Serum dehydroepiandrosterone sulphate levels in patients with early rheumatoid arthritis: positive association with C-reactive protein, but not with HLA-DR genotype.
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Adult↗
Biomedical subjects
L J Gooren
Publications and source records attributed to L J Gooren.
Androgenizing effects of low-dose cyclosporin in male patients with early RA.
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Adult↗
Effects of dehydroepiandrosterone administration on disease activity in patients with rheumatoid arthritis.
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Administration, Oral↗
Visceral fat accumulation is an important determinant of PAI-1 levels in young, nonobese men and women: modulation by cross-sex hormone administration.
Increased plasminogen activator inhibitor type-1 (PAI-1) levels, leading to impaired fibrinolysis, are associated with increased visceral fat in middle-aged and obese subjects. It is unknown, however, whether this association is independent of other disturbances clustered in the insulin resistance syndrome. We analyzed this association in young, nonobese transsexual men and women before and after administration of cross-sex steroids, which potentially influence many elements of the insulin resistance syndrome, including PAI-1 levels and visceral fat accumulation. We assessed the visceral fat area (by MRI); total body fat; insulin sensitivity (with a glucose clamp technique); and plasma levels of PAI-1, insulin, and triglycerides in young (<37 years old), nonobese (body mass index <28 kg/m2), healthy men (n=18) and women (n=15) before and after 12 months of cross-sex hormone administration. Men were treated with ethinyl estradiol 100 microgram/d plus cyproterone acetate 100 mg/d, and women were treated with testosterone esters 250 mg IM every 2 weeks. At baseline, only visceral fat area was significantly correlated with plasma PAI-1 levels in both men (r=0.57, P=0.03) and women (r=0.59, P=0.03). In multivariate linear regression analysis, this association was independent of total body fat, insulin sensitivity, and plasma levels of triglycerides and insulin. After 12 months of cross-sex hormone administration, the plasma PAI-1 levels were no longer correlated with visceral fat (which had increased). We conclude that in young, nonobese men and women, visceral fat area is an important determinant of plasma PAI-1 levels. After cross-sex hormone administration, this association was no longer demonstrable.
Adipose Tissue↗
Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females.
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 (M-->F) transsexuals treated with ethinyl estradiol (100 micrograms/day), in combination with the antiandrogen, cyproterone acetate (100 mg/day), and in 17 female-to-male (F-->M) transsexuals treated with testosterone esters (250 mg/2 weeks, im). In M-->F transsexuals, the plasma tHcy level decreased from geometric mean 8.2 mumol/L to 5.7 mumol/L (P < 0.001); and in F-->M transsexuals, it increased from 7.7 mumol/L to 9.0 mumol/L (P = 0.005). In M-->F 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 F-->M transsexuals, changes in serum 17 beta-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.
Androgen Antagonists↗
The effects of sex steroids on plasma levels of marker proteins of endothelial cell functioning.
We studied thirteen male-to-female (M-->F) and ten female-to-male (F-->M) transsexuals who, for four months, received cross-sex treatment with, respectively, ethinylestradiol and cyproterone acetate, and with testosterone esters. We assessed the effects of treatment on plasma levels of tissue-type plasminogen activator (tPA), von Willebrand factor (vWF), vWF-propeptide (vWF:AgII) and big-endothelin-1 (big-ET-1), four proteins that are markers of endothelial cell functioning. We also measured urokinase-type PA (uPA) and plasminogen activator inhibitor-type 1 (PAI-1), which may not be endothelium-derived but share major clearance pathways with tPA. In M-->F transsexuals, mean plasma levels of tPA (minus 4.4 ng/ml), big-ET-1 (minus 0.8 pg/ml), uPA (minus 0.5 ng/ml) and PAI-1 (minus 26 ng/ml) decreased (all Ps < or =0.02). The level of vWF increased (plus 24%; P = 0.005), while vWF: AgII did not change (P = 0.49). In F-->M transsexuals, levels of big-ET-1 increased (plus 0.4 pg/ml; P = 0.02), while tPA, uPA and PAI-1 did not change (all Ps >0.25). In this group vWF decreased (minus 14%; P = 0.06), but vWF:AgII did not change (P = 0.38). Estrogens and androgens have clear effects on plasma levels of endothelial marker proteins. The mechanisms behind these effects are complex and appear to involve both altered secretion (big-ET-1) and processing and/or clearance (vWF and possibly tPA). Therefore, effects of hormones on the levels of endothelial marker proteins do not necessarily reflect changes in endothelial cell functioning, at least with regard to changes in vWF level associated with the oral administration of high doses of ethinylestradiol and cyproterone acetate to healthy men and the parenteral administration of testosterone to healthy women.
Biomarkers↗
Serum testosterone levels are not elevated in patients with ankylosing spondylitis.
OBJECTIVE: Studies in patients with ankylosing spondylitis (AS) describe slightly elevated serum testosterone levels, but these studies were not properly controlled for possible confounders. METHODS: In a case-control study serum levels of sex steroids, luteinizing hormone, and sex hormone binding globulin (SHGB) were measured in patients with AS and in age and sex matched controls. The body mass index, smoking status, use of alcohol, and fat intake were recorded. RESULTS: Testosterone levels measured in serum extracts did not differ in 50 male patients with AS compared to controls (mean +/- SD 16 +/- 4 vs 15 +/- 5 nmol/l, respectively; p = 0.54). In unextracted serum, however, male patients showed elevated testosterone (p < 0.001) and dehydroepiandrosterone sulfate levels (p = 0.003), even after controlling for confounders (p < 0.001). One of 10 female patients had an elevated testosterone level in unextracted serum. The 17 male users and one of the 2 female users of phenylbutazone had the highest testosterone levels in unextracted serum, and all showed a significant decline after extraction. Serum levels of other sex steroids, luteinizing hormone, and SHGB did not differ significantly between patients and controls. CONCLUSION: Serum testosterone levels are not elevated in male patients with AS. Spuriously elevated testosterone levels in unextracted serum might be related to the use of phenylbutazone in our patient sample.
Adult↗
Safety of cyproterone acetate: report of active surveillance.
Concern about a potentially increased risk of liver cancer associated to cyproterone acetate (CPA) treatment led to a postmarketing long-term surveillance study with historic accural of four groups of patients with sexual-hormonal disorders under treatment with CPA. The aim of the study was to provide a description of potential ADRs under CPA treatment with special emphasis on liver cancer. A long-term follow-up of 2506 patients was conducted. Six hundred and two persons were followed up retrospectively for longer than 10 years. In 16,721 patient-years of observation after the first CPA dose no malignant liver tumour was observed, whereas six would have been expected in this cohort. Seven incident, non-fatal benign liver tumours were found. Altogether 9.6% of a subset of 1685 patients with reported liver tests had, at some time, elevated liver enzymes. No cases were reported where CPA therapy had been discontinued due to severe liver disorder. We concluded from this active surveillance project, that CPA treatment is probably safe in the groups of patients followed up. Even though there was not a single case of liver cancer detected, the hypothesis of an elevated risk is being tested in an ongoing collaborative European case-control study which is examining the association of CPA use and primary hepatocellular cancer.
Journal Article↗
Reproducibility of fat area measurements in young, non-obese subjects by computerized analysis of magnetic resonance images.
OBJECTIVE: To assess reproducibility, expressed as both inter-observer variability and intra-observer variability, of fat area measurements on images obtained by magnetic resonance (MR); to compare variability between fat area measurements, calculated from a single image per body region and from the average fat area of three images, and to determine reproducibility of image acquisition at the abdominal level. SUBJECTS: Thirty young, non-obese subjects (reproducibility of image analysis) and nine young, non-obese subjects (reproducibility of image acquisition). METHODS: Three MR images at the level of the abdomen (in 30 subjects) and at the level of the hip and thigh (in 14 of them). Quantification of subcutaneous fat depots (abdomen, hip and thigh) and visceral fat depots using an image-analyzing computer program. Assessment of variability of image analysis for fat area measurements between two observers and within observers. Assessment of reproducibility of image acquisition at the abdominal level (in nine subjects). RESULTS: Subcutaneous fat areas in all body regions were quantified with coefficients of variation (CV) ranging from only 2.1%-4.9%. By contrast, visceral fat area measurements showed markedly higher CVs (range: 9.4%-17.6%). Moreover, relative variability was much larger in small visceral fat areas (CVs up to 25.6%). The majority of CVs, calculated for intra-observer variability and calculated from the average fat area measurements of three images, was lower than calculated for inter-observer variability and for one single image, respectively. In particular, for the visceral fat depot, this reduction in variability had practical consequences for the number of subjects required for a study. Variation of repeated image acquisition was in the same range as variation of repeated measurements on the same image. CONCLUSION: One image per body site is sufficient to obtain a reliable estimate of subcutaneous fat depots. For estimations of the visceral fat depot, the average area measurements of three images reduces variability and increases statistical power. The availability of one single experienced observer during a study adds to accuracy.
Abdomen↗
Growth hormone substitution in adult growth hormone-deficient men augments androgen effects on the skin.
OBJECTIVE: To assess whether growth hormone (GH) administration to adult GH-deficient men leads to increased sexual hair. The sexual hair scores are subnormal in these patients, even in the presence of normal serum androgen levels. PATIENTS: Forty-six adult men with childhood-onset of GH deficiency of whom 25 were androgen deficient and received replacement. DESIGN: Double-blind and placebo-controlled. Of the 46 patients, 33 started immediately with GH administration; the remaining 13 received placebo for the first 6 months followed by GH for the next 6 months. Sixty-one age-matched healthy men with normal height and serum concentrations of IGF-I served as a comparison group. MEASUREMENTS: Hair scores at 13 defined body regions were assessed before, and after 6 and 12 months of the intervention. At the same time levels of IGF-I, dehydroepiandrosterone sulphate, androstenedione, dihydrotestosterone (DHT), testosterone and sex hormone binding globulin (SHBG) were measured. From the latter two, the free androgen index (FAI) was calculated. RESULTS: Before GH administration, hair scores in the GH deficient patients were lower than in the comparison group. In the 33 men treated with GH from the beginning, there was an increase in hair scores after 6 months. The increase in hair scores was not seen during 6 months of placebo treatment. When the placebo group switched to GH administration, their hair scores had also significantly increased after 6 months of GH substitution therapy. Upon GH administration both levels of SHBG and testosterone/DHT declined while the FAI remained unchanged. CONCLUSION: GH substitution therapy to GH deficient men has an auxiliary effect on androgen action in the skin without an increase of the FAI.
Adult↗
Mortality and morbidity in transsexual subjects treated with cross-sex hormones.
OBJECTIVE: The optimum steroid hormone treatment regimes for transsexual subjects has not yet been established. We have investigated the mortality and morbidity figures in a large group of transsexual subjects receiving cross-sex hormone treatment. DESIGN: A retrospective, descriptive study in a university teaching hospital. SUBJECTS: Eight hundred and sixteen male-to-female (M-->F) and 293 female-to-male (F-->M) transsexuals. INTERVENTIONS: Subjects had been treated with cross-sex hormones for a total of 10,152 patient-years. OUTCOME MEASURES: Standardized mortality and incidence ratios were calculated from the general Dutch population (age- and gender-adjusted) and were also compared to side effects of cross-sex hormones in transsexuals reported in the literature. RESULTS: In both the M-->F and F-->M transsexuals, total mortality was not higher than in the general population and, largely, the observed mortality could not be related to hormone treatment. Venous thromboembolism was the major complication in M-->F transsexuals treated with oral oestrogens and anti-androgens, but fewer cases were observed since the introduction of transdermal oestradiol in the treatment of transsexuals over 40 years of age. No cases of breast carcinoma but one case of prostatic carcinoma were encountered in our population. No serious morbidity was observed which could be related to androgen treatment in the F-->M transsexuals. CONCLUSION: Mortality in male-to-female and female-to-male transsexuals is not increased during cross-sex hormone treatment. Transdermal oestradiol administration is recommended in male-to-female transsexuals, particularly in the population over 40 years in whom a high incidence of venous thromboembolism was observed with oral oestrogens. It seems that in view of the deep psychological needs of transsexuals to undergo sex reassignment, our treatment schedule of cross-sex hormone administration is acceptably safe.
Adolescent↗
Signs of testicular insufficiency in adrenomyeloneuropathy and neurologically asymptomatic X-linked adrenoleukodystrophy: a retrospective study.
X-linked adrenoleukodystrophy (X-ALD) is characterized by central nervous system demyelination, and impaired steroidogenesis in the adrenal cortex and testis. Most patients develop adrenocortical insufficiency. We studied retrospectively the frequency and severity of testicular dysfunction in 26 men with X-ALD. Twenty-one had adrenomyeloneuropathy and five patients were neurologically asymptomatic. In addition to obtaining a routine history and physical examination, we studied plasma levels of testosterone, sex hormone binding globulin, the free androgen index, and the plasma concentrations of dehydroepiandrosterone-sulphate, LH and FSH. In a subset of patients, the testosterone response to hCG and the LH and FSH responses to GnRH were also determined. Clinical signs of gonadal dysfunction were manifested by diminished libido (46%), largely overlapping with erectile dysfunction (58%), and failure of the testes to descend (15%). Physical examination revealed diminished body sexual hair (50%), gynaecomastia (35%), and small testes (12%). Laboratory studies showed low plasma total testosterone levels in 12%, and an insufficient increase after stimulation with hCG in 88% (15 of 17 patients tested). Plasma LH concentration was increased in 16%, and the plasma FSH level was elevated in 32%. The response of LH concentrations to GnRH stimulation was abnormally high in 47% (nine of 19 patients studied), and the response of FSH levels was too low in 16% (three of 19 patients tested). In conclusion, in a retrospective study of 26 men' with X-ALD, in 20 some signs of clinical hypogonadism were found. Plasma testosterone values were generally in the normal range, but upon testing of the hypothalamo-pituitary-testis axis some abnormalities became apparent.
Adolescent↗
Chronic renal failure and sexual functioning: clinical status versus objectively assessed sexual response.
BACKGROUND: Sexual dysfunctions are common among patients with chronic renal failure. The prevalence was assessed in a population of 281 patients (20-60 years), and it was attempted to determine whether their mode of treatment (haemodialysis, peritoneal dialysis, or kidney transplantation), or biochemical and endocrine variables and neuropathy affect sexual functioning. Patients with rheumatoid arthritis served as a comparison group. METHODS: Assessment included clinical history, physical and laboratory examinations, questionnaires measuring erotosexual dysfunctions, and a psychophysiological test procedure. The latter is a laboratory method which measures, in a waking state, subjective and physiological sexual arousal. RESULTS: Men on haemodialysis or peritoneal dialysis suffered significantly more often from 'Hypoactive Sexual Desire Disorder', 'Sexual Aversion Disorder' and 'Inhibited Male Orgasm' than men with kidney transplantation or rheumatoid arthritis. Interestingly, the prevalence of 'Male Erectile Disorder' did not differ significantly between the four groups and ranged between 17 and 43%. Of the women, transplanted patients suffered significantly less from 'Hypoactive Sexual Desire Disorder' than the other three groups; the prevalence of other sexual dysfunctions did not differ between the groups. Although 'Male Erectile Disorder' and 'Female Sexual Arousal Disorder' had a relatively high prevalence there were no differences in the four groups of patients in genital responses during psychophysiological testing. Genital responses during psychophysiological assessment had no relationship to the duration of renal replacement treatment, biochemical/endocrine variables, or the presence/ absence of neuropathy. CONCLUSION: The prevalence of sexual dysfunction was high. Sexual dysfunction in men on haemodialysis or peritoneal dialysis was not so much due to erectile failure but largely to loss of sexual interest, subjectively ascribed to fatigue. The latter was also found in women on haemodialysis or peritoneal dialysis.
Adult↗
Reversal of the sex difference in serum leptin levels upon cross-sex hormone administration in transsexuals.
Women have higher circulating leptin levels than men. This sex difference is not simply explained by differences in the amount of body fat and is possibly influenced by their different sex steroid milieus. This prompted us to study prospectively the effects of cross-sex steroid hormones on serum leptin levels in 17 male to female transsexuals and 15 female to male transsexuals. Male to female transsexuals were treated with 100 micrograms ethinyl estradiol and 100 mg cyproterone acetate (antiandrogen) daily, and female to male transsexuals received testosterone esters (250 mg/2 weeks, im). Before and after 4 and 12 months of cross-sex hormone treatment, serum leptin levels and measures of body fatness were assessed. Before treatment, female subjects had higher serum leptin levels than male subjects independently of the amount of body fat (P < 0.01). Cross-sex hormone administration induced a reversal of the sex difference in serum leptin levels. Estrogen treatment in combination with antiandrogens in male subjects increased median serum leptin levels from 1.9 ng/mL before treatment to 4.8 ng/mL after 4 months and 5.5 ng/mL after 12 months of treatment (P < 0.0001). Testosterone administration in female subjects decreased median serum leptin levels from 5.6 to 2.6 ng/mL after 4 months and to 2.5 ng/mL after 12 months (P < 0.0001). Analysis of covariance revealed that the changes in serum leptin levels were independent of changes in body fatness in both groups (P < 0.01). In conclusion, these results indicate that sex steroid hormones, in particular testosterone, play an important role in the regulation of serum leptin levels. The prevailing sex steroid milieu, not genetic sex, is a significant determinant of the sex difference in serum leptin levels.
Adipose Tissue↗
Long-term testosterone administration increases visceral fat in female to male transsexuals.
The amount of intraabdominal (visceral) fat is an important determinant of disturbances in lipid and glucose metabolism. Cross-sectional studies in women have found associations between high androgen levels and visceral fat accumulation. The causal relation between these phenomena is unknown. We, therefore, studied prospectively the effect of testosterone administration on body fat distribution in 10 young, nonobese, female to male transsexuals undergoing sex reassignment. Before, after 1 yr, and after 3 yr of testosterone administration, magnetic resonance images were obtained at the level of the abdomen, hip, and thigh to quantify both sc and visceral fat depots. After 1 yr of testosterone administration, sc fat depots at all levels showed significant reductions compared to baseline measurements. The mean visceral fat area did not change significantly, but subjects who gained weight in the first year after testosterone administration showed an increase in visceral fat. After 3 yr of testosterone administration, sc fat depots were no longer significantly lower compared to pretreatment measurements, but the mean visceral fat depot had increased significantly by 13 cm2 (95% confidence interval, 4-22 cm2), a relative increase of 47% (95% confidence interval, 8-91%) from baseline. The increase in visceral fat was most pronounced in those subjects who had gained weight. We conclude that long term testosterone administration in young, nonobese, female subjects increases the amount of visceral fat. In addition, an increase in weight in this hyperandrogenic state leads to a preferential storage of fat in the visceral depot.
Abdomen↗
Androgen-resistance syndromes: considerations of gender assignment.
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Androgens↗
The effect of androgen treatment on bone metabolism in female-to-male transsexuals.
Histomorphometry was performed in iliac crest biopsies from 15 female-to-male (F-M) transsexuals with a mean age of 30 +/- 6.1 (SD) years. At the time of study, they had been treated with parenteral testosterone esters (250 mg/2 weeks) or oral testosterone undecanoate (160 mg/day). The median androgen treatment duration was 39 months. The patients had undergone hysterectomy and bilateral ovariectomy. The bone biopsy was obtained after double tetracycline labeling. Histomorphometric results were compared with data from 8 postmenopausal women and with data from 11 healthy men who had died suddenly. Dynamic parameters were compared with data from the literature. The biochemical picture was characterized by serum testosterone concentrations lower than in eugonadal men and estradiol concentrations lower than in eugonadal women and elevated gonadotrophin levels. The bone mineral density in the F-M transsexuals was as expected for age (Z-score -0.31 +/- 1.49). Cortical thickness was significantly higher in F-M transsexuals than in both control groups. Trabecular bone structure was similar in F-M transsexuals and both control groups. The bone formation parameters were generally lower in F-M transsexuals than in the control groups. The eroded surface was lower in F-M transsexuals than in postmenopausal women. The low bone turnover and preservation of trabecular bone is consistent with the assumption that testosterone treatment protects the bone in these F-M transsexuals from the deleterious effects of estrogen deficiency. The increased cortical thickness suggests an anabolic effect of the testosterone treatment.
Adult↗
Birth order and sibling sex ratio in two samples of Dutch gender-dysphoric homosexual males.
Two studies were undertaken to confirm the previous findings that homosexual men in general tend to have a later than expected birth order and that extremely feminine homosexual men also tend to have a higher than expected proportion of brothers (i.e., a higher sibling sex ratio). Subjects in Study 1 were Dutch, adult and adolescent, biological male patients with gender dysphoria (persistent and recurrent desires to belong to the opposite sex), who were undergoing treatment with feminizing hormones. These comprised 83 patients who reported sexual attraction to other males (the homosexual group) and 58 who reported sexual attraction to females or equal attraction to males and females (the non-homosexual group). Subjects in Study 2 were Dutch adolescent male patients at another hospital. The homosexual group consisted of 21 gender-dysphoric homosexual teenagers referred to a gender identity clinic for children and adolescents. The control group were 21 adolescent males referred to the child psychiatry department of the same hospital for reasons other than gender identity disorder, homosexuality, or transvestism. These were individually matched to the homosexual subjects on age and sibship size. In both studies, the homosexual group had a significantly later average birth order than the comparison group. In Study 1, the homosexual group had a significantly elevated sibling sex ratio; this was not tested in Study 2 because of its small sample size. These studies add to the mounting evidence that late birth orders are common to all homosexual samples and that elevated sibling sex ratios are an additional characteristic of extremely feminine ones.
Adolescent↗