Oral ethinyl estradiol, but not transdermal 17beta-estradiol, increases plasma C-reactive protein levels in men.
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Biomedical subjects
Publications and source records attributed to L J Gooren.
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This review provides an overview of the literature on aspects of reproductive endocrinology wherein Asian men may differ from Caucasian, notably, prostatic neoplasm and the sensivity to pharmacological regimens of male contraception. Both genetic and environmental factors, such as nutrition, might be relevant. Asian men residing in Asia seem to be relatively protected from clinical prostatic neoplasm while the prevalence of preclinical prostatic neoplasm is not different. Migration to an area with a higher prevalence reduces this difference but does not undo it. With regard to prostatic neoplasm the following factors have been considered as relevant in Asian men: 1) a reduction in 5 alpha-reductase level, 2) decreased levels of androgenic ketosteroid precursors of 5 alpha-reduced androgen metabolites, 3) the decreased presence of a P53 mutation, 4) a higher CAG-repeat length of the androgen receptor, 5) a possible higher level of physical activity, 6) differences in sexual activity. Furthermore, Asian men respond to a higher degree with azoospermia in response to contraceptive steroids. Possible explanations offered for the more pronounced response to contraceptive steroids are: 1) differences in testicular structure and decreased spermatogenic potential, 2) an earlier and more marked suppression in LH secretion by exogenous androgens. The differences may be due to genetical and/or environmental factors influencing the peripheral testosterone metabolism. Dietary factors such as the higher intake of phytoestrogens in Asians might exert effects on 5 alpha-reductase activity and/or on sex hormone binding globulin (SHBG) levels, thus having an impact on the biological efficacy of circulating androgens.
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The frequency and severity of ankylosing spondylitis (AS) show a male preponderance, and androgenic steroids have been implicated in its etiology. Some reports have indicated that serum androgen levels are slightly elevated relative to estrogen levels in patients with AS as compared to controls. In more recent studies, however, serum testosterone, 17 beta-estradiol, and androstenedione levels did not significantly differ between AS patients and controls. Moreover, testosterone levels measured directly in serum can be spuriously elevated, especially in patients using phenylbutazone. Elevated serum levels of the adrenal steroids 17 alpha-hydroxyprogesterone and dehydroepiandrosterone (DHEA) sulfate have been found in patients with AS. These elevations might be explained by partial 11 beta- or 21-hydroxylase deficiencies, but may also be secondary to an enhanced stress response. In vitro studies as well as studies in animals and humans indicate that DHEA enhanced, and 17 beta-estradiol and progesterone inhibit, the cell-mediated immune response, which may play a role in the pathogenesis of AS. Oral estrogen therapy in female patients and human chorionic gonadotrophin injections in male patients with AS, increased the 17 beta-estradiol/testosterone ratio and resulted in a moderate clinical improvement. In conclusion, serum testosterone levels are not elevated in patients with AS. Therefore testosterone probably has no role in the perpetuation of long-standing AS and provides no basis for antiandrogenic treatment. Cross-sectional case-control studies, however, cannot clearly distinguish etiological factors from secondary disease effects, especially when blood sampling occurs many years after the onset of AS. Consequently, the role of sex steroids in the pathogenesis is still insufficiently elucidated.
Large artery stiffening could contribute to the development of cardiovascular disease. The aim of this study was to investigate associations between arterial stiffness and diameter with insulin sensitivity and body composition in healthy men and women. In healthy, young (< 41 years old), non-obese (BMI < 27 kg/m2) men (n = 17) and women (n = 17), we measured the arterial diameter, the distension, the distensibility coefficient and the compliance coefficient of the elastic common carotid and muscular femoral arteries with a non-invasive ultrasonographic method. We also assessed glucose uptake (by a euglycaemic hyperinsulinaemic clamp technique), total body fat and lean body mass (by bioelectrical impedance analysis) and abdominal subcutaneous and visceral fat area (by magnetic resonance imaging). In women, but not in men, the distension and distensibility and compliance coefficients of the femoral artery were negatively associated with insulin concentrations (beta = -0.62, p = 0.008; beta = -0.65, p = 0.005 and beta = -0.59, p = 0.01), and positively with glucose uptake (beta = 0.59, p = 0.02; beta = 0.68, p = 0.005 and beta = 0.54, p = 0.04). Associations with glucose uptake were independent of the mean arterial pressure and body composition. In men and women, arterial compliance was positively associated with fat mass variables, which were mediated by a strong association between the femoral artery diameter and lean body mass (beta = 0.80, p < 0.001) and between the common carotid artery diameter and visceral fat area (beta = 0.56, p = 0.001). We found an independent association between insulin resistance and arterial stiffness, which was more pronounced in women than in men.
Transsexualism is considered to be the extreme end of the spectrum of gender identity disorders characterized by, among other things, a pursuit of sex reassignment surgery (SRS). The origins of transsexualism are still largely unclear. A first indication of anatomic brain differences between transsexuals and nontranssexuals has been found. Also, certain parental (rearing) factors seem to be associated with transsexualism. Some contradictory findings regarding etiology, psychopathology and success of SRS seem to be related to the fact that certain subtypes of transsexuals follow different developmental routes. The observations that psychotherapy is not helpful in altering a crystallized cross-gender identity and that certain transsexuals do not show severe psychopathology has led clinicians to adopt sex reassignment as a treatment option. In many countries, transsexuals are now treated according to the Standards of Care of the Harry Benjamin International Gender Dysphoria Association, a professional organization in the field of transsexualism. Research on postoperative functioning of transsexuals does not allow for unequivocal conclusions, but there is little doubt that sex reassignment substantially alleviates the suffering of transsexuals. However, SRS is no panacea. Psychotherapy may be needed to help transsexuals in adapting to the new situation or in dealing with issues that could not be addressed before treatment.
We prospectively studied the effects of cross-sex hormone administration on fat cell size and in vitro lipolytic activity in subcutaneous abdominal and gluteal fat biopsies obtained from 19 male-to-female (M-F) transsexuals and 17 female-to-male (F-M) transsexuals. The amount of subcutaneous fat at the abdominal and gluteal levels was quantified with the use of magnetic resonance imaging (MRI). Before cross-sex hormone administration, M-F transsexuals had less subcutaneous fat with smaller fat cells compared with F-M transsexuals, with a higher baseline in vitro lipolytic activity expressed as glycerol release per milligram of triglyceride (TG) in the abdominal region (P < .05). Before cross-sex hormone treatment, no differences in lipolytic activity stimulated with arterenol (ART), isoproterenol (ISO), or ISO + insulin (INS) were observed between groups or regions. After a 1-year treatment with estrogens and antiandrogens in M-F transsexuals, subcutaneous fat areas on MRI and fat cell size were increased (P < .001) and reductions were observed in the basal lipolytic activity of gluteal and abdominal fat biopsies (P < .05). Following administration of testosterone to F-M transsexuals, subcutaneous fat and fat cell size at the gluteal and abdominal depots were decreased (P < .01) and basal lipolysis was increased significantly at the abdominal level (P < .05) but not at the gluteal level. In both M-F and F-M transsexuals, no effect of sex hormone administration was observed on stimulated lipolytic activities. In conclusion, regional sex differences in the amount of subcutaneous fat, adipocyte size, and in vitro basal lipolytic activity were demonstrated that could be largely reversed by cross-sex hormone treatment in adult subjects, providing evidence for their dependence on the sex steroid milieu.
In an earlier study we demonstrated that 3 months of cross-sex hormone treatment clearly influenced cognitive functioning in transsexuals. The aims of the present study were to examine: (a) whether we could replicate these findings in a new group of transsexuals; (b) whether a similar pattern of change could be found for novel tasks, i.e. tasks, not used in the previous study, that measured closely related cognitive abilities; (c) whether the cognitive changes following cross-sex hormone treatment had stabilized after 3 months or continued to develop over a period of 1 year; and finally, (d) whether the effects were quickly reversible when the hormone treatment was temporarily stopped. Again a pronounced effect of androgen treatment was found on spatial ability in female-to-male transsexuals (FMs) over a period of one and a half years. As expected, untreated male-to-female transsexuals (MFs) had higher scores on visuo-spatial tasks than untreated FMs; after 3 months of cross-sex hormone treatment, the group difference had disappeared, while after about 10 months of hormone treatment, the sex difference was reversed. These effects did not disappear after termination of cross-sex hormone therapy for a period of 5 weeks, but continued to change slightly in the same direction. Earlier findings of an opposite effect of cross-sex hormones on verbal fluency (i.e. MFs improved and FMs deteriorated after 3 months of cross-sex hormone treatment) were not replicated in this study, nor did we find an hormonal influence on other cognitive functions. This study shows that testosterone had an enhancing, and not quickly reversible effect, on spatial ability performance, but no deteriorating effect on verbal fluency in adult women (FMs). In contrast, anti-androgen treatment in combination with estrogen therapy had no declining effect on spatial ability, nor an enhancing effect on verbal fluency in adult men (MFs).
OBJECTIVES: There is a lack of unanimity about (increased) serum levels of creatine kinase (CK) in patients with ankylosing spondylitis (AS), perhaps because of the inclusion of inappropriate controls. Therefore, serum levels of biochemical markers of muscle origin were assessed in AS patients compared with controls. METHODS: In a comparative study serum levels of sarcoplasmic proteins indicating muscle cell leakage, creatinine, and C reactive protein (CRP) were measured. Fifty eight AS patients with a mean disease duration of 22 (SD 11) years and 58 age and sex matched controls (without back complaints) were included. RESULTS: Lower serum levels in AS patients compared with controls were found for CK (mean (SD): 46 (21) v 76 (44) IU/l; p<0.001), aldolase (0.43 (0.36) v 0.58 (0. 32) IU/l; p=0.001), creatinine (91 (13) v 96 (11) micromol/l; p=0. 02), alanine aminotransferase (2.8 (1.5) v 4.1 (2.9) IU/l; p=0.001) and aspartate aminotransferase (7.0 (2.7) v 8.4 (3.5) IU/l; p=0.02). Also the lean body mass, as estimated by a formula using height, weight, age and sex, showed lower values in patients versus controls (56 (9) v 59 (9) kg; p=0.004), but creatinine clearance (by Cockcroft and Gault formula) was not different (p=0.48). Partial correlation coefficients adjusted for age and sex showed that CRP levels correlated negatively with CK and aldolase levels in AS patients (r= -0.48, p<0.001 and r= -0.37, p=0.005, respectively). CONCLUSION: Serum levels of biochemical markers of muscle origin were lower in AS patients compared with controls. Patients with active AS, as reflected by high CRP levels, may have an increased protein degradation, predominantly in skeletal muscle.
We investigated prospectively the effect of sex steroids on regional fat depots and thigh muscle mass in adult transsexuals. Ethinyl estradiol in combination with cyproterone acetate, a progestational antiandrogen, was given to 20 male-to-female (M-F) transsexuals, and parenteral testosterone esters were given to 17 female-to-male (F-M) transsexuals. Before and after 12 mo of cross-sex hormone administration, several anthropometric measurements (weight, skinfolds, body circumferences, and bioimpedance) were performed, and transverse magnetic resonance images were obtained at the level of the abdomen, hip, and thigh to quantify fat depots (subcutaneous and visceral) and muscle areas. We observed that treatment with ethinyl estradiol in M-F transsexuals induced a significant increase in all subcutaneous fat depots, with a lesser but proportional and significant increase in the visceral fat depot and a decrease in thigh muscle area. Testosterone administration in F-M transsexuals markedly increased thigh muscle area, reduced subcutaneous fat deposition at all levels measured, but slightly increased the visceral fat area. We conclude that sex steroid hormones are important determinants of the sex-specific localization of body fat.
Arterial stiffness may be influenced by sex steroids and insulin; the association with fasting insulin level may be stronger in women than in men. Therefore, we analyzed the effects of sex steroid administration on (1) arterial stiffness and (2) the relationship between fasting insulin level and arterial stiffness. Twelve male-to-female transsexuals were treated with ethinyl estradiol and cyproterone acetate, and 18 female-to-male transsexuals were treated with testosterone esters, with assessments made at baseline and after 4 and 12 months. Changes in distensibility and compliance coefficients (DC and CC, respectively) of the common carotid artery, femoral artery (FA), and brachial artery (BA) were analyzed in relation to changes in fasting plasma levels of glucose, insulin, HDL-cholesterol, and triglycerides. After 4 months of estrogens and antiandrogens in men, significant reductions in the CC and DC of the FA (P=0.006 and P=0.04, respectively) and BA (P=0.04 and P=0.04, respectively) were observed. In women, testosterone, on average, did not affect DC or CC, but the changes in fasting insulin level were strongly negatively associated with changes in the CC and DC, especially in the FA and BA. These associations were significantly less strong in genetic men and were independent of age, mean arterial pressure, and glucose and lipid levels. This experimental study shows (1) that short-term administration of estrogens and antiandrogens increases FA and BA stiffness in men and (2) that the fasting insulin level is a stronger determinant of arterial stiffness in women than in men.
The introduction of designer oestrogens as a treatment modality in hormone replacement in women has invited to consider the concept of compounds with selective androgenic effects for male hormone replacement therapy. The full spectrum of the actions of testosterone may not be necessary of even undesired for certain indications for testosterone treatment. To define for what indications certain androgenic properties are desired and undesired more insight in basic androgen (patho)physiology is required. There is convincing evidence that aromatization of androgenic compounds to oestrogens might be an advantage for maintenance of bone mass and it might also mitigate negative effects of androgens on biochemical parameters of cardiovascular risks; the potentially negative effects of oestrogens on prostate pathology in ageing men needs further elucidation. While the role of dihydro-testosterone (DHT) for the male sexual differentiation and for pubertal sexual maturation is evident, its role in mature and ageing males seems less significant or may even be harmful. It is, however, of note that a negative effect of DHT on prostate pathophysiology is certainly not proven. For male contraception a progestational agent with strong androgenic properties might be an asset. For most of the androgenic actions the critical levels of androgens are not well established. The latter is relevant since the large amount of androgen molecules required for its biological actions (as compared to oestrogens) is an impediment in androgen replacement modalities. There may be room for more biopotent androgens since delivery of large amounts of androgen molecules to the circulation poses problems for treatment modalities.
There is a statistical decline of testosterone levels in ageing men, most manifest in free testosterone. While this fall is only moderate, ageing men show clinical signs of hypogonadism (loss of muscle mass/strength, reduction in bone mass and an increase in visceral fat). This might represent not only a fall but (also) an impairment of the biological action of androgens in target organs. The first small scale studies of androgen supplement administration in ageing men were not disappointing. Anticipated risks lie with the prostate and the cardiovascular system. The risks with regard to prostate disease are often over-rated. The question remains how the segment of the ageing male population possibly benefiting from androgen supplements, can be identified. For the treatment of postmenopausal women 'designer oestrogens' are being developed; similarly, designer androgens retaining beneficial anabolic effects with elimination of harmful effects on the prostate and cardiovascular system, could be devised.
Substantial evidence from animal research indicates that enhanced memory associated with emotional experiences involves activation of the beta-adrenergic system. This hypothesis is further supported by the finding in human subjects that blockade of beta-adrenergic receptors with propranolol selectively reduced memory for emotional events. In the present study, we compared the effects of propranolol, a lipid soluble drug which crosses the blood-brain barrier easily, with those of nadolol, a water soluble drug which crosses the blood-brain barrier to a considerably lesser extent, to determine whether the effect involved peripheral or central beta-adrenergic receptors. The effects of these drugs, taken before subjects watched a slide show that was either emotionally arousing or relatively neutral in content, were tested 1 week later with a surprise memory test. Consistent with previous results, propranolol impaired memory (recall and recognition) in the subjects who saw the emotional version of the slide show. In contrast, nadolol did not impair memory of the emotional slide show. These results indicate that the blockade of central beta-adrenergic receptors is responsible for the reduction in storage of emotional events. The results support the view that memory of a mild emotional event involves activation of central, but not necessarily peripheral beta-adrenergic receptors.
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It is still unclear to what extent cross-gender identity is due to pre- and perinatal organising effects of sex hormones on the brain. Empirical evidence for a relationship between prenatal hormonal influences and certain aspects of gender typical (cognitive) functioning comes from pre- and postpubertal clinical samples, such as women suffering from congenital adrenal hyperplasia and studies in normal children. In order to further investigate the hypothesis that cross-gender identity is influenced by prenatal exposure to (atypical) sex steroid levels we conducted a study with early onset, adult male-to-female and female-to-male transsexuals, who were not yet hormonally treated, and nontranssexual adult female and male controls. The aim of the study was to find out whether early onset transsexuals performed in congruence with their biological sex or their gender identity. The results on different tests show that gender differences were pronounced, and that the two transsexual groups occupied a position in between these two groups, thus showing a pattern of performance away from their biological sex. The findings provide evidence that organisational hormonal influences may have an effect on the development of cross-gender identity.
OBJECTIVE: It is unknown whether long term cross-sex hormone treatment affects the human skeleton. We monitored bone mineral density and biochemical markers of bone turnover for 28-63 months in 20 male-to-female transsexuals (M-->F) treated with anti-androgens and oestrogens, and 19 female-to-male transsexuals (F-->M) treated with androgens. They underwent gonadectomy 13-35 months after the start of cross-sex hormone administration. DESIGN: Bone mineral density (BMD) and the markers of bone turnover osteocalcin, alkaline phosphatase, fasting urinary calcium/creatinine and hydroxyproline/creatinine, were measured at baseline, after 1 year and after 28-63 months of cross-sex hormone administration. RESULTS: In oestrogen-treated M-->F, variables of bone turnover decreased significantly with consecutive measurements. BMD had increased significantly after 1 year, but decreased again to baseline levels after 28-63 months of cross-sex hormones. In F-->M, alkaline phosphatase levels increased during the first year. BMD did not change during the first year but had decreased significantly after 28-63 months following ovariectomy. In both M-->F and F-->M, the change of BMD correlated inversely with serum LH and FSH levels. Of all biochemical variables LH levels appeared to be the best predictor of loss of BMD; in the long-term LH levels were more elevated in testosterone-treated F-->M than in oestrogen-treated M-->F transsexuals. CONCLUSION: In M-->F, oestrogen treatment prevented bone loss after testosterone deprivation. In F-->M the testosterone dosage used, associated with a decline in serum oestradiol levels, was unable to maintain bone mass fully in all subjects in the longer term. The inverse relationship between BMD and serum LH levels suggests that the dose of hormone replacement has been too low in subjects with a decline in their BMD. Its cause might be underdosing or non-compliance in some patients. We propose that serum LH levels may be used as a measure of the adequacy of replacement with sex steroids.
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