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Geestelijke Gezondheidszorg Delfland, Institute of Mental Health, PO Box 5016, 2600 GA Delft, The Netherlands
1 Radboud University Nijmegen Medical Centre, Department of Neurology, Laboratory of Pediatrics and Neurology, Nijmegen, The Netherlands
2 Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands
3 Department of Endocrinology, Andrology Unit, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands
(Requests for offprints should be addressed to E J Giltay; Email: giltay{at}dds.nl)
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Abstract |
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Introduction |
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), and in human (Amin et al. 1995, Amin et al. 1998) and animal (Bacopoulos et al. 1979) research its plasma concentration was found to be indicative of brain dopamine turnover. Plasma HVA is not only elevated in neuroblastomas and pheochromacytomas, but also in schizotypical personality disorders (Siever et al. 1991). In some (Pickar et al. 1986, Davidson & Davis 1988, Maas et al. 1988, Davidson et al. 1991, Koreen et al. 1994, Sumiyoshi et al. 1997a) but not all (Sumiyoshi et al. 1997b) studies, the baseline and/or change in plasma HVA was related to psychopathology and treatment response in schizophrenic patients.
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Studies in transsexual subjects have shown that cross-sex hormones affect psychological variables of aggression, mood, sexual motivation and sex-related cognitive functions, such as verbal fluency and visuospatial functions (Van Goozen et al. 1995, Slabbekoorn et al. 1999). Studies of the brains of transsexuals have shown that certain sex dimorph areas of the brain have a differentiation of the opposite sex (female in male-to-female transsexuals and vice versa). These anatomical brain structures were not affected by the administration of cross-sex hormones (Zhou et al. 1995, Kruijver et al. 2000). In the present study, we have investigated whether changes in sex hormones affect the sex difference in plasma HVA, to test the hypothesis as to whether human dopamine metabolism is under sex steroidal influence. Blood samples were collected as part of a study on the effects of sex hormones on cardiovascular risk factors (Giltay et al. 2000, 2003). We measured fasting plasma HVA levels because of the better reproducibility and smaller variability as compared with urinary HVA (Donnelly et al. 1996, Amin et al. 1998). It is also a less invasive approach than sequentially obtaining cerebrospinal fluid.
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Materials and Methods |
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Secondly, the effects of cross-sex hormone administration on HVA and 5-HIAA were studied in transsexual subjects in blood samples collected from 1996 to 1998 (Giltay et al. 2000, 2003). Psychological criteria for the diagnosis and treatment followed the guidelines provided by the Harry Benjamin International Gender Dysphoria Association. Fifteen male-to-female (M
F) transsexuals were treated with ethinyl estradiol (Lynoral; 100 µg/day; Organon, Oss, The Netherlands) in combination with cyproterone acetate (Androcur; 100 mg/day; Schering, Berlin, Germany), an anti-androgen that blocks androgen receptors. Seventeen female-to-male (FM) transsexuals were treated with testosterone esters (Sustanon; 250 mg/2 weeks i.m.; Organon) according to our standard treatment. To monitor the anabolic/catabolic effects on body composition, the BMI was assessed, and lean body mass and total body fat were estimated using bioelectrical impedance analysis (BIA 101/S; RJL Systems, Clinton Twp, MI, USA). Informed consent was obtained from all subjects, and the study was conducted according to the principles of the Declaration of Helsinki and approved by the Ethical Review Committee of the Vrije Universiteit University Medical Center.
Laboratory tests
A single non-fasting blood sample was first obtained from elderly subjects. Venipuncture was performed between 0800 and 1730 h using citrate collection tubes. Samples were stored at –80 °C, and only thawed once before analysis. Secondly, in transsexual subjects, blood was sampled before and 2 and 4 months after initiation of cross-sex hormone administration. Blood was drawn from genetic women before testosterone treatment between days 5 and 9 of the follicular phase and again during testosterone treatment, within 5 to 9 days after the testosterone injection. All blood was sampled after a 12-h fast, immediately placed on ice, centrifuged at 3500 g for 30 min at 4 °C, stored within 1 h at –80 °C and never thawed until analysis. EDTA plasma samples (Becton Dickinson Vacutainer Systems, Franklin Lakes, NJ, USA) were obtained. Serum measurements were made of 17ß-estradiol (by radioimmunoassay; Sorin Biomedica, Saluggia, Italy) and testosterone (by radioimmunoassay; Coat-A-Count; Diagnostic Products, Los Angeles, CA, USA), luteinizing hormone (LH; by immunometric luminescence assay; Amerlite; Amersham Pharmacia Biotech, Aylesbury, Bucks, UK) and follicle-stimulating hormone (FSH; by immunometric luminescence assay; Amerlite). Since estrogens increase the secretion of prolactin by the pituitary gland and prolactin release is tonically inhibited by dopamine, we measured prolactin levels (by immunoradiometric assay; Biosource Technologies, Inc., Fleurus, Belgium). HVA and 5-HIAA are cleared by the kidney so we therefore assessed creatinine levels by using standard laboratory methods. Because HVA is formed in close conjunction with homocysteine synthesis (Fig. 1
), we measured plasma levels of total homocysteine and folate by high-performance liquid chromatography (HPLC) as previously published (Giltay et al. 2003). Moreover, folate may also be indirectly involved in rate-limiting enzymes for dopamine and serotonin production through tetra-hydrobiopterin (Bottiglieri et al. 2000).
To measure HVA and 5-HIAA, the major metabolite of serotonin, samples were mixed with an equal volume of perchloric acid (1 M) in order to precipitate proteins. After centrifugation, the supernatant (250 µl) was loaded on a Hypersil ODS HPLC column (Thermo Electron Corporation, Breda, The Netherlands) at 30 °C. The mobile phase consisted of ammonium acetate (0.02 M), sodium-EDTA (0.25 mM), sodium chloride (6.5 mM) and methanol (9.5%) at pH 4.95. The flow was set at 1.25 ml/min by using an isocratic Sp8810 pump (Thermo Electron Corporation). Detection was performed by using an electrochemical detector (INTRO; Antec Leyden, Zoeterwoude, The Netherlands; potential: 0.525 mV). Chromatographic data were recorded by using PC1000 software (Thermo Electron Corporation). The intra-assay coefficient of variation (C.V.) for HVA was 2.0% at a concentration of 156 nM (n=9) and interassay C.V. was 2.7% at a concentration of 160 nM (n=7). The intra-assay C.V. for 5-HIAA was 3.8% at a concentration of 93 nM (n=9) and the interassay C.V. was 5.5% at a concentration of 55 nM (n=7).
Statistical analysis
Data are presented as means (with S.D.) or geometric means (with percentiles: P10 and P90) for right-skewed data (i.e. total homocysteine, folate and HVA). HVA and 5-HIAA values were correlated with other variables using Spearman’s correlation coefficient. For the comparison at baseline between the two groups, a t-test for independent samples or analysis of covariance was used. For MF transsexuals, a two-factor repeated measures ANOVA with interaction was used to study the effects of estrogens plus anti-androgens in time, as well as to compare the effects of the two treatment regimens in time. Post-hoc comparisons were made using a Sidak test to identify significant differences between time-points. For FM transsexuals, a Student’s t-test for paired samples was used to study the effects of androgen administration in time. A two-tailed P<0.05 was considered statistically significant. The software used was SPSS 10.0, Chicago, IL, USA.
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Results |
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Men were, on average, 72.5 years old (S.D. 4.9; range 65–84) and women were 72.8 years old (S.D. 5.8; range 65–83; for sex difference P=0.79). The BMI was a mean of 24.6 (S.D. 3.0) in men and 26.1 (S.D. 5.0) in women (for sex difference P=0.15). Plasma HVA levels were lower in elderly men than postmenopausal women (geometric mean 25.4 nmol/l (P10 4.9; P90 69.8) vs 39.0 nmol/l (19.0; 76.1); P=0.027). Plasma HVA was positively associated with age (r=0.26, P=0.026). The sex difference for plasma HVA remained present after adjusting for age (P=0.033). Plasma 5-HIAA levels were similar in elderly men and women (P=0.42), also when one outlier (323 nmol/l) was excluded from the analysis (21.6 nmol/l (S.D. 15.3) vs 21.9 nmol/l (S.D. 24.6); P=0.94).
Intervention studies with sex steroids
Pretreatment values
The mean age of MF transsexuals was 32.4 (S.D. 6.6; range 20–43) years with a BMI of 22.8 (S.D. 2.7) kg/m2 and that of FM transsexuals was 27.1 (S.D. 6.3; range 18–37) years with a BMI of 23.9 (S.D. 4.3) kg/m2. Of the MF transsexuals, nine (60%) were smokers and of the FM transsexuals ten (59%) were smokers.
In MF transsexuals, baseline HVA levels were inversely associated with testosterone levels (r=– 0.61, P=0.017) and LH levels (r=–0.70, P=0.003), whereas baseline 5-HIAA levels were positively associated with creatinine levels (r=0.53, P=0.050). Smokers had significantly lower HVA levels as compared with non-smokers (P=0.003), and similar levels of 5-HIAA (P=0.18). In FM transsexuals, baseline HVA and 5-HIAA levels were not correlated with levels of hormones, creatinine or folate, and baseline HVA levels were not correlated with levels of total homocysteine. Smokers had similar levels of HVA and 5-HIAA as compared with non-smokers (P=0.50 and P=0.54 respectively). Age was unrelated to plasma HVA or 5-HIAA in either group (P>0.20).
At baseline, plasma HVA was significantly lower in genetic men as compared with women (geometric mean 14.8 nmol/l (P10 7.0; P90 35.0) vs (P10 34.3 P90 21.8; 61.4); P<0.0005; Fig. 2 and Table 1). The sex difference remained present (P=0.003) after adjusting for age, smoking status, BMI and creatinine levels as covariates. No sex difference was found for 5-HIAA (P=0.981; Fig. 2 and Table 1).
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F transsexuals, estrogen administration substantially decreased serum levels of testosterone, LH and FSH, whereas prolactin levels increased. The synthetic estrogen, ethinyl estradiol, could not be detected by the 17ß-estradiol assay used (Table 1). There were no significant effects on plasma HVA and 5-HIAA (Fig. 2 and Table 1), although the change in plasma 5-HIAA was of borderline significance (P<0.10), though quantitatively small. The proportional increase in prolactin or decrease in testosterone, LH, FSH and total homocysteine were not related to proportional changes in plasma HVA or 5-HIAA.
In FM transsexuals, testosterone administration increased serum levels of testosterone and creatinine levels, while serum levels of 17ß-estradiol, LH and FSH were suppressed. Partly reflecting the anabolic effects, there were increases in BMI, lean body mass and plasma creatinine and homocysteine. Again, there were no significant effects on plasma HVA and 5-HIAA (Fig. 2), although there was a tendency for plasma 5-HIAA to increase of borderline significance (P=0.074; Table 1). The proportional changes in hormones, total homocysteine and creatinine were not related to the proportional changes in plasma HVA or 5-HIAA.
When baseline and 4-month values were used, there was no treatment effect when the two groups were combined in an ANOVA for repeated measurements, either for HVA (P=0.79) or for 5-HIAA (P=0.21). Thus, the effects of estrogen plus anti-androgen administration were not significantly different from the effects of testosterone administration. After 2 and 4 months of estrogen plus anti-androgen administration, smoking MF transsexuals still had lower plasma HVA levels as compared with non-smoking MF transsexuals (P<0.01). After 4 months of cross-sex hormone administration, there was still a lower mean level of plasma HVA in MF transsexuals (genetic men) as compared with FM transsexuals (genetic women) (15.2 nmol/l (P10 6.1; P90 37.5) vs 31.7 (P10 14.6; P90 72.7); P=0.003; Fig. 2 and Table 1).
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Discussion |
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What mechanism may explain the sex difference in HVA? Since sex steroids did not affect HVA, a putative explanation may be a sex differences in gene expression. MAO A and especially MAO B are responsible for the oxidative deamination of dopamine (Fig. 1), and are both coded for on the X chromosome (i.e. Xp11 region). There is evidence that MAO A and especially MAO B escape X-chromosome inactivation (Good et al. 2003). Since (genetic) women have two X chromosomes and MAO may be expressed from both X chromosomes, this would result in higher MAO activity and consequently higher HVA levels in women then in men. Alternatively, there are sex differences in the brain which develop and mature until early adulthood (Gogtay et al. 2004) and sex steroids may have produced lasting, so-called organizational, effects on dopamine-producing tissue during fetal, perinatal and pubertal periods. Previous studies in transsexuals also suggest that sexually dimorphic brain structures are resistant to exposure to cross-sex hormones and are not influenced by gonadal steroids during adulthood, but they have rather originated by direct action of the genetic factors (e.g. difference in gene dosage) or by the organizational effects of gonadal steroids during early development (Zhou et al. 1995, Kruijver et al. 2000).
We found that MF transsexuals who were smokers had significantly lower plasma HVA as compared with non-smokers, which is in accordance with the finding that male smokers had lower cerebrospinal fluid levels of HVA (Geracioti et al. 1999). Cigarette smoke may have substantially inhibited the central nervous system MOA activity, leading to increased dopaminergic activity (Fig. 1) (Brody et al. 2004) as well as lower plasma HVA. Alternatively, men with low HVA levels may be more prone to become smokers (i.e. reverse causation). The increase in prolactin levels in MF transsexuals upon estrogen administration is likely the reflection of a direct estrogenic enhancement or lower dopaminergic inhibitory effects on prolactin secretion. In previous studies in postmenopausal women, estrogen replacement therapy increased prolactin and cortisol responses to the serotonin agonist metachloro-phenylpiperazine (Halbreich et al. 1995) and hormone replacement therapy increased prolactin secretion in response to the dopamine-blocking agent sulpiride (Paoletti et al. 2001). The findings were thought to reflect changes in serotonergic and dopaminergic activity upon estrogen administration (Halbreich et al. 1995, Paoletti et al. 2001). These estrogenic effects may be confined to the pituitary gland and the hypothalamic structures that control the pituitary production of prolactin, but the effects of sex hormones are likely to differ from one brain region to another. Dopamine degradation proceeds by MOA and COMT, which catalyze the transfer of a methyl group from methionine to dopamine, resulting in homocysteine and HVA (Fig. 1). Because the synthetic pathways are coupled, it is of note that the profound decrease and increase in plasma total homocysteine in MF and FM transsexuals respectively (Giltay et al. 2003) were not paralleled by changes in plasma HVA.
Methodologically, the use of plasma levels of HVA has its limitations. Plasma levels of HVA are dependent upon the balance between both delivery into the plasma and clearance from the plasma (half-life: ± 40 min) (Goldstein et al. 2003). Only 12–40% of HVA in plasma is of central nervous system origin (Swann et al. 1980, Maas et al. 1988, Lambert et al. 1991, Lambert et al. 1993, Amin et al. 1995, 1998); much more is derived from central and peripheral sympathetic nerves and the adrenal medulla. It is possible that sex steroids affected biosynthesis, transport, concentration, uptake, receptor potentiation and density, post-synaptic responsivity, blood–brain barrier, degradation, or clearance of dopamine and serotonin (Halbreich & Kahn 2001). Potential effects on dopamine and serotonin activity may have been obscured by compensatory (i.e. negative feedback) mechanisms, and by the indirect assessment of monoamine status in plasma samples. Finally, alterations in renal clearance may cause concomitant changes in the plasma HVA. However, the increase in plasma creatinine upon testosterone administration is not caused by a decrease in renal function, since creatinine clearance was unaffected by testosterone administration in another study of cross-sex hormone administration to transsexuals (Giltay et al. 1998). The increase in plasma creatinine is rather a reflection of the anabolic effect of testosterone in genetic females, as indicated by the increase in lean body mass.
The interpretation of our results is limited by the inclusion of a relatively small numbers of subjects. Furthermore, the intervention study had a relatively short follow-up of 4 months, had an open-label design and lacked a true placebo group, due to the nature of the study population and the treatment indication. Moreover, different effects may have been found in hypogonadal men and women undergoing sex-appropriate hormone replacement. Yet, the dose of cross-sex hormone administration was high and the levels of HVA were consistently lower in men than in women as well as in MF transsexuals than in FM transsexuals, both before and after cross-sex hormone administration.
We found that fasting plasma levels of HVA, the major metabolites of dopamine, was not significantly changed by administration of high-dose cross-sex hormone administration in FM and MF transsexual subjects. Our results have suggested that the sex difference in plasma HVA – with higher HVA levels in females than in males – is related to mechanisms other than exposure to sex steroids in adulthood, and may rather be the result of a sex difference in genetic factors or of organizing effects of sex hormones during early development.
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Acknowledgements |
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Received 7 July 2005
Accepted 18 July 2005
Made available online as an Accepted Preprint 2 August 2005
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) at baseline and after 4 months of administration of testosterone esters. Back-transformed mean values (with confidence intervals) at 0 and 4 months are identified by diamonds. P values were assessed by ANOVA for repeated measurements for M