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Effects of Sex Steroids on Plasma Total Homocysteine Levels: A Study in Transsexual Males and Females

Department of Endocrinology, Division of Andrology (E.J.G., J.M.H.E., L.J.G.G., H.A.), the Institute for Research in Extramural Medicine (E.K.H., C.D.A.S.), the Department of Internal Medicine (C.D.A.S.), and the Institute for Cardiovascular Research (C.D.A.S.), Hospital Vrije Universiteit and Vrije Universiteit, 1007 MB, Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Prof. Dr. Louis J. G. Gooren, M.D., Department of Endocrinology, Division of Andrology, Hospital Vrije Universiteit, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.

	Abstract

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Plasma total homocysteine (tHcy) levels are higher in men vs. premenopausal women, but it is not known whether this difference is related to sex steroids. The effects of cross-sex hormone administration on plasma tHcy levels were therefore investigated.

Plasma tHcy levels were measured at baseline and after 4 months of treatment in 17 male-to-female (MF) transsexuals treated with ethinyl estradiol (100 µg/day), in combination with the antiandrogen, cyproterone acetate (100 mg/day), and in 17 female-to-male (FM) transsexuals treated with testosterone esters (250 mg/2 weeks, im).

In MF transsexuals, the plasma tHcy level decreased from geometric mean 8.2 µmol/L to 5.7 µmol/L (P < 0.001); and in FM transsexuals, it increased from 7.7 µmol/L to 9.0 µmol/L (P = 0.005). In MF transsexuals, changes in serum sex hormone-binding globulin levels correlated negatively, and changes in plasma creatinine and albumin levels correlated positively, with changes in plasma tHcy levels. In FM transsexuals, changes in serum 17ß-estradiol levels correlated negatively, and changes in plasma creatinine levels correlated positively, with changes in plasma tHcy levels.

We conclude that tHcy levels decrease after estrogen + antiandrogen administration to male (transsexual) subjects, and levels increase after androgen administration to female (transsexual) subjects. These changes may be both primary and secondary to the anabolic/catabolic effects, as reflected by changes of creatinine and albumin levels after cross-sex hormone administration.

	Introduction

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MEN HAVE a higher risk of developing cardiovascular disease (CVD) than do premenopausal women. After menopause, the risk of CVD in women increases rapidly (1) and is reduced by estrogen replacement therapy (2). An elevated plasma level of total (free and protein-bound) homocysteine (tHcy) is a risk factor independent of other known risk factors for CVD (3, 4, 5, 6). A sex difference in plasma tHcy levels has been found (7, 8, 9, 10), with approximately 10–15% higher levels in men vs. women. There are indications that plasma tHcy is influenced by sex steroid hormones. Low plasma tHcy levels were found during pregnancy (11, 12), a state characterized by high levels of endogenous estrogens. Furthermore, in postmenopausal women, treatment with oral 17ß-estradiol or conjugated estrogens resulted in a decrease of the plasma tHcy level by 11%, after 6 months (13, 14), which returned to base-line during a second half-year of treatment with conjugated estrogens (14). Supraphysiologic testosterone administration to normal males did not alter tHcy levels after 3 weeks, in a cross-over study (15). The aim of this study was to determine the effects on tHcy levels of cross-sex hormone administration to transsexuals undergoing sex-reassignment, creating a sex steroid milieu of the opposite sex.

	Subjects and Methods

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We included 17 male-to-female MF transsexuals (median age: 28 yr; range: 18–40) and 17 female-to-male FM transsexuals (median age: 22 yr; range: 16–34). MF transsexuals were treated with ethinyl estradiol (100 µg/day; Lynoral, Organon, Oss, The Netherlands), in combination with the antiandrogen, cyproterone acetate (100 mg/day; Androcur, Schering, Weesp, The Netherlands). FM transsexuals were treated with testosterone esters (Sustanon, Organon; 250 mg/2 weeks, im). There was no evidence of diabetes, hypertension, or other CVD in the subjects. None reported intake of hormones (such as oral contraceptives), medication known to affect sex steroid or lipid metabolism, or vitamin B₆, vitamin B₁₂, or folic acid supplements. The body mass index (BMI = weight/height²) was determined. In 15 MF transsexuals and 16 FM transsexuals, the lean body mass (LBM) was estimated using bioelectrical impedance analysis (BIA 101/S, RJL Systems, Clinton Twp, Detroit, MI) (16). Before hormone administration, all FM transsexuals had a regular menstrual cycle (28–31 days). Informed consent was obtained from all subjects, and the study was approved by the Ethical Review Committee of the Hospital Vrije Universiteit.

Fasting plasma tHcy levels were measured before and again after 4 months of cross-sex hormone therapy. At study entry, blood was drawn from FM transsexuals between days 3 and 9 of the menstrual cycle during the follicular phase, and after 4 months within 5–9 days after the preceding testosterone injection. Samples were obtained between 0930 h and 1030 h and were immediately placed in ice and centrifuged at 3500 x g for 30 min at 4 C. After separation, plasma was stored at -70 C until analysis. To minimize the imprecision of the assay, samples from the same subject were analyzed in the same run. The plasma tHcy level was measured by using tri-n-butylphosphine as the reducing agent and ammonium 7-fluorobenzo-2-oxa-1,3-diazole-4-sulphonate as the fluorochromophore, followed by high-performance liquid chromatography with fluorescence detection (coefficients of variation: intraassay, 2.1%; interassay, 5.1%) (17).

Standardized RIAs were used to measure serum levels of 17ß-estradiol (Double Antibody, Sorin Biomedica, Saluggia, Italy) and testosterone (Coat-A-Count, Diagnostic Products Corp., Los Angeles, CA). Serum levels of LH and FSH were measured by immunometric luminescence assays (Amerlite, Amersham, UK). The lower limits of detection for LH, FSH, 17ß-testosterone, estradiol, and were 0.3 IU/L, 0.5 IU/L, 90 pmol/L, and 1.0 nmol/L, respectively. Serum levels of sex hormone-binding globulin (SHBG) were measured by an immunoradiometric assay (Orion Diagnostica, Espoo, Finland). Plasma levels of creatinine, albumin, total cholesterol, low-density lipoprotein cholesterol, and liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and -glutamyl transpeptidase), as well as hemoglobin and packed cell volume, were assessed using standard laboratory methods. In 15 MF transsexuals and 15 FM transsexuals, the creatinine excretion rate was assessed using a 24-h urine collection. All laboratory measurements were carried out in blinded fashion, with respect to gender and hormone treatment status.

Statistical analysis

Because the distribution of plasma tHcy level was positively skewed, we used logarithmically transformed data in our analysis. Antilogarithms of the transformed means for plasma tHcy levels are presented (i.e. geometric means). The independent sample t test was used to compare tHcy levels between males and females at baseline. MF and FM transsexuals were analyzed separately. Statistical analysis of all variables was performed by the paired Student’s t test. The Spearman’s correlation coefficient was used to correlate proportional changes of tHcy levels with proportional changes of previously mentioned variables. Univariate and forward linear regression analysis was performed with the proportional change in plasma tHcy level as the dependent variable. If measurements were below the lower limit of detection, the value of that lower limit was used for statistical calculations (for LH, 0.3 IU/L; for FSH, 0.5 IU/L; for 17ß-estradiol, 90 pmol/L; and for testosterone, 1.0 nmol/L). Two-sided P < 0.05 was considered statistically significant. The software used was SPSS for Windows 7.0 (SPSS Inc., Chicago, IL).

	Results

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Pretreatment values

All subjects were eugonadal at baseline by clinical and laboratory criteria. Lipoprotein distribution, liver enzymes, and plasma creatinine levels were within normal limits (Table 1). At study entry, the geometric mean of plasma tHcy in MF transsexuals was 8.2 µmol/L (range: 4.6–36.7), and in FM transsexuals, it was 7.7 µmol/L (range: 2.9–19.0). The sex difference of 6.5% was not statistically significant (P = 0.66). One MF and one FM transsexual had pretreatment levels higher than 15 µmol/L, which may be regarded as the upper normal limit (Fig. 1) (18).

View this table: [in this window] [in a new window]   Table 1. Laboratory data before and after 4 months of cross-sex hormone treatment in 17 M F and 17 F M transsexuals

View larger version (29K): [in this window] [in a new window]   Figure 1. Changes and proportional changes in plasma tHcy levels in 17 MF transsexuals and 17 FM transsexuals after 4 months of cross-sex hormone treatment, compared with baseline. Geometric mean values of the plasma tHcy level are identified by open circles and decreased with 30% (P < 0.001) in MF transsexuals and increased with 17% (P = 0.005) in FM transsexuals.

After estrogen + antiandrogen administration to MF transsexuals, serum levels of testosterone decreased below the lower limit of detection. The administered ethinyl estradiol could not be detected by the assay used for measuring 17ß-estradiol. After testosterone administration to FM transsexuals, serum levels of testosterone increased markedly, whereas serum 17ß-estradiol levels did not decrease substantially. However, in three subjects, the serum 17ß-estradiol levels decreased below the lower limit of detection (Table 1).

In MF transsexuals receiving estrogens + antiandrogens, plasma tHcy levels decreased from geometric mean 8.2 µmol/L (range: 4.6–36.7) to 5.7 µmol/L (range: 2.7–16.0), a mean decrease of 30% (P < 0.001). In FM transsexuals receiving androgens, plasma tHcy levels increased from geometric mean 7.7 µmol/L (range: 2.9–19.0) to 9.0 µmol/L (range: 3.6–27.1), a mean increase of 17% (P = 0.005, Fig. 1). Proportional changes between plasma levels of tHcy correlated negatively with proportional changes in SHBG levels in MF transsexuals (r = -0.65, P = 0.008), and with proportional changes in 17ß-estradiol levels in FM transsexuals (r = -0.51, P = 0.04), which remained significant after exclusion of the three subjects with estrogen levels below the lower limit of detection.

Effects of cross-sex hormone administration on other factors correlated with homocysteine levels

In MF transsexuals, plasma levels of albumin, creatinine, hemoglobin, and packed cell volume significantly decreased. In FM transsexuals, the plasma creatinine levels, the creatinine excretion rate, the LBM, and the BMI increased. None of the plasma creatinine levels were above the upper normal limit. Values of liver enzymes all remained within the normal range (Table 1).

The proportional change in plasma tHcy levels correlated with proportional changes in plasma creatinine and albumin levels in MF transsexuals (r = 0.55, P = 0.02; r = 0.59, P = 0.01, respectively), and with proportional changes in plasma creatinine levels in FM transsexuals (r = 0.86, P < 0.00l) (Fig. 2); no correlations were found with the proportional changes in urinary creatinine excretion rate, LBM, BMI, hemoglobin, packed cell volume, plasma total cholesterol, and low-density lipoprotein cholesterol.

View larger version (20K): [in this window] [in a new window]   Figure 2. Scatter plots, showing the correlation between the proportional change in plasma creatinine levels and proportional change in plasma tHcy levels in MF transsexuals (r = 0.55, n = 17, P = 0.02) and in FM transsexuals (r = 0.86, n = 16, P < 0.001). For MF transsexuals in a regression model, the constant coefficient was -20% (95% confidence interval: -30% to -10%; P = 0.001).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
A substantial reduction in plasma tHcy levels was found in male subjects after estrogen + antiandrogen administration. Because of simultaneous administration of antiandrogens, the observed effects may not be ascribed solely to estrogen administration. Conversely, a significant increase in plasma tHcy levels after testosterone administration was found in female subjects. This may have implications for the use of androgens in the treatment of hypoandrogenic males and for their growing use as a substitution therapy in aging males (19) or as a contraceptive agent in reproductive males (20). There have been reports of young weight lifters, using androgens, who developed myocardial infarction and stroke (21, 22).

Besides possible direct effects of the administered sex steroids on homocysteine metabolism, there also may be changes in plasma tHcy levels secondary to other biological effects of these steroids. First, deficiencies of vitamin B₁₂ and folate lead to markedly increased plasma tHcy levels (18, 23). Oral contraceptives, containing ethinyl estradiol, are known to decrease serum concentrations of vitamin B₁₂ and folate (24, 25). Levels of these vitamins were not determined in this study, because ethinyl estradiol was expected to lower tHcy levels (13, 14). Estrogen-induced effects on these vitamins should, if anything, have led to an increase of tHcy levels, but the opposite was observed. Second, plasma tHcy levels are related to protein turnover and muscle mass (26). In two studies, the sex difference of plasma tHcy levels disappeared after adjustment for plasma creatinine level (8, 9). This may be explained by the larger creatine synthesis and larger muscle mass in men, compared with women (27). Accordingly, we found that plasma creatinine was a strong correlate of the plasma tHcy level in both MF and FM transsexuals. An explanation for this could be that homocysteine production occurs in direct conjunction with creatine-creatinine synthesis (27). Renal failure, known to increase the plasma tHcy level (18, 28), did not occur in our subjects. Therefore, sex steroid-induced changes in plasma tHcy levels could conceivably be explained by their anabolic/catabolic effects.

Third, a large fraction (about 70%) of homocysteine is protein-bound, mainly by albumin (29), which was lowered during estrogen administration in MF transsexuals. We did find a correlation between the change in plasma albumin and the change in plasma tHcy level in MF transsexuals. Besides dilutional (12) or catabolic effects, a decrease in the plasma tHcy level could be a direct result of a reduction of albumin-bound homocysteine in MF transsexuals. However, this seems unlikely, because the binding capacity of albumin for homocysteine is high.

Fourth, androgens have anabolic effects on erythropoiesis (30). To a small extent, synthesis of homocysteine takes place in erythrocytes (31), a potential source of homocysteine. However, there was no correlation between changes in hemoglobin or packed cell volume and changes in plasma tHcy levels. Anabolic steroids can induce liver-damaging side effects (32) and the enzyme [betaine]-homocysteine methyltransferase, necessary for the salvage of homocysteine to methionine, is mainly confined to the liver (18, 26). In our subjects, there were no changes in values of liver enzymes in response to cross-sex hormone administration.

Our findings provide support for indirect effects of sex steroids on plasma tHcy levels, secondary to anabolic/catabolic effects. However, primary hormonal effects can certainly not be excluded. MF transsexuals who had no change in plasma creatinine level showed a decrease in plasma tHcy levels of 20%, suggesting a direct estrogenic effect on plasma tHcy levels (Fig. 2). Further, significant correlations were found in FM transsexuals between changes in tHcy and 17ß-estradiol levels and in MF transsexuals between changes in tHcy and SHBG levels.

This study shows that plasma tHcy levels decrease after estrogen + antiandrogen administration to male subjects, and increase after androgen administration to female subjects. These changes may be direct or indirect through anabolic/catabolic effects. The sex difference in plasma tHcy levels thus seems related to their differences in sex steroid milieu.

	Acknowledgments

 
We are indebted to J. A. J. Megens and Dr. P. J. M. van Kesteren for assistance in the logistics of this study; to C. Jacobs (Department of Clinical Chemistry) for measurement of plasma tHcy levels; and to Prof. Dr. A. J. M. Donker (Department of Internal Medicine, Hospital of the Vrije Universiteit), Prof. Dr. A. G. Smals, and Dr. G. H. Boers (Department of Endocrinology, University of Nijmegen) for their valuable comments.

Received March 24, 1997.

Revised September 5, 1997.

Revised October 17, 1997.

Accepted October 21, 1997.

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