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LE Magazine May 2003

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Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease.

BACKGROUND: The increased incidence of coronary artery disease in men compared with premenopausal women suggests a detrimental role of male hormones on the cardiovascular system. However, testosterone has direct relaxing effects on coronary arteries in animals, as shown both in vitro and in vivo. The effect of testosterone on the human coronary circulation remains unknown. METHODS AND RESULTS: We studied 13 men (aged 61+/-11 years) with coronary artery disease. They underwent measurement of coronary artery diameter and blood flow after a three-minute intracoronary infusion of vehicle control (ethanol) followed by two-minute intracoronary infusions of acetylcholine (10(-7) to 10(-5) mol/L) until peak velocity response. A dose-response curve to three-minute infusions of testosterone (10(-10) to 10(-7) mol/L) was then determined, and the acetylcholine infusions were repeated. Finally, an intracoronary bolus of isosorbide dinitrate (1000 microgram) was given. Coronary blood flow was calculated from measurements of blood flow velocity using intracoronary Doppler and coronary artery diameter using quantitative coronary angiography. Testosterone significantly increased coronary artery diameter compared with baseline (2.78+/-0. 74 mm versus 2.86+/-0.72 mm [P=0.05], 2.87+/-0.71 mm [P=0.038], and 2.90+/-0.75 mm [P=0.005] for baseline versus testosterone 10(-9) to 10(-7) mol/L, respectively). A significant increase in coronary blood flow occurred at all concentrations of testosterone compared with baseline (geometric mean [95% CI]: 32 [25, 42] versus 36.3 [27, 48] inverted question markP=0.006 inverted question mark, 35.3 [26, 47] inverted question markP=0.029 inverted question mark, 36.8 [28, 49] inverted question markP=0.002 inverted question mark, and 37 [28, 48] inverted question markP=0.002 inverted question mark mL/min for baseline versus testosterone 10(-10) to 10(-7) mol/L, respectively). No differences existed in coronary diameter or blood flow responses to acetylcholine before versus after testosterone. CONCLUSIONS: Short-term intracoronary administration of testosterone, at physiological concentrations, induces coronary artery dilatation and increases coronary blood flow in men with established coronary artery disease.

Circulation 1999 Oct 19;100(16):1690-6

Testosterone and other anabolic steroids as cardiovascular drugs.

There has been much interest in the effect of sex hormones on cardiovascular risk factors and as a therapeutic modality in both men and women. In this article, testosterone is considered as a possible therapy for cardiovascular disease. It has been shown that the level of serum testosterone decreases in men as they age. Healthy men with low testosterone levels have increased cardiovascular risk factors, including high fasting and two-hour plasma glucose, serum triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol, and apo A-I lipoprotein. Injections of testosterone to raise the levels to midnormal range have been shown to decrease total cholesterol and LDL cholesterol, while increasing high-density lipoprotein (HDL) cholesterol. Testosterone affects the clotting system by increasing thromboxane A (2) receptor activity and platelet aggregability. Testosterone has also been shown to augment the fibrinolytic system and antithrombin III activity. In men, testosterone has been shown to have antianginal effects, and endogenous levels have an inverse relationship to systolic blood pressure. Testosterone can be given in oral, injectable, pellet and transdermal patch forms. There may be a role in administering testosterone to return men to normal physiologic range who have low serum levels. This treatment increases the risk of prostatic cancer, benign prostatism, erythrocytosis and edema. No long-term studies of the effects of long-term testosterone replacement have been undertaken, so it is difficult to recommend this treatment as yet, but it is being considered as a therapy for augmenting skeletal muscle strength in patients with congestive heart failure.

Am J Ther 1999 May;6(3):167-74

The association of low plasma testosterone level with coronary artery disease in Chinese men.

The incidence rate and mortality of coronary heart disease (CHD) is obviously higher in men than in women, which may be related to the influence of plasma lipoprotein metabolism by endogenous sex hormones. We determined plasma testosterone (TTT), estradiol, total cholesterol (TC), triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), HDL2-C, HDL3-C, apolipoprotein (Apo) AI, Apo B100 and lipoprotein (a) [Lp(a)] in 201 subjects, among them 102 patients with CHD and 99 healthy subjects. It was found that, mean plasma TTT levels in patients with CAD (252+/-125 ng/ml) was significantly lower than in the healthy subjects (412+/-309 ng/ml). There was a negative association between plasma TTT level and plasma TG level (r=-0.239; P<0.001) and Lp(a) (r=-0.163, P<0.05), and a positive association between plasma TTT level and HDL-C (r=0.301, P<0.001) and HDL3-C (r=0.328, P<0.001). The results in the present study suggest that low plasma TTT level may be a risk factor for CHD, which may relate to the influence of plasma lipoprotein metabolism by endogenous testosterone.

Int J Cardiol 1998 Jan 31;63(2):161-4

Decreased serum testosterone in men with acute ischemic stroke.

Serum levels of total and free testosterone and 17 beta-estradiol were determined in 144 men with acute ischemic stroke and 47 healthy male control subjects. Blood samples from patients were drawn a mean of three days after stroke onset and also six months after admission in a subgroup of 45 patients. Initial stroke severity was assessed on the Scandinavian Stroke Scale and infarct size by computed tomographic scan. Mean total serum testosterone was 13.8 +/- 0.5 nmol/L in stroke patients and 16.5 +/- 0.7 nmol/L in control subjects (P = .002); the respective values for free serum testosterone were 40.8 +/- 1.3 and 51.0 +/- 2.2 pmol/L (P = .0001). Both total and free testosterone were significantly inversely associated with stroke severity and six-month mortality, and total testosterone was significantly inversely associated with infarct size. The differences in total and free testosterone levels between patients and control subjects could not be explained by 10 putative risk factors for stroke, including age, blood pressure, diabetes, ischemic heart disease, smoking and atrial fibrillation. Total and free testosterone levels tended to normalize six months after the stroke. There was no difference between patients and control subjects in serum 17 beta-estradiol levels. These results support the idea that testosterone affects the pathogenesis of ischemic stroke in men.

Arterioscler Thromb Vasc Biol 1996 Jun;16(6):749-54

SAMe

S-adenosylmethionine improves depression in patients with Parkinson's disease in an open-label clinical trial.

We report a pilot study of S-adenosylmethionine (SAMe) in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAMe was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and was 9.55 +/- 7.29 after SAMe treatment (p < 0.0001). Although uncontrolled and preliminary, this study suggests that SAMe is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease.

Mov Disord 2000 Nov;15(6):1225-9

Rapidity of onset of the antidepressant effect of parenteral S-adenosylmethionine.

A possible method of reducing the delay in antidepressant response is to use S-adenosylmethionine (SAMe), a naturally occurring compound that appears to have a rapid onset of effect in the treatment of depression. In this open, multicenter study, 195 patients were given 400 mg of SAMe, administered parenterally, for 15 days. Depressive symptoms remitted after seven and 15 days of treatment with SAMe, and no serious adverse events were reported. Further studies with a double-blind design are needed to confirm this preliminary indication that SAMe is a relatively safe and fast-acting antidepressant.

Psychiatry Res 1995 Apr 28;56(3):295-7

Role of S-adenosylmethionine in the treatment of depression: a review of the evidence.

Major depression remains difficult to treat, despite the wide array of registered antidepressants available. In recent years there has been a surge in the popularity of natural or alternative medications. Despite this growing popularity, there is limited evidence for the effectiveness of many of these natural treatments. S-adenosylmethionine (SAMe) is one of the better studied of the natural remedies. SAMe is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. Derived from the amino acid L-methionine through a metabolic pathway called the one-carbon cycle, SAMe has been postulated to have antidepressant properties. A small number of clinical trials with parenteral or oral SAMe have shown that, at doses of 200 to 1600 mg/d, SAMe is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses. SAMe may have a faster onset of action than do conventional antidepressants and may potentiate the effect of tricyclic antidepressants. SAMe may also protect against the deleterious effects of Alzheimer's disease. SAMe is well tolerated and relatively free of adverse effects, although some cases of mania have been reported in bipolar patients. Overall, SAMe appears to be safe and effective in the treatment of depression, but more research is needed to determine optimal doses. Head-to-head comparisons with newer antidepressants should help to clarify SAMe's place in the psychopharmacologic armamentarium.

Am J Clin Nutr 2002 Nov;76(5):1158S-61S

Open trial of S-adenosylmethionine for treatment of depression.

Nine depressed inpatients completed trials with S-adenosylmethionine. Seven showed improvement or remission of their symptoms. As in European studies, no side effects were seen except the apparent induction of mania in two patients with bipolar disorder.

Am J Psychiatry 1984 Mar;141(3):448-50

The antidepressant potential of oral S-adenosylmethionine.

S-adenosylmethionine (SAMe), a naturally occurring brain metabolite, has previously been found to be effective and tolerated well in parenteral form as a treatment of major depression. To explore the antidepressant potential of oral SAMe, we conducted an open trial in 20 outpatients with major depression, including those with (n = 9) and without (n = 11) prior history of antidepressant nonresponse. The group as a whole significantly improved with oral SAMe: seven of 11 non-treatment-resistant and two of nine treatment-resistant patients experienced full antidepressant response. Side effects were mild and transient.

Acta Psychiatr Scand 1990 May;81(5):432-6

The influence of S-adenosylmethionine (SAMe) on prolactin in depressed patients.

Twenty subjects entered a double-blind placebo-controlled trial of SAMe in depression. Prolactin concentrations were measured before and after 14 days treatment. There was a highly significant fall in prolactin concentrations in the SAMe-treated group.

Int Clin Psychopharmacol 1987 Apr;2(2):97-102

S-adenosylmethionine in the treatment of Alzheimer's disease.

Patients with Alzheimer's disease (AD) have an apparent abnormality possibly representing an increase in the average fluidity of their cell membranes. Changes in membrane fluidity of similar magnitude to those observed in AD have been noted to lead to marked alterations in cell function. Therefore, the changes in fluidity observed in AD may be related to the symptoms of that disorder, representing either an underlying cause of dysfunction or cellular attempts to compensate for dysfunction in AD. To test these possibilities, we administered S-adenosylmethionine (SAMe), an agent shown to increase membrane fluidity in animals, to patients with AD. Treatment with SAMe led to marked increases in membrane fluidity. However, it produced neither improvement nor worsening of symptoms. The results imply that while SAMe may be useful for other conditions associated with altered membrane fluidity (such as normal aging), changing membrane fluidity per se is not likely to lead to marked changes in symptoms in AD.

J Clin Psychopharmacol 1988 Feb;8(1):43-7

C-reactive protein

Risk of cardiovascular disease in relation to achieved office and ambulatory blood pressure control in treated hypertensive subjects.

Objective: We investigated the prognostic impact of 24-hour blood pressure control in treated hypertensive subjects. Background: There is growing evidence that ambulatory blood pressure improves risk stratification in untreated subjects with essential hypertension. Surprisingly, little is known on the prognostic value of this procedure in treated subjects. Methods: Diagnostic procedures including 24-hour noninvasive ambulatory blood pressure monitoring were undertaken in 790 subjects with essential hypertension (mean age 48 years) before therapy and after an average follow-up of 3.7 years (2,891 patient-years). Results: At the follow-up visit, 26.6% of subjects achieved adequate office blood pressure control (<140/90 mm Hg), and 37.3% of subjects achieved adequate ambulatory blood pressure control (daytime blood pressure <135/85 mm Hg). Months or years after the follow-up visit, 58 patients suffered a first cardiovascular event. Event rate was lower (0.71 events/100 person-years) among the subjects with adequate ambulatory blood pressure control than among those with higher blood pressure levels (1.87 events/100 person-years) (p = 0.0026). Ambulatory blood pressure control predicted a lesser risk for subsequent cardiovascular disease independently of other individual risk factors (RR 0.36; 95% confidence intervals: 0.18 to 0.70; P = 0.003), including age, diabetes and left ventricular hypertrophy. Office blood pressure control was associated with a nonsignificant lesser risk of subsequent events (RR 0.63; 95% confidence intervals: 0.31 to 1.31; P = NS). In-treatment ambulatory blood pressure was more potent than pre-treatment blood pressure for prediction of subsequent cardiovascular disease. Conclusions: Ambulatory blood pressure control is superior to office blood pressure control for prediction of individual cardiovascular risk in treated hypertensive subjects.

J Clin Psychopharmacol 1988 Feb;8(1):43-7

C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus.

CONTEXT: Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus (DM); however, clinical data addressing this issue are limited. OBJECTIVE: To determine whether elevated levels of the inflammatory markers interleukin 6 (IL-6) and C-reactive protein (CRP) are associated with development of type 2 DM in healthy middle-aged women. DESIGN: Prospective, nested case-control study. SETTING: The Women's Health Study, an ongoing U.S. primary prevention, randomized clinical trial initiated in 1992. PARTICIPANTS: From a nationwide cohort of 27,628 women free of diagnosed DM, cardiovascular disease, and cancer at baseline, 188 women who developed diagnosed DM over a four-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls. MAIN OUTCOME MEASURES: Incidence of confirmed clinically diagnosed type 2 DM by baseline levels of IL-6 and CRP. RESULTS: Baseline levels of IL-6 (P<.001) and CRP (P<.001) were significantly higher among cases than among controls. The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 (95% confidence interval [CI], 3.7-15.4) and 15.7 for CRP (95% CI, 6.5-37.9). Positive associations persisted after adjustment for body mass index, family history of diabetes, smoking, exercise, use of alcohol and hormone replacement therapy; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 (95% CI, 0.9-5.6; P for trend =.07) and 4.2 for CRP (95% CI, 1.5-12.0; P for trend =.001). Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c) of 6.0% or less and after adjustment for fasting insulin level. CONCLUSIONS: Elevated levels of CRP and IL-6 predict the development of type 2 DM. These data support a possible role for inflammation in diabetogenesis.

JAMA 2001 Jul 18;286(3):327-34

Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.

PURPOSE: To investigate whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population-based sample of nondisabled older people. SUBJECTS AND METHODS: A sample of 1,293 healthy, nondisabled participants in the Iowa 65+ Rural Health Study was followed prospectively for a mean of 4.6 years. Plasma interleukin-6 and C-reactive protein levels were measured in specimens obtained from 1987 to 1989. RESULTS: Higher interleukin-6 levels were associated with a two-fold greater risk of death [relative risk (RR) for the highest quartile (> or = 3.19 pg/mL) compared with the lowest quartile of 1.9 [95% confidence interval, CI, 1.2 to 3.1]). Higher C-reactive protein levels (> or = 2.78 mg/L) were also associated with increased risk (RR = 1.6; CI, 1.0 to 2.6). Subjects with elevation of both interleukin-6 and C-reactive protein levels were 2.6 times more likely (CI, 1.6 to 4.3) to die during follow-up than those with low levels of both measurements. Similar results were found for cardiovascular and noncardiovascular causes of death, as well as when subjects were stratified by sex, smoking status, and prior cardiovascular disease, and for both early (<2.3 years) and later follow-up. Results were independent of age, sex, body mass index and history of smoking, diabetes and cardiovascular disease, as well as known indicators of inflammation including fibrinogen and albumin levels and white blood cell count. CONCLUSIONS: Higher circulating levels of interleukin-6 and C-reactive protein were associated with mortality in this population-based sample of healthy older persons. These measures may be useful for identification of high-risk subgroups for anti-inflammatory interventions.

Am J Med 1999 May;106(5):506-12

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