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15 March 1993 | Volume 118 Issue 6 | Pages 429-432
Objective: To determine whether a sex-associated difference in endothelin levels exists and to assess whether this difference is mediated by sex hormones.
Design: Initial survey in healthy persons, followed by a nonrandomized intervention.
Setting: A university teaching hospital.
Patients: Twenty-three healthy men, 29 healthy women, 20 pregnant women, and 12 male-to-female and 13 female-to-male transsexual patients.
Measurements: Plasma levels of endothelin were first assessed in healthy men, healthy women, and pregnant women; subsequently, endothelin levels were determined in male-to-female and female-to-male transsexual patients both before and during cross-gender hormone treatment. This treatment involves administration of testosterone esters to women and of ethynylestradiol and cyproterone acetate to men.
Results: Endothelin levels were higher in men than in women (5.9 ± 1.2 compared with 4.17 ± 0.67 pg/mL; P < 0.01). Endothelin levels were lower in pregnant women than in age- and sex-matched nonpregnant controls (2.19 ± 0.73 compared with 4.17 ± 0.67 pg/mL; P < 0.01). In 12 male-to-female transsexuals treated with estradiol and the progestational agent cyproterone acetate, endothelin levels decreased from 8.1 ± 3.0 to 5.1 ± 2.0 pg/mL (P < 0.01). In 13 female-to-male transsexuals treated with testosterone, endothelin levels increased from 6.2 ± 1.1 to 7.8 ± 1.2 pg/mL (P < 0.01).
Conclusion: Sex hormones may modulate plasma endothelin levels, with male hormones raising levels and female hormones lowering them. This finding may be important in explaining sex-associated differences in susceptibility to atherosclerotic cardiovascular disease.
Endothelial cells synthesize many active substances that regulate local blood pressure and maintain the fluidity of blood and the patency of blood vessels [7]. These include vasodilators such as endothelium-derived relaxing factor and prostacyclin (which also inhibit platelet adhesion and aggregation), vasoconstrictors such as endothelin, and larger molecules such as fibronectin. Endothelin may also have mitogenic properties [7, 8]. The release of these substances affects the local environment in the blood vessel; endothelin may also have a systemic function [7]. Some evidence has emerged that endothelin may be involved in the pathogenesis of hypertension [7, 9] and atherosclerosis [10]. Elevated plasma levels of endothelin have been observed in patients with myocardial infarction and diabetes. Whether sex hormones have direct effects on the endothelium is not known.
We found that plasma endothelin levels tended to be higher in men than in women and lower in pregnant women than in nonpregnant controls. These considerations prompted us to compare endothelin levels in healthy young men and women and to assess the effects of long-term sex hormone therapy in male-to-female and female-to-male transsexuals on plasma endothelin levels.
All patients were within 10% of their ideal body weight (Metropolitan Life Insurance Tables, 1959). None had a personal or family history of diabetes or hypertension or had evidence of cardiovascular disease on routine examination (medical history, physical examination, and electrocardiogram). No hormone preparations (such as oral contraceptives) had been used by any of the participants in the 6 months before the study. All women had a regular menstrual cycle (28 to 31 days) before hormone treatment; blood samples were drawn during the follicular phase of the menstrual cycle (days 3 to 5).
Female-to-male transsexuals received intramuscular injections of testosterone esters (Sustanon, Organon, Oss, the Netherlands), 250 mg every 2 weeks. Male-to-female transsexuals received oral ethynylestradiol (Lynoral, Organon), 0.1 mg/d, and cyproterone acetate (Androcur, Schering, Weesp, the Netherlands), 100 mg/d, to counteract the effects of testosterone.
Plasma endothelin levels were measured before therapy and after 4 months of hormone use. Blood samples were drawn between 0900 hours and 0930 hours after an overnight fast, patients having rested in the supine position for at least 30 minutes. Samples were immediately placed in ice. Testosterone levels were determined 10 to 14 days after injection, and blood samples were drawn simultaneously with those in which plasma endothelin levels were determined.
Plasma was separated within 1 hour and then stored at –20°C until assayed. Plasma endothelin was measured by radioimmunoassay (Nichols Institute [formerly ITS], Wijchen, the Netherlands) after extraction on Sep-Pak C18 cartridges (Waters, Milford, Massachusetts), as described previously [17]. Recovery rate for this assay is 92.4%. Intra-assay and interassay coefficients of variation according to the manufacturer are 2.4% and 4.2%, respectively. (We found these values to be slightly higher: 3.6% and 5.1%, respectively.) Sensitivity of the assay is 1 pg/mL; cross-reactivity with endothelin-2 is 52%; with endothelin-3, 96%; and with "big" endothelin, 7%. Intra-assay variation ranged from 2% to 8%, and interassay variation ranged from 4% to 9%.
In all patients, blood pressure was determined during a 2-hour period using an automatic sphygmomanometer; patients remained at rest during this period. Blood pressure measurements were done every 5 minutes, and the results were averaged.
Results are expressed as mean ±SD. The Student two-tailed t-test for paired data was used to compare measurements within the same group before and during hormone therapy. The Student two-tailed unpaired t-test was used for between-group comparisons. A P value of less than 0.05 was considered statistically significant. ARTICLE
Influence of Sex Hormones on Plasma Endothelin Levels
Atherosclerosis and hypertension are more common in men than in women, a difference that may be due, in part, to the actions of their respective sex hormones. Men have more atherogenic lipid profiles than women, and sex hormones play an important role in the development of this difference [1-3]. In addition, some evidence has emerged that androgens can induce insulin resistance [3, 4]; several case reports describe cardiovascular events in young persons after the use of anabolic steroids [5, 6]. Sex hormone-associated differences in lipid profiles and insulin sensitivity may partly explain why premenopausal women are relatively protected against cardiovascular disease. It remains to be determined, however, whether the difference between men and age-matched women in the incidence of atherosclerosis can be explained by differences in lipid profiles and insulin sensitivity alone or whether other mechanisms might be involved.
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We measured endothelin levels in 29 healthy young women (18 to 31 years of age; mean age, 24.1 years), 20 pregnant women (20 to 32 years of age; mean age, 26.3 years), and 23 healthy men (23 to 33 years of age; mean age, 24.7 years). To assess the effects of sex hormone therapy on plasma levels of endothelin, we measured endothelin levels before and during sex hormone therapy in 12 male-to-female transsexual patients (17 to 33 years of age; mean age, 28.4 years) and 13 female-to-male transsexual patients (17 to 26 years of age; mean age, 24.4 years). Informed consent was obtained from all participants, and the study was approved by the hospital ethics committee.
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Plasma endothelin levels were significantly higher in men than in women (5.9 ± 1.2 compared with 4.17 ± 0.67 pg/mL; P < 0.01). Endothelin levels were lower in pregnant women than in nonpregnant controls (2.19 ± 0.73 compared with 4.17 ± 0.67 pg/mL; P < 0.01), suggesting that high levels of estradiol and progesterone found during pregnancy are associated with low endothelin levels (Figure 1).
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In biological women treated with intramuscular injections of testosterone esters, basal testosterone levels increased from 1.25 ± 0.66 nmol/L to 24.8 ± 13.0 nmol/L (P < 0.01). No significant change was seen in levels of estradiol-17 ß (247 ± 207 compared with 185 ± 94 pmol/L). Biological men were treated with oral ethynylestradiol, 0.1 mg/d, and cyproterone acetate, 100 mg/d. Testosterone levels decreased from 18.4 ± 8.6 to 1.1 ± 0.4 nmol/L in this group (P < 0.01). Levels of estradiol-17 ß and ethynylestradiol were not assessed. The biological effects of sex hormone therapy were manifest in both groups.
Effects of sex hormone therapy on endothelin levels in both groups are shown in Figure 2. Endothelin levels before treatment tended to be higher in men than in women (8.1 ± 3.1 compared with 6.2 ± 1.1 pg/mL; P = 0.06), confirming our earlier observations. In biological women treated with testosterone, average endothelin levels increased from 6.2 ± 1.1 to 7.8 ± 1.2 pg/mL (P < 0.01) after 4 months of therapy. In men treated with estradiol and cyproterone acetate, endothelin levels decreased from 8.1 ± 3.0 to 5.1 ± 2.0 pg/mL (P < 0.01). Thus, the decrease in endothelin levels in men was greater than the increase in women treated with testosterone (37% and 26%, respectively); antiandrogenic actions of cyproterone acetate may have contributed to the decrease in endothelin levels in men.
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Blood pressure was measured in all participants (at rest) during a 2-hour period before and during hormone therapy. No significant alterations were seen; mean systolic and diastolic pressures were unchanged.
To investigate the variability of endothelin plasma levels, we measured endothelin levels twice within a period of 2 months in 10 normal men. Endothelin levels were 5.90 ± 0.85 pg/mL at the first measurement and 5.85 ± 1.05 pg/mL at the second measurement (P 
0.05), the coefficient of variation being 16.2%. These data suggest that endothelin levels are relatively stable over a period of several months.
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Atherosclerosis is characterized by endothelial injury and the proliferation of intimal smooth-muscle cells, which may be a result of the release of growth factors from the vessel wall [11]. The evidence suggests that endothelin, which is a strong vasoconstrictor, also has mitogenic properties [7, 8]. A correlation between endothelin levels and atherosclerosis has been described [10], suggesting that endothelin might participate in atherogenesis. Thus, if sex hormones affect levels of endothelin, this might be one of the mechanisms by which sex hormones influence the risk for cardiovascular disease. We speculate that a sex-associated difference in levels of endothelin may be one of the mechanisms underlying the difference in the incidence of cardiovascular disease between men and women.
In our patients, blood pressure did not change during hormonal treatment. Asscheman and colleagues [12] assessed blood pressure in 425 transsexual patients (303 biological men and 122 biological women) receiving long-term sex hormone therapy. High blood pressure developed in 10 biological men treated with estrogens (2.4% of the total group of 425 patients) and in none of the women treated with testosterone. Studies of the effect of estrogen therapy on blood pressure in postmenopausal women [13, 14] and in women using oral contraceptives [15] have produced conflicting results. Thus, the effect of sex hormone therapy on blood pressure remains unclear. In healthy men, the intravenous administration of endothelin induces an increase in blood pressure and serum potassium level when endothelin levels are increased four to ten times [16]. Thus, the increase in endothelin levels observed in our patients may have been too small to increase systemic vascular resistance and blood pressure. Alternatively, any such effect may have been offset by counter-regulatory forces that were not assessed in our study.
We conclude that administration of pharmacologic doses of androgens and estrogens induces changes in plasma endothelin levels. Our results indicate that the differences in sex steroid levels between the sexes may play a role in the regulation of local factors implicated in atherogenesis. We speculate that, by such mechanisms, androgens may have deleterious effects on the endothelial wall, whereas estrogens may enhance protective mechanisms.
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1. Mooradian AD, Morley JE, Korenman SG. Biological actions of androgens. Endocr Rev. 1987; 8:1-28.
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