Exploring gender dysphoria and related outcomes in a prospective cohort study: protocol for the Swedish Gender Dysphoria Study (SKDS).

INTRODUCTION: There has been a drastic increase in the reported number of people seeking help for gender dysphoria in many countries over the last two decades. Yet, our knowledge of gender dysphoria and related outcomes is restricted due to the lack of high-quality studies employing comprehensive approaches. This longitudinal study aims to enhance our knowledge of gender dysphoria; different aspects will be scrutinised, focusing primarily on the psychosocial and mental health outcomes, prognostic markers and, secondarily, on the underlying mechanisms for its origin. METHODS AND ANALYSIS: The Swedish Gender Dysphoria Study is an ongoing multicentre longitudinal cohort study with 501 registered participants with gender dysphoria who are 15 years old or older. Participants at different phases of their clinical evaluation process can enter the study, and the expected follow-up duration is three years. The study also includes a comparison group of 458 age- and county-matched individuals without gender dysphoria. Data on the core outcomes of the study, which are gender incongruence and experienced gender dysphoria, body satisfaction and satisfaction with gender-affirming treatments, as well as other relevant outcomes, including mental health, social functioning and life satisfaction, are collected via web surveys. Two different research visits, before and after starting on gender-affirming hormonal treatment (if applicable), are planned to collect respective biological and cognitive measures. Data analysis will be performed using appropriate biostatistical methods. A power analysis showed that the current sample size is big enough to analyse continuous and categorical outcomes, and participant recruitment will continue until December 2022. ETHICS AND DISSEMINATION: The ethical permission for this study was obtained from the Local Ethical Review Board in Uppsala, Sweden. Results of the study will be presented at national and international conferences and published in peer-reviewed journals. Dissemination will also be implemented through the Swedish Gender Dysphoria Study network in Sweden.

Distribution of electric field in patients with obsessive compulsive disorder treated with deep brain stimulation of the bed nucleus of stria terminalis.

BACKGROUND: Deep brain stimulation (DBS) is being investigated as a treatment for therapy-refractory obsessive compulsive disorder (OCD). Many different brain targets are being trialled. Several of these targets such as the ventral striatum (including the nucleus accumbens (NAc)), the ventral capsule, the inferior thalamic peduncle, and the bed nucleus of stria terminalis (BNST)) belong to the same network, are anatomically very close to one another, or even overlap. Data is still missing on how various stimulation parameters in a given target will affect surrounding anatomical areas and impact the clinical outcome of DBS. METHODS: In a pilot study of eleven participants with DBS of the BNST, we investigate through patient-specific simulation of electric field, which anatomical areas are affected by the electric field, and if this can be related to the clinical results. Our study combined individual patient's stimulation parameters at 12- and 24-month follow-up with image data from the preoperative MRI and postoperative CT. These data were used to calculate the distribution of electric field and create individual anatomical models of the field of stimulation. RESULTS: The individual electric stimulation fields by stimulation in the BNST were similar at both the 12- and 24-month follow-up, involving mainly anterior limb of the internal capsule (ALIC), genu of the internal capsule (IC), BNST, fornix, anteromedial globus pallidus externa (GPe), and the anterior commissure. A statistical significant correlation (p < 0.05) between clinical effect measured by the Yale-Brown Obsessive Compulsive Scale and stimulation was found at the 12-month follow-up in the ventral ALIC and anteromedial GPe. CONCLUSIONS: Many of the targets under investigation for OCD are in anatomical proximity. As seen in our study, off-target effects are overlapping. Therefore, DBS in the region of ALIC, NAc, and BNST may perhaps be considered to be stimulation of the same target.

Deep Brain Stimulation in the Bed Nucleus of Stria Terminalis in Obsessive-Compulsive Disorder-1-Year Follow-up.

BACKGROUND: Deep brain stimulation (DBS) is under investigation as a treatment for therapy-refractory obsessive-compulsive disorder (OCD). As a crucial part of the anxiety circuit, the bed nucleus of stria terminalis (BNST) has been proposed as a target for DBS in OCD. Here, we investigate clinical outcomes and safety of DBS in the BNST in a series of 11 participants with severe therapy-refractory OCD. METHODS: Eleven consecutive participants diagnosed with refractory OCD were treated with BNST DBS and completed follow-up. The primary outcome was a change in scores of the Yale Brown Obsessive Compulsive Scale (YBOCS) at 1 year after surgery. Secondary outcomes included changes in scores of the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Global Assessment of Functioning. RESULTS: At baseline, the mean ± SD YBOCS score was 33 ± 3.0, MADRS score was 29 ± 4.5, and GAF score was 49 ± 5.4. One year after DBS, mean ± SD YBOCS score was 20 ± 4.8 (38% improvement (range 10%-60%) P < 0.01), MADRS score was 21 ± 5.8 (27% improvement, range 4%-74%, P < 0.01), and Global Assessment of Functioning score was 55 ± 6.5 (12% improvement, range 4%-29%, P < 0.05). Of the 11 participants, 6 were considered responders (decrease in YBOCS ≥35%) and 4 partial responders (decrease in YBOCS 25%-34%). Surgical adverse events included 1 case of skin infection leading to reimplantation. The most common transient stimulation-related side effects were anxiety and insomnia. CONCLUSIONS: BNST DBS is a promising therapy in severe therapy-refractory OCD. Our results are in line with previous publications regarding effect and safety profile. Nevertheless, DBS for OCD remains an investigational therapy and should therefore be performed in multidisciplinary clinical studies.

Deep brain stimulation for obsessive-compulsive disorder: Knowledge and concerns among psychiatrists, psychotherapists and patients.

BACKGROUND: Deep brain stimulation (DBS) is under investigation for severe obsessive-compulsive disorder (OCD) resistant to other therapies. The number of implants worldwide is slowly increasing. Therefore, it is of importance to explore knowledge and concerns of this novel treatment among patients and their psychiatric healthcare contacts. This information is relevant for scientific professionals working with clinical studies for DBS for this indication. Especially, for future study designs and the creation of information targeting healthcare professionals and patients. The aim of this study was to explore the knowledge and concerns toward DBS among patients with OCD, psychiatrists, and cognitive behavioral therapists. METHODS: The study was conducted through web-based surveys for the aimed target groups -psychiatrist, patients, and cognitive behavioral therapists. The surveys contained questions regarding previous knowledge of DBS, source of knowledge, attitudes, and concerns towards the therapy. RESULTS: The main source of information was from scientific sources among psychiatrists and psychotherapists. The patient's main source of information was the media. Common concerns among the groups included complications from surgery, anesthesia, stimulation side effects, and the novelty of the treatment. Specific concerns for the groups included; personality changes mentioned by patients and psychotherapists, and ethical concerns among psychiatrists. CONCLUSION: There are challenges for DBS in OCD as identified by the participants of this study; source and quality of information, efficacy, potential adverse effects, and eligibility. In all of which the current evidence base still is limited. A broad research agenda is needed for studies going forward.

Deep brain stimulation in the bed nucleus of the stria terminalis and medial forebrain bundle in a patient with major depressive disorder and anorexia nervosa.

Deep brain stimulation (DBS) may be considered in severe cases of therapy-refractory major depressive disorder (MDD). However, DBS for MDD is still an experimental therapy. Therefore, it should only be administered in clinical studies driven by multidisciplinary teams, including surgeons with substantial experience of DBS in the treatment of other conditions.

[Deep brain stimulation for psychiatric disorders]. / Djup hjärnstimulering vid psykiska sjukdomar visar lovande resultat - Men behandlingen är fortfarande experimentell.

Deep brain stimulation for psychiatric disorders Deep brain stimulation is an established treatment for movement disorders. It has been proven to be a safe method; only minor complications have been reported in larger studies. New indications for deep brain stimulation are under investigation; among them major depressive disorder and obsessive-compulsive disorder. Deep brain stimulation for severe and therapy-resistant major depressive disorder and obsessive compulsive-disorder shows promising results. However, the experience of deep brain stimulation in psychiatric disorders is limited. Several potential target areas for stimulation have been presented; which are the most effective is still an open question. Deep brain stimulation in psychiatric disorders is a highly experimental treatment and should only be performed by a multidisciplinary team with extensive experience with deep brain stimulation in other conditions.

A systematic review of psychiatric indications for deep brain stimulation, with focus on major depressive and obsessive-compulsive disorder.

BACKGROUND: Deep brain stimulation is a treatment under investigation for a range of psychiatric disorders. It has shown promising results for therapy-refractory obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). Other indications under investigation include Tourette's syndrome, anorexia nervosa and substance use disorders. AIMS: To review current studies on psychiatric indications for deep brain stimulation (DBS), with focus on OCD and MDD. METHOD: A systematic search was carried out in MEDLINE, and the literature was searched to identify studies with DBS for psychiatric disorders. The identified studies were analysed based on patient characteristics, treatment results and adverse effects of DBS. RESULTS: A total of 52 papers met the inclusion criteria and described a total of 286 unique patients treated with DBS for psychiatric indications; 18 studies described 112 patients treated with DBS for OCD in six different anatomical targets, while nine studies presented 100 patients with DBS for MDD in five different targets. CONCLUSION: DBS may show promise for treatment-resistant OCD and MDD but the results are limited by small sample size and insufficient randomized controlled data. Deep brain stimulation for OCD has received United States Food and Drug Administration approval. Other psychiatric indications are currently of a purely experimental nature.

Moderation and mediation of the effect of attention training in social anxiety disorder.

UNLABELLED: While attention modification programs (AMP) have shown promise as laboratory-based treatments for social anxiety disorder, trials of internet-delivered AMP have not yielded significant differences between active and control conditions. To address these inconsistencies, we examined the moderational and mediational role of attention bias in the efficacy of attention training. We compared data reported by Carlbring et al. (2012) to an identical AMP condition, with the exception that participants were instructed to activate social anxiety fears prior to each attention training session (AMP + FACT; n = 39). We also compared all attention training groups to an internet-delivered cognitive-behavioral therapy (iCBT) condition (n = 40). Participants in the AMP + FACT group experienced greater reductions in social anxiety symptoms than both active (n = 40) and control (n = 39) groups reported by Carlbring et al., and did not differ in symptom reductions from the iCBT group. Higher attention bias predicted greater symptom reductions for participants who completed AMP, but not for the control group. Moreover, change in attention bias mediated the relationship between AMP group (active condition reported by Carlbring et al. versus AMP + FACT) and change in social anxiety symptoms. These results suggest the importance of interpreting findings related to symptom change in attention training studies in the context of bias effects. TRIAL REGISTRATION: ISRCTN01715124.

Altered neural correlates of affective processing after internet-delivered cognitive behavior therapy for social anxiety disorder.

Randomized controlled trials have yielded promising results for internet-delivered cognitive behavior therapy (iCBT) for patients with social anxiety disorder (SAD). The present study investigated anxiety-related neural changes after iCBT for SAD. The amygdala is a critical hub in the neural fear network, receptive to change using emotion regulation strategies and a putative target for iCBT. Twenty-two subjects were included in pre- and post-treatment functional magnetic resonance imaging at 3T assessing neural changes during an affective face processing task. Treatment outcome was assessed using social anxiety self-reports and the Clinical Global Impression-Improvement (CGI-I) scale. ICBT yielded better outcome than ABM (66% vs. 25% CGI-I responders). A significant differential activation of the left amygdala was found with relatively decreased reactivity after iCBT. Changes in the amygdala were related to a behavioral measure of social anxiety. Functional connectivity analysis in the iCBT group showed that the amygdala attenuation was associated with increased activity in the medial orbitofrontal cortex and decreased activity in the right ventrolateral and dorsolateral (dlPFC) cortices. Treatment-induced neural changes with iCBT were consistent with previously reported studies on regular CBT and emotion regulation in general.

Deep brain stimulation in the treatment of obsessive-compulsive disorder.

BACKGROUND: Deep brain stimulation (DBS) has emerged as a treatment for severe cases of therapy-refractory obsessive-compulsive disorder (OCD), and promising results have been reported. The literature might, however, be somewhat unclear, considering the different targets used, and due to repeated inclusion of individual patients in multiple publications. The aim of this report was to review the literature on DBS for OCD. METHODS: The modern literature concerning studies conducted on DBS in the treatment of OCD was reviewed. RESULTS: The results of DBS in OCD have been presented in 25 reports with 130 patients, of which, however, only 90 contained individual patients. Five of these reports included at least 5 individual patients not presented elsewhere. Sixty-eight of these patients underwent implantation in the region of the internal capsule/ventral striatum, including the nucleus accumbens. The target in this region has varied between groups and over time, but the latest results from bilateral procedures in this area have shown a 50% reduction of OCD scores, depression, and anxiety. The subthalamic nucleus has been suggested as an alternative target. Although beneficial effects have been demonstrated, the efficacy of this procedure cannot be decided, because only results after 3 months of active stimulation have been presented so far. CONCLUSIONS: DBS is a promising treatment for therapy-refractory OCD, but the published experience is limited and the method is at present an experimental therapy.

What made me feel better? Patients' own explanations for the improvement of their depression.

BACKGROUND: Depression is common among primary care patients and the usual treatment often consists of antidepressant medication and supportive counselling/follow-ups. Previous studies have shown that patients and professionals have different beliefs about treatment, which in turn can decrease acceptance of the diagnosis, compliance and treatment outcome. AIMS: The purpose of this study was to investigate previously depressed patients' beliefs about the cause of their improvement. METHODS: Depressed primary care patients (n = 184) who considered themselves improved at follow-up answered an open-ended question about what they believed had made them better. Among these 117 patients had, in addition to treatment as usual, participated in an intervention with patient education and group counselling (the Contactus programme), whereas 67 were controls. The groups were comparable at baseline and 82% were on antidepressants. RESULTS: In total, the patients mentioned 14 separate improving factors, which could be organized to the larger themes external factors, self-management, passing spontaneously and professional help. The most frequently mentioned factors for improvement were the Contactus programme (53.0%), antidepressants (40.2%) and personal development (27.2%). Few gender and age differences were seen. The controls who mentioned professional help were more likely to have a better outcome. CONCLUSIONS: The patients were generally positive to professional help such as antidepressants and the Contactus programme. Patient education and group counselling seems to be a valuable supplement to treatment of depressed patients in primary care.

Patients' beliefs about the cause of their depression.

BACKGROUND: Patients' beliefs about the cause of their depression can affect their help-seeking behavior, treatment preferences, coping strategies and treatment compliance. There are few studies exploring depressed patients' beliefs about the causes and to our knowledge none in a Swedish population. However, previous studies show that the patients more often mention environmental and psychological causes than biological. The aim of this study was to further explore depressed patients' answers to an open-ended question about the etiology of their depression. METHODS: Primary care patients, participating in a study evaluating patient education, were asked an open-ended question about their beliefs about what had caused their depression. Answers were obtained from 303 patients. RESULTS: The analysis of the patients' beliefs emerged into 16 different categories of explanations for depression that could be organized into three larger themes: current life stressors, past life events and constitutional factors. Work-related stress was the most commonly mentioned cause, followed by personality and current family situation. Only 3.6% stated biological reasons. LIMITATIONS: We could only count the frequency of mentioned causes, but no ranking of the importance of these causes. CONCLUSIONS: Primary care patients often gave multi-causal explanations to their depression. Biological explanations were rare. Their beliefs were predominantly current life stressors such as work or family situation and also their own personality. Patients' beliefs about their illness are important in the patient-doctor encounter, when developing new treatment strategies aiming at improved adherence to both psychopharmacological and psychotherapeutic treatments and also in patient education programs.

A five-year follow-up study of Swedish adults with gender identity disorder.

This follow-up study evaluated the outcome of sex reassignment as viewed by both clinicians and patients, with an additional focus on the outcome based on sex and subgroups. Of a total of 60 patients approved for sex reassignment, 42 (25 male-to-female [MF] and 17 female-to-male [FM]) transsexuals completed a follow-up assessment after 5 or more years in the process or 2 or more years after completed sex reassignment surgery. Twenty-six (62%) patients had an early onset and 16 (38%) patients had a late onset; 29 (69%) patients had a homosexual sexual orientation and 13 (31%) patients had a non-homosexual sexual orientation (relative to biological sex). At index and follow-up, a semi-structured interview was conducted. At follow-up, 32 patients had completed sex reassignment surgery, five were still in process, and five-following their own decision-had abstained from genital surgery. No one regretted their reassignment. The clinicians rated the global outcome as favorable in 62% of the cases, compared to 95% according to the patients themselves, with no differences between the subgroups. Based on the follow-up interview, more than 90% were stable or improved as regards work situation, partner relations, and sex life, but 5-15% were dissatisfied with the hormonal treatment, results of surgery, total sex reassignment procedure, or their present general health. Most outcome measures were rated positive and substantially equal for MF and FM. Late-onset transsexuals differed from those with early onset in some respects: these were mainly MF (88 vs. 42%), older when applying for sex reassignment (42 vs. 28 years), and non-homosexually oriented (56 vs. 15%). In conclusion, almost all patients were satisfied with the sex reassignment; 86% were assessed by clinicians at follow-up as stable or improved in global functioning.

Comparison of two self-rating scales to detect depression: HADS and PHQ-9.

BACKGROUND: More than half of patients with depression go undetected. Self-rating scales can be useful in screening for depression, and measuring severity and treatment outcome. AIM: This study compares the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire (PHQ-9) with regard to their psychometric properties, and investigates their agreement at different cut-off scores. METHOD: Swedish primary care patients and psychiatric outpatients (n = 737) who reported symptoms of depression completed the self-rating scales. Data were collected from 2006 to 2007. Analyses with respect to internal consistency, factor analysis, and agreement (Cohen's kappa) at recommended cut-offs were performed. RESULTS: Both scales had high internal consistency (alpha = 0.9) and stable factor structures. Using severity cut-offs, the PHQ-9 (> or =5) diagnosed about 30% more patients than the HADS depression subscale (HADS-D; > or =8). They recognised the same prevalence of mild and moderate depression, but differed in relation to severe depression. When comparing recommended screening cut-offs, HADS-D > or =11 (33.5% of participants) and PHQ-9 > or =10 (65.9%) agreement was low (kappa = 0.35). Using the lower recommended cut-off in the HADS-D (> or =8), agreement with PHQ-9 > or =10 was moderate (kappa = 0.52). The highest agreement (kappa = 0.56) was found comparing HADS-D > or =8 with PHQ-9 > or =12. This also equalised the prevalence of depression found by the scales. CONCLUSION: The HADS and PHQ-9 are both quick and reliable. The HADS has the advantage of evaluating both depression and anxiety, and the PHQ-9 of being strictly based upon the Diagnostic and Statistical Manual of Mental Disorders. The agreement between the scales at the best suitable cut-off is moderate, although the identified prevalence was similar. This indicates that the scales do not fully identify the same cases. This difference needs to be further explored.

Every third patient in primary care suffers from depression, anxiety or alcohol problems.

The aims of the study were to explore the prevalence of patients with depression and anxiety in primary care, its co-occurrence with hazardous/harmful alcohol use, and its relation to gender, age and reason for visit. A questionnaire, including the self-rating Hospital Anxiety and Depression scale and the Alcohol Use Disorder Identification Test, was consecutively distributed to 1800 patients at 11 primary healthcare centres in the county of Västerbotten, Sweden. The response rate was 77.3% (1392 patients), 38% men and 62% women. A total of 31.9% showed symptoms of depression and/or anxiety, with no gender differences. Harmful/hazardous alcohol use was found in 11.9% of the patients, 17.3% in men and 8.8% in women, although the region in Sweden has relatively low alcohol consumption among the population. Age was an important factor. Incidences of the conditions often occurred simultaneously. About half (51%) of those with harmful/hazardous alcohol use also showed symptoms of depression and/or anxiety. The most common causes for patients with symptoms of depression, anxiety or risk consumption of alcohol to seek care were the same as for the general population, namely complaints of pain or infection. Only 7.8% visited the primary care for psychiatric reasons, according to their own given reasons. In all, 38% of the patients showed signs of psychiatric symptoms and/or alcohol problems or a combination of these. The fact that every third patient showed symptoms of depression, anxiety and/or alcohol problems underlines the strategic position for early identification, intervention and treatment within primary healthcare.

Patient education and group counselling to improve the treatment of depression in primary care: a randomized controlled trial.

BACKGROUND: The Contactus program for depressed patients in primary care, consists of six lectures about depression, each followed by a group discussion. The aim of this study was to investigate if Contactus can improve treatment outcome in comparison to a control group. METHODS: Forty-six primary care centres in Sweden, each randomly allocated either to the Contactus group or to the control group, included depressed patients, 205 in the Contactus group and 114 in the control group. Besides regular treatment of depression, the Contactus group participated in the educational program. At start and after 6 weeks, patients filled in a questionnaire and the self-reports: HADS (Hospital Anxiety and Depression Scale) and GAF-self (Global Assessment of Functioning). RESULTS: After 6 weeks, clinically depressed patients (HAD-depression score >10) had a mean improvement in HAD-D of 4.6 in Contactus vs. 3.0 in controls (p=0.02), and 72% vs. 47% considered themselves to feel better (p=0.01). Increase in GAF score was 11.8 vs. 5.8 (p=0.04), respectively. According to HADS, 55% in Contactus were responders vs. 29% among controls (p=0.006), and 42% vs. 21% (p=0.02) were in remission. LIMITATIONS: Only 40% of the patients in Contactus and 35% among controls were clinically depressed according to the HADS (>10 points) at inclusion. CONCLUSIONS: Patient education and group counselling contributes significantly to better improvement among depressed patients. Group treatment is inexpensive and could be implemented in the routine care of depressed patients in primary care.

Efficacy and tolerability of reboxetine compared with citalopram: a double-blind study in patients with major depressive disorder.

The objective of this study was to compare efficacy and tolerability of the selective noradrenaline reuptake inhibitor reboxetine with the selective serotonin reuptake inhibitor citalopram, in the treatment of major depressive disorder (MDD). In total, 357 outpatients with MDD were randomized to treatment with reboxetine 8-10 mg or citalopram 20-40 mg per day during 24 weeks. Primary end-point was change from baseline in the Hamilton Depression Rating Scale (HAM-D, 21 items). Sexual function/dysfunction was measured by the Sexual Function scale (SF). Observed case analysis showed that both treatments yielded a gradual reduction of HAM-D scores: reboxetine with -21.4 and citalopram with -22.1 points (NS). LOCF analysis showed a greater reduction of the HAM-D scores with citalopram compared with reboxetine (-19.6 vs. -17.8; P = 0.034). The response rate was 90.3% for reboxetine and 92.7% for citalopram (NS). The most common side effect in the reboxetine group was dry mouth, and in the citalopram group sexual dysfunction. At week 24, anorgasmia was reported by 5.9% of the sexually active women in the reboxetine group vs 39% in the citalopram group. The dropout number was 91 in the reboxetine group, and 54 in the citalopram group. To summarize, both treatments gave a satisfactory antidepressant effect. The side effect profile differed between the groups, with a notably high prevalence of sexual dysfunctions in the citalopram group. The high number of dropouts in the reboxetine group, is considered as a result of the non-titration starting dose of 8 mg reboxetine per day, which gave a high incidence of early side-effects.

[Sexual problems are common during antidepressive treatment. What do general practitioners know about this adverse effect and how is it handled?]. / Sexuella problem är vanliga vid antidepressiv behandling. Vad vet allmänläkarna om denna biverkan, och hur hanteras den?

At least five per cent of the Swedish population is treated with some kind of antidepressant (AD) drug, mostly SSRI's. Sexual adverse effects, mainly loss of libido and anorgasmia or delayed orgasm/ejaculation concern more than 50% of these patients. The antidepressive effects of treatment are generally satisfying, but the sexual side effects may be a reason for non-compliance. This article refers to studies that specifically have investigated sexual adverse effects caused by AD-treatment and strategies to handle and prevent these problems. A questionnaire sent to general practitioners showed that they are well aware of the problem with sexual adverse effect in AD treatment and ascribe it great importance. The knowledge of effects and side effects of newer AD drugs seemed somewhat insufficient. An increased knowledge about these substances and alternative treatment strategies would perhaps make it easier for the physicians to handle or avoid AD induced sexual side effects.

Sex steroid-related genes and male-to-female transsexualism.

Transsexualism is characterised by lifelong discomfort with the assigned sex and a strong identification with the opposite sex. The cause of transsexualism is unknown, but it has been suggested that an aberration in the early sexual differentiation of various brain structures may be involved. Animal experiments have revealed that the sexual differentiation of the brain is mainly due to an influence of testosterone, acting both via androgen receptors (ARs) and--after aromatase-catalyzed conversion to estradiol--via estrogen receptors (ERs). The present study examined the possible importance of three polymorphisms and their pairwise interactions for the development of male-to-female transsexualism: a CAG repeat sequence in the first exon of the AR gene, a tetra nucleotide repeat polymorphism in intron 4 of the aromatase gene, and a CA repeat polymorphism in intron 5 of the ERbeta gene. Subjects were 29 Caucasian male-to-female transsexuals and 229 healthy male controls. Transsexuals differed from controls with respect to the mean length of the ERbeta repeat polymorphism, but not with respect to the length of the other two studied polymorphisms. However, binary logistic regression analysis revealed significant partial effects for all three polymorphisms, as well as for the interaction between the AR and aromatase gene polymorphisms, on the risk of developing transsexualism. Given the small number of transsexuals in the study, the results should be interpreted with the utmost caution. Further study of the putative role of these and other sex steroid-related genes for the development of transsexualism may, however, be worthwhile.