Prostate Cancer Incidence under Androgen Deprivation: Nationwide Cohort Study in Trans Women Receiving Hormone Treatment.

CONTEXT: Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer. OBJECTIVE: To assess the incidence of prostate cancer in trans women using hormone treatment. The incidence of prostate cancer in trans women using hormone treatment. DESIGN: In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality. SETTING: Gender identity clinic. PARTICIPANTS: Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included. MAIN OUTCOME MEASURES: Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization. RESULTS: The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42). CONCLUSIONS: Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer.

The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment.

Benign brain tumours may be hormone sensitive. To induce physical characteristics of the desired gender, transgender individuals often receive cross-sex hormone treatment, sometimes in higher doses than hypogonadal individuals. To date, long-term (side) effects of cross-sex hormone treatment are largely unknown. In the present retrospective chart study we aimed to compare the incidence of common benign brain tumours: meningiomas, pituitary adenomas (non-secretive and secretive), and vestibular schwannomas in transgender individuals receiving cross-sex hormone treatment, with those reported in general Dutch or European populations. This study was performed at the VU University Medical Centre in the Netherlands and consisted of 2555 transwomen (median age at start of cross-sex hormone treatment: 31 years, interquartile range 23-41) and 1373 transmen (median age 23 years, interquartile range 18-31) who were followed for 23 935 and 11 212 person-years, respectively. For each separate brain tumour, standardized incidence ratios with 95% confidence intervals were calculated. In transwomen (male sex assigned at birth, female gender identity), eight meningiomas, one non-secretive pituitary adenoma, nine prolactinomas, and two vestibular schwannomas occurred. The incidence of meningiomas was higher in transwomen than in a general European female population (standardized incidence ratio 4.1, 95% confidence interval 1.9-7.7) and male population (11.9, 5.5-22.7). Similar to meningiomas, prolactinomas occurred more often in transwomen compared to general Dutch females (4.3, 2.1-7.9) and males (26.5, 12.9-48.6). Noteworthy, most transwomen had received orchiectomy but still used the progestogenic anti-androgen cyproterone acetate at time of diagnosis. In transmen (female sex assigned at birth, male gender identity), two cases of somatotrophinomas were observed, which was higher than expected based on the reported incidence rate in a general European population (incidence rate females = incidence rate males; standardized incidence ratio 22.2, 3.7-73.4). Based on our results we conclude that cross-sex hormone treatment is associated with a higher risk of meningiomas and prolactinomas in transwomen, which may be linked to cyproterone acetate usage, and somatotrophinomas in transmen. Because these conditions are quite rare, performing regular screenings for such tumours (e.g. regular prolactin measurements for identifying prolactinomas) seems not necessary.

The Amsterdam Cohort of Gender Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets.

BACKGROUND: Over the past decade, the number of people referred to gender identity clinics has rapidly increased. This raises several questions, especially concerning the frequency of performing gender-affirming treatments with irreversible effects and regret from such interventions. AIM: To study the current prevalence of gender dysphoria, how frequently gender-affirming treatments are performed, and the number of people experiencing regret of this treatment. METHODS: The medical files of all people who attended our gender identity clinic from 1972 to 2015 were reviewed retrospectively. OUTCOMES: The number of (and change in) people who applied for transgender health care, the percentage of people starting with gender-affirming hormonal treatment (HT), the estimated prevalence of transgender people receiving gender-affirming treatment, the percentage of people who underwent gonadectomy, and the percentage of people who regretted gonadectomy, specified separately for each year. RESULTS: 6,793 people (4,432 birth-assigned male, 2,361 birth-assigned female) visited our gender identity clinic from 1972 through 2015. The number of people assessed per year increased 20-fold from 34 in 1980 to 686 in 2015. The estimated prevalence in the Netherlands in 2015 was 1:3,800 for men (transwomen) and 1:5,200 for women (transmen). The percentage of people who started HT within 5 years after the 1st visit decreased over time, with almost 90% in 1980 to 65% in 2010. The percentage of people who underwent gonadectomy within 5 years after starting HT remained stable over time (74.7% of transwomen and 83.8% of transmen). Only 0.6% of transwomen and 0.3% of transmen who underwent gonadectomy were identified as experiencing regret. CLINICAL IMPLICATIONS: Because the transgender population is growing, a larger availability of transgender health care is needed. Other health care providers should familiarize themselves with transgender health care, because HT can influence diseases and interact with medication. Because not all people apply for the classic treatment approach, special attention should be given to those who choose less common forms of treatment. STRENGTHS AND LIMITATIONS: This study was performed in the largest Dutch gender identity clinic, which treats more than 95% of the transgender population in the Netherlands. Because of the retrospective design, some data could be missing. CONCLUSION: The number of people with gender identity issues seeking professional help increased dramatically in recent decades. The percentage of people who regretted gonadectomy remained small and did not show a tendency to increase. Wiepjes CM, Nota NM, de Blok CJM, et al. The Amsterdam Cohort of Gender Dysphoria Study (1972-2015): Trends in Prevalence, Treatment, and Regrets. J Sex Med 2018;15:582-590.

A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones.

OBJECTIVE: Adverse effects of long-term cross-sex hormone administration to transsexuals are not well documented. We assessed mortality rates in transsexual subjects receiving long-term cross-sex hormones. DESIGN: A cohort study with a median follow-up of 18.5 years at a university gender clinic. Methods Mortality data and the standardized mortality rate were compared with the general population in 966 male-to-female (MtF) and 365 female-to-male (FtM) transsexuals, who started cross-sex hormones before July 1, 1997. Follow-up was at least 1 year. MtF transsexuals received treatment with different high-dose estrogen regimens and cyproterone acetate 100 mg/day. FtM transsexuals received parenteral/oral testosterone esters or testosterone gel. After surgical sex reassignment, hormonal treatment was continued with lower doses. RESULTS: In the MtF group, total mortality was 51% higher than in the general population, mainly from increased mortality rates due to suicide, acquired immunodeficiency syndrome, cardiovascular disease, drug abuse, and unknown cause. No increase was observed in total cancer mortality, but lung and hematological cancer mortality rates were elevated. Current, but not past ethinyl estradiol use was associated with an independent threefold increased risk of cardiovascular death. In FtM transsexuals, total mortality and cause-specific mortality were not significantly different from those of the general population. CONCLUSIONS: The increased mortality in hormone-treated MtF transsexuals was mainly due to non-hormone-related causes, but ethinyl estradiol may increase the risk of cardiovascular death. In the FtM transsexuals, use of testosterone in doses used for hypogonadal men seemed safe.

Effects of testosterone supplementation on markers of the metabolic syndrome and inflammation in hypogonadal men with the metabolic syndrome: the double-blinded placebo-controlled Moscow study.

OBJECTIVE: Men with the metabolic syndrome (MetS) have low plasma testosterone (T) levels. The aim of this study was to establish whether the normalization of plasma T improves the features of the MetS. DESIGN: A randomized, placebo-controlled, double-blinded, phase III trial of 184 men suffering from both the MetS and hypogonadism. PATIENTS: One hundred and eighty-four men, aged 35-70, with the MetS and hypogonadism (baseline total T level <12·0 nm or calculated free T level <225 pm.), recruited in the outpatient andrology and urology clinic, Research Center for Endocrinology in Moscow, Russia. INTERVENTION: Treatment for 30 weeks with either parenteral T undecanoate (n = 113; TU; 1000 mg IM) or placebo (n = 71), administered at baseline, and after 6 and 18 weeks. One hundred and five (92·9%) men receiving TU and 65 (91·5%) receiving placebo completed the trial. MEASUREMENTS: Body weight, body mass index (BMI), waist circumference (WC), hip circumference, waist-to-hip ratio, insulin, leptin, glucose, cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, C-reactive protein (CRP), interleukin-1-beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10) and tumour necrosis factor-alpha (TNF-α). RESULTS: There were significant decreases in weight, BMI and WC in the TU vs placebo group. Levels of leptin and insulin also decreased, but there were no changes in serum glucose or lipid profile. Of the inflammatory markers, IL-1ß, TNF-α and CRP decreased, while IL-6 and IL-10 did not change significantly. CONCLUSIONS: Thirty weeks of T administration normalizing plasma T in hypogonadal men with the MetS improved some components of the MetS and a number of inflammatory markers.

The treatment of adolescent transsexuals: changing insights.

INTRODUCTION: Treatment of individuals with gender identity disorder (GID) has in medicine nearly always met with a great deal of skepticism. Professionals largely follow the Standards of Care of the World Professional Association for Transgender Health. For adolescents, specific guidelines have also been issued by the British Royal College of Psychiatrists. AIM: To describe the stepwise changes in treatment policy which, in recent years, have been made by the team of the Gender Identity Clinic at the VU University Medical Center in Amsterdam, The Netherlands. METHODS: The first step taken to treat adolescents was that, after careful evaluation, (cross-sex hormone) treatment could start between the ages of 16 and 18 years. A further step was the suppression of puberty by means of gonadotropin-releasing hormone analogs in 12-16 year olds; the latter serves also as a diagnostic tool. Very recently, other clinics in Europe and North America have followed this policy. Results. The first results from the Amsterdam clinic show that this policy is promising. CONCLUSIONS: Professionals who take responsibility for these youth and are willing to help should yet be fully aware of the impact of their interventions. In this article, the pros and cons of the various approaches to youngsters with GID are presented, hopefully inciting a sound scientific discussion of the issue.

Review of studies of androgen treatment of female-to-male transsexuals: effects and risks of administration of androgens to females.

INTRODUCTION: Testosterone supplementation in ovariectomized or elderly women may improve their sense of well-being and libido, muscle mass and strength, and bone mineral density. Naturally, androgens may have virilizing effects in women. It is often believed that androgens have deleterious effects on cardiovascular risks. AIM: To obtain an inventory of the effects of administration of testosterone on female biological functions. METHODS: We reviewed here our publications on the effects of high-dose androgen administration to female-to-male transsexuals treated between 1975 and 2004 (N = 712). Annual accrual was at a steady rate of 22-30 persons. Dosages administered were far above those suited for women. MAIN OUTCOME MEASURES: There was special focus on the potential negative effects on cardiovascular risk markers. RESULTS: The standard treatment was administration of testosterone esters, 250 mg/2-3 weeks, parenterally). With this dose, virilizing effects on the skin and clitoris were prominent. Spatial ability improved, while verbal fluency deteriorated. The ovaries developed polycystic characteristics. Adequate dosages of testosterone preserved bone mass in females. Androgens increased kallikreins, such as prostate-specific antigen, in female reproductive tissues. High-dose testosterone administration appeared to increase weight, visceral fat, and hematocrit, decrease high-density lipoprotein cholesterol, increase endothelin-1, increase C-reactive protein, and increase total homocysteine. But blood pressure, insulin sensitivity, fibrinolytic markers, arterial stiffness, and levels of von Willebrand factor, fibrinogen, and interleukin-6 remained largely unchanged. CONCLUSIONS: Our studies demonstrated that, while some markers of cardiovascular risk factors showed a shift to a more negative risk profile, others were not affected. Androgen effects on cardiovascular risk markers are therefore not universally negative, and it is reasonable to assume that the latter effects will not be negative with the much lower doses suited for administration to women.

Transgender feminization of the facial skeleton.

In transsexualism, there is a strong and ongoing cross-gender identification, and a desire to live and be accepted as a member of the opposite gender; thus there is a wish for somatic treatment to make one's body as congruent as possible with gender identity. Makeup and change in hairstyle and accessories further feminize the face, and in time, most persons became more adapted to their life as a member of the opposite gender. There is a need for more objective standardization of the differences in the facial features of the two sexes, to facilitate surgical treatment planning and more objectively assess the outcome of the facial surgery on psychosocial functioning and appearance.

Effect of testosterone administration on serum and urine kallikrein concentrations in female-to-male transsexuals.

BACKGROUND: Concentrations of human tissue kallikreins (hKs), a group of 15 secreted serine proteases found in many tissues, are modulated by steroid hormones in cancer cell lines. To gain insight into in vivo kallikrein regulation we measured kallikrein concentrations in serum and urinary tissue in female-to-male transsexuals before and after testosterone administration. METHODS: We collected blood and urine samples before treatment and after 4 and 12 months from 28 female-to-male transsexuals who received 250 mg of testosterone esters intramuscularly every 2 weeks. We used ELISA assays to measure multiple kallikreins in serum and urine. RESULTS: After testosterone administration, serum testosterone concentrations increased by approximately 15-fold. Serum kallikrein concentrations increased dramatically for hK3 (prostate-specific antigen) and increased moderately for hK2, hK5, hK6, hK7, hK8, hK10, and hK11. In urine, we noted major increases for hK3 and hK2 only. For all other kallikrein concentrations, we observed no considerable changes. CONCLUSIONS: We conclude that, in serum and urine of female-to-male transsexuals after testosterone administration, hK3 (prostate-specific antigen) and to a lesser extent hK2 concentrations increase dramatically, but concentration of other kallikreins increase either moderately in serum (hK5, hK6, hK7, hK8, hK10, and hK11) or not at all in either serum (hK4, hK13, hK14) or urine (hK4, hK5, hK6, hK7, hK8, hK10, hK11, hK13, hK14).

Effects of long-term androgen administration on breast tissue of female-to-male transsexuals.

Our aim was to examine the effects of androgen administration on breast tissue histology of female-to-male transsexuals and to study the immunohistochemical expression of three human tissue kallikreins, hK3 (PSA), hK6, and hK10. We studied 23 female-to-male transsexuals who were treated with injectable testosterone for 18-24 months. We also used 10 control female breast tissues. All tissues were fixed in buffered formalin, embedded in paraffin, and examined by hematoxylin-eosin staining and immunohistochemical staining for PSA, hK6, and hK10. Females treated with androgens exhibited similar involutionary changes as those seen in breast of menopausal women, such as marked reduction of glandular tissue, involution of the lobuloalveolar structures, and prominence of fibrous connective tissue, but presence of only small amounts of fat tissue. Fibrocystic lesions were generally not observed. In immunohistochemistry, in control breast tissues, we found moderate to strong cytoplasmic immunoexpression of hK6 and hK10 in the epithelial ductal and lobuloalveolar structures, but myoepithelial cells were negative. Luminal secretions were also positive. In menopausal breast, the immunoexpression of hK6 and hK10 was weaker and focal. No control case showed immunoexpression for PSA. In female-to-male transsexuals, one case showed focal PSA cytoplasmic immunoexpression in the epithelium of moderately involuting lobules. Long-term administration of androgens in female-to-male transsexuals causes marked reduction of glandular tissue and prominence of fibrous connective tissue. These changes are similar to those observed at the end-stage of menopausal mammary involution.

Serum and urine tissue kallikrein concentrations in male-to-female transsexuals treated with antiandrogens and estrogens.

BACKGROUND: The expression of human tissue kallikrein genes is regulated by steroid hormones, but most studies have been conducted with cancer cell lines. Our purpose was to examine serum and urinary tissue kallikrein concentration changes in male-to-female transsexuals before and after treatment with antiandrogens and estrogens. METHODS: Thirty-five male-to-female transsexuals receiving cyproterone acetate and estrogens (orally or transdermally) were included in this study. Serum and urine samples were collected before initiation of therapy and 4 and 12 months post therapy. ELISAs were used to measure multiple kallikreins in serum and urine. RESULTS: After antiandrogen and estrogen therapy, serum testosterone concentrations decreased dramatically, as did serum and urinary concentrations of human glandular kallikrein (hK2) and prostate-specific antigen (PSA; hK3). Statistically significant but relatively small changes in serum and urinary concentrations of many other kallikreins were also seen. Kallikreins in serum and urine were correlated before and after treatment. CONCLUSIONS: The concentrations of hK2 and hK3, but not of any other kallikreins, decrease dramatically after combined antiandrogen and estrogen treatment in male-to-female transsexuals. The smaller responses of the other kallikreins presumably reflect their expression in multiple tissues.

The effects of the aromatase inhibitor anastrozole on bone metabolism and cardiovascular risk indices in ovariectomized, androgen-treated female-to-male transsexuals.

OBJECTIVE: Cases of men with estrogen resistance and aromatase deficiency have highlighted the effects of estrogens on bone metabolism, the cardiovascular system and biochemical variables of the metabolic syndrome. In eugonadal men, administration of an aromatase inhibitor induces a substantial elevation of LH and testosterone due to the decreased negative-feedback signal of estrogen and may thwart the interpretation of results. As there is no gonad for LH to act on, no increase of serum testosterone concentration will be seen in female-to-male transssexuals. The aim of this study was to investigate the effects of estrogen deprivation on bone metabolism and vascular parameters without the interference of counter-regulatory effects as seen in eugonadal men. DESIGN: Thirty ovariectomized female-to-male transsexuals participated in this double-blind, randomized trial. During 3 months, subjects received the aromatase inhibitor anastrozole 1 mg/day (n = 16) or a placebo (n = 14) in addition to parenteral testosterone esters (Sustanon 250 every 2 weeks). RESULTS: Serum 17beta-estradiol (E(2)) concentration fell significantly from 134.0 +/- 78.8 to 77.7 +/- 130.6 pmol/l compared with placebo (P < 0.01). LH and FSH levels rose without the rise of testosterone levels observed in eugonadal men. Within the placebo group, E(2) remained at baseline levels. Of the endpoint variables measured (bone metabolism and vascular parameters) no significant changes were observed compared with placebo, or within the anastrozole-treated group. CONCLUSIONS: These results may indicate that the negative effects of estrogen deprivation in men only become manifest when the concentration falls below the levels induced by our intervention with anastrozole (77 pmol/l). This assumption is supported by the observation in the anastrozole group that, although effects of the reduction of serum E(2) on vascular parameters could not be demonstrated in subjects as a group, there was a correlation between individual serum E(2) and several vascular parameters.

The sex difference of plasma homovanillic acid is unaffected by cross-sex hormone administration in transsexual subjects.

There is a close relationship between the brain and the endocrine system. The brain expresses receptors for sex steroids and is capable of metabolizing these hormones. We explored (1) sex differences in homovanillic acid (HVA), a metabolite of the neurotransmitter dopamine, and (2) the effects of cross-sex steroid administration in transsexual subjects. First, we compared plasma HVA levels between 38 male and 34 female healthy volunteers (not using hormone replacement therapy) of a mean age of 72 years (range 65-84 years). Secondly, we measured plasma HVA levels in 15 male-to-female transsexuals treated with 100 microg ethinyl estradiol/day and 100 mg cyproterone acetate/day for 4 months, and in 17 female-to-male transsexuals treated with testosterone esters (250 mg/2 weeks i.m. for 4 months). Plasma HVA levels were lower in elderly men than in elderly postmenopausal women (geometric mean 25.4 nmol/l (percentile (P)10 4.9; P90 69.8) vs 39.0 nmol/l (19.0; 76.1); P=0.027). In transsexuals before cross-sex hormone administration, genetic males also had lower plasma levels of HVA than genetic females (geometric mean 14.8 nmol/l (P10 7.0; P90 35.0) vs 34.3 nmol/l (21.8; 61.4); P<0.001). Cross-sex hormone administration did not affect plasma HVA in either group (P>0.5). The pretreatment sex difference in plasma HVA was unaffected after 4 months of cross-sex hormone administration (P=0.003). The sex difference in plasma HVA was not reversed by cross-sex hormone administration in transsexuals, and was also preserved in elderly subjects. This indicated that differences in dopamine gene expression were largely unaffected by exposure to sex hormone levels in adulthood, but must rather be explained by a sex difference in genetic factors or by the organizing effects of sex hormones during early development.

The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women.

OBJECTIVE: The objective of this study was to examine whether low levels of oestradiol and testosterone are associated with impaired mobility, low muscle strength and the incidence of falls in a population-based sample of older men and women. DESIGN: Cross-sectional population-based study, based on data of the Longitudinal Ageing Study Amsterdam (LASA), including 623 men and 663 women, aged 65-88 years. MEASUREMENTS: Serum levels of oestradiol, testosterone, albumin and sex hormone-binding globulin (SHBG) were measured. Physical performance, functional limitations and muscle strength were assessed, and a follow-up on falls was performed prospectively within 3 years. RESULTS: After adjustment for age, level of education, alcohol use, physical activity, chronic disease and body mass index (BMI), men in the highest quartile of the oestradiol/SHBG ratio had significantly higher physical performance scores than men in the lowest quartile (beta = 0.103). Serum levels of total testosterone were positively associated with muscle strength (beta = 0.085). Calculated bioavailable testosterone levels were positively associated with physical performance and muscle strength (beta = 0.128 and 0.109 respectively). No associations of oestradiol levels with mobility were seen in women. Levels of oestradiol and testosterone were not associated with falls. CONCLUSIONS: It can be concluded that low levels of sex hormones were associated with impaired mobility and low muscle strength in men, but not in women. Levels of sex hormones were not associated with the incidence of falls neither in men, nor in women.

Associations of sex-hormone-binding globulin (SHBG) with non-SHBG-bound levels of testosterone and estradiol in independently living men.

Results of in vitro experiments indicate that with increasing concentrations of SHBG, testosterone (T) is preferentially bound to SHBG in comparison with estradiol (E2). In these studies, the ratio of non-SHBG-bound E2 (non-SHBG-E2) to non-SHBG-T increased with increasing levels of SHBG. SHBG has consequently been regarded as an estrogen amplifier. In this cross-sectional study in 399 men aged between 40 and 80 yr we tested whether higher levels of SHBG are associated with a higher estrogen/androgen ratio in vivo. The mean T level of these men was in the eugonadal range [536 +/- 152 ng/dl (18.6 +/- 5.26 nmol/liter), mean +/- sd]. With increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T [regression coefficient (beta) after adjustment for age and body mass index, 286 +/- 15.8; P < 0.001] and total E2 (beta = 4.47 +/- 0.90; P < 0.001). However, SHBG levels were negatively related with levels of non-SHBG-E2 (beta = -1.78 +/- 0.69; P < 0.001), whereas there was a positive association between levels of SHBG and non-SHBG-T (beta = 32.0 +/- 9.78; P = 0.001). Furthermore, we observed a negative relationship between SHBG levels and the E2/T ratio of either total (beta = -0.016 +/- 0.002; P < 0.001) or non-SHBG-bound (beta = -0.011 +/- 0.002; P < 0.001) hormone. Therefore, we conclude that in eugonadal men, higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.

Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects.

BACKGROUND: During pregnancy there is a high demand for docosahexaenoic acid (DHA), which is needed for formation of the fetal brain. Women who do not consume marine foods must synthesize DHA from fatty acid precursors in vegetable foods. OBJECTIVE: We studied sex differences in DHA status and the role of sex hormones. DESIGN: First, DHA status was compared between 72 male and 103 female healthy volunteers who ate the same rigidly controlled diets. Second, the effects of sex hormones were studied in 56 male-to-female transsexual subjects, who were treated with cyproterone acetate alone or randomly assigned to receive oral ethinyl estradiol or transdermal 17beta-estradiol combined with cyproterone acetate, and in 61 female-to-male transsexual subjects, who were treated with testosterone esters or randomly assigned for treatment with the aromatase inhibitor anastrozole or placebo in addition to the testosterone regimen. RESULTS: The proportion of DHA was 15 +/- 4% (x +/- SEM; P < 0.0005) higher in the women than in the men. Among the women, those taking oral contraceptives had 10 +/- 4% (P = 0.08) higher DHA concentrations than did those not taking oral contraceptives. Administration of oral ethinyl estradiol, but not transdermal 17beta-estradiol, increased DHA by 42 +/- 8% (P < 0.0005), whereas the antiandrogen cyproterone acetate did not affect DHA. Parenteral testosterone decreased DHA by 22 +/- 4% (P < 0.0005) in female-to-male transsexual subjects. Anastrozole decreased estradiol concentrations significantly and DHA concentrations nonsignificantly (9 +/- 6%; P = 0.09). CONCLUSION: Estrogens cause higher DHA concentrations in women than in men, probably by upregulating synthesis of DHA from vegetable precursors.

Oral and transdermal estrogens both lower plasma total homocysteine in male-to-female transsexuals.

Plasma total homocysteine (tHcy) levels are on average lower in women versus men, indicating an estrogenic effect. Oral estrogens (absorbed via the liver) may be hypothesized to have stronger effects on hepatic homocysteine metabolism than transdermal estrogens. We randomly assigned 30 male-to-female transsexuals (20-44 years old) to 4 months' administration of oral ethinyl estradiol (n=15) or transdermal 17beta-estradiol (n=15), both with the antiandrogen cyproterone acetate (CA). Ten other male controls were treated with CA only. At baseline and after 2 and 4 months, plasma tHcy was analyzed in conjunction with plasma folate. Oral ethinyl estradiol and transdermal 17beta-estradiol similarly reduced plasma tHcy (geometric mean 10.6 micromol/l [95% CI 8.2-13.9] to 7.5 [6.5; 8.8], and 11.3 [8.1; 16.4] to 8.4 [6.5; 11.1]; P<0.001 for both), whereas CA had no effects. No effects were found on folate levels. Thus, oral and transdermal estrogens decrease plasma tHcy to a similar degree (by geometric mean -26%), which suggests that a hepatic mechanism is unlikely to play an important role in the decline of tHcy levels.

Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects.

OBJECTIVE: Sex differences are found in most components of the insulin resistance syndrome and the associated cardiovascular risk profile. These differences are attributed to sex-specific sex steroid profiles, but the effects of sex steroids on the individual components of the insulin resistance syndrome remain incompletely understood. DESIGN: Prospective, intervention study. SUBJECTS: In 37 young (age range 16-36 years), nonobese [body mass index (BMI) < 29], transsexual subjects, effects of ethinyl oestradiol (100 micro g/day) + cyproterone acetate (100 mg/day) administration were evaluated in 20 male-to-female transsexuals and of testosterone-ester administration [250 mg intramuscularly (i.m.)/2 weeks] in 17 female-to-male transsexuals. MEASUREMENTS: We studied lipid spectrum, postheparin hepatic lipase (HL) and lipoprotein lipase (LPL) activity, blood pressure, glucose utilization (by euglycaemic hyperinsulinaemic clamp), and fat areas (by magnetic resonance imaging) at baseline and during 1-year cross-sex hormone administration. RESULTS: Oestrogens + antiandrogens increased high-density lipoprotein (HDL)-cholesterol and decreased LDL-cholesterol, and HL activity, which are considered beneficial. But this combination also increased triglycerides, blood pressure, subcutaneous fat and visceral fat, and decreased the LDL-particle size, LPL activity and insulin sensitivity, which are all considered detrimental. Testosterone reduced HDL-cholesterol and the LDL-particle size, and increased triglycerides and HL activity. An android fat distribution was induced (i.e. decreased subcutaneous and increased visceral fat). Blood pressure, total and LDL-cholesterol, LPL activity and insulin sensitivity were mainly unaffected. CONCLUSIONS: The effects of cross-sex hormone treatment - in the dosages used in this study - in healthy, nonobese, young transsexual subjects do not show unequivocally that female sex steroids, given in large amounts to male subjects, have beneficial effects on cardiovascular profile and that high dose testosterone administration to female subjects is detrimental with respect to cardiovascular risk.