive Agents. Effects of treatment on morbidity from Hypertension III. Influence of age, diastolic pressure and prior cardiovascular disease: Further analysis of side-effects. Circ 1972; 55: 991. 5. Burnett W.G. and Chanine, R.A. Sexual dysfunction as a complication of propranolol therapy in men. Cardiovascular Med 1979; 4: 811.
DISCUSSION Macklem (Montreal): I would have thought that one of the major problems in getting accurate statistics is to define the prevalence of erectile problems in normal males not on any medication at all. One gets the impression that's a pretty common problem, but are the statistics accurate and what do the prevalence levels suggest, and how do they compare to hypertensive patients? Langford: There have been studies on normal men, population based studies, asking about frequency of difficulty. The data on the hypertensive men do not come from probability samples. They come from clinical samples and therefore are not strictly comparable. They are all from self-reports, in one manner or another. For this study, we had a placebo control on regular diet and we were asking not about basal function, but about change in functioning so these data are all right. I'm not completely happy about the quote on the increased frequency of complaints in the hypertensive. Hellems (Jackson): I point out to Dr. Langford that his questionnaire about erectile problems in males is flawed. He really should ask the females and the partner relating to that to get reliable data. I'm going to ask him another question. What's the evidence in females of changes in libido on thiazides? Langford: I accept the desirability of having that kind of information. It has come out differently for some of the side effects of drugs when you ask partners, than when you ask the persons. Some women psychologists who have worked with us have looked at the questionnaires that we've given the patients. We've found very little change in the women, but the psychologists told us we had lousy questionnaires to elicit information on sexual function in women. We should not have expected to get anything of value and we
didn't. Barondess (New York): Dr. Hellems answered my question. I was going to introduce it by saying that one hesitates to say he rises to discuss this paper.
