Early Mental Response to Hormonal Treatment in Transgender Men - The EMRE Study
Phase: NA
Conditions: Gender Dysphoria, Gender Identity, Gender Issues
Sponsor: Karolinska University Hospital

The EMRE Study 
 
2022-07-15 
 
1 
 
 
 
 
 
 
 
 
 
Early Mental Response - The EMRE Study 
[NCT ID not yet assigned] 
Protocol ID: 2019-004349-34 SE 
Study Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical Study Protocol - English 
 
Early mental response to hormonal treatment in 
transmen – The EMRE Study 
 
 
EudraCT number:  
2019-004349-34 
Version number:  
4  
Date:  
20220715  
 
 
Sponsor:  
Region Stockholm / Karolinska University Hospital, Stockholm, 
Sweden 
Principal Investigator: 
Mats Holmberg 
 
 
 
 
 
 
 

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Table of contents 
 
Signatures .............................................................................................................................................. 6 
Contact information .............................................................................................................................. 7 
List of used acronyms and abbreviations.......................................................................................... 8 
1. 
Synopsis ......................................................................................................................................... 9 
2. 
Background information and rationale ..................................................................................... 11 
3. 
Risk-benefit evaluation ............................................................................................................... 14 
4. 
Objectives .................................................................................................................................... 15 
4.1. 
Primary aim ........................................................................................................................... 16 
4.2. 
Secondary aim ....................................................................................................................... 16 
4.3. 
Primary variabel .................................................................................................................... 16 
4.4. 
Secondary variabel ................................................................................................................ 16 
5. 
Study design and Procedures ................................................................................................... 16 
5.1. 
Overall study design .............................................................................................................. 16 
5.2. 
Procedures and flow chart .................................................................................................... 18 
5.3. 
Biological sampling procedures ............................................................................................. 18 
5.3.1. 
Handling, storage and destruction of biological samples ............................................. 18 
5.3.2. 
Total volume blood per study subject ........................................................................... 19 
5.4. 
Study end ............................................................................................................................... 19 
6. 
Selection of study subjects ........................................................................................................ 19 
6.1. 
Inclusion criteria .................................................................................................................... 19 
6.2. 
Exclusion criteria ................................................................................................................... 19 
6.3. 
Management of pregnancy ................................................................................................... 20 
6.4. 
Screening ............................................................................................................................... 20 
6.5. 
Discontinuation criteria ......................................................................................................... 20 
6.6. 
Handling of other medication during the study period ........................................................ 20 
6.7. 
Management of possible interactions ................................................................................... 21 
7. 
Trial drugs ...................................................................................................................................... 21 
7.1. 
Description of trial drug ........................................................................................................ 21 
7.2. 
Dosage and route of administration ..................................................................................... 21 
7.3. 
Packing, labeling, and handling ............................................................................................. 21 

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7.4. 
Traceability and adherence to the treatment of the trial drug ............................................. 21 
7.5. 
Randomization....................................................................................................................... 21 
7.6. 
Blinding .................................................................................................................................. 22 
7.7. 
Breaking code ........................................................................................................................ 22 
7.8. 
Treatment after the end of the study ................................................................................... 22 
8. 
Assessment of efficacy and safety ................................................................................................. 22 
8.1. 
Primary variable .................................................................................................................... 22 
8.2. 
Secondary variable ................................................................................................................ 22 
9. 
Management of adverse medical events ...................................................................................... 22 
9.1. 
Definitions ............................................................................................................................. 22 
9.1.1. 
Adverse Event (AE) ........................................................................................................ 22 
9.1.2. 
Adverse Drug Reaction (ADR) ........................................................................................ 22 
9.1.3. 
Serious Adverse Event (SAE) .......................................................................................... 23 
9.1.4. 
Suspected, unexpected, serious adverse reaction (SUSAR) .......................................... 23 
9.2. 
Assessment of adverse medical events ................................................................................. 23 
9.2.1. 
Assessment of causation ............................................................................................... 23 
9.2.2. 
Assessment of intensity ................................................................................................. 24 
9.3. 
Reporting and recording of adverse medical events ............................................................ 24 
9.3.1. 
Reporting of adverse medical events (AE) .................................................................... 24 
9.3.2. 
Reporting of serious adverse medical events (SAE) ...................................................... 24 
9.3.3. 
Reporting of suspicious, unexpected, serious adverse reactions (SUSAR) ................... 24 
9.4. 
Follow-up of incidents (AE / SAE) .......................................................................................... 25 
9.5. 
Annual Safety Report (DSUR) ................................................................................................ 25 
9.6. 
Reference safety information ................................................................................................ 25 
9.7. 
Analysis population ............................................................................................................... 25 
9.8. 
Statistical analysis .................................................................................................................. 25 
9.8.1. 
Statistical method .......................................................................................................... 25 
9.8.2. 
Loss ................................................................................................................................ 26 
9.9. 
Dimension calculation ........................................................................................................... 26 
9.10. Monitoring ............................................................................................................................. 26 
9.11. Source data ............................................................................................................................ 26 
9.12. Deviations or serious violations ............................................................................................ 26 
9.13. Audit and inspections ............................................................................................................ 27 

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10. Ethics ............................................................................................................................................ 27 
10.1. Compliance with the protocol, GCP and regulations ............................................................ 27 
10.2. Ethical review of the study .................................................................................................... 27 
10.3. Procedure for obtaining informed consent ........................................................................... 27 
10.4. Data protection ..................................................................................................................... 28 
10.5. Insurance ............................................................................................................................... 28 
11. Significant change to the study ..................................................................................................... 28 
12. Collection, handling and archiving of data .................................................................................... 28 
12.1. Case Report Form (Researcher Form) ................................................................................... 29 
13. Notice that the study has been completed, reporting and publication ........................................ 29 
14. References................................................................................................................................... 29 
15. Appendix ...................................................................................................................................... 31 
 
 
 

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Signatures 
 
Sponsor 
I am responsible for ensuring that this protocol contains all the essential elements for 
conducting the study. I will provide the protocol and all other important study-related 
information to the responsible examiners so that they can complete the study in the right 
way. I am aware of my responsibility to keep the staff working on the study informed and 
educated. 
 
 
Sponsor signature                                                                 Date 220715 
 
David Nathansson 
 
 
Principal investigator 
I have read this protocol and it contains all the essential parts to carry out the study. By 
signing, I agree to conduct the study in all its parts in accordance with this protocol, the 
informed consent, and to comply with the ICH GCP, the Declaration of Helsinki and the 
national and international regulations concerning the current clinical study. 
I will share the minutes and all other important study-related information with the co-workers 
involved so that they can complete the study in the right way. I am aware of my responsibility 
to keep the staff working on the study informed and educated. 
I am aware that quality control will take place of the study in the form of monitoring, audit and 
possible inspection. 
 
Principal investigator signature                                                          Date 220715 
 
Mats Holmberg 
 
 
 

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Contact information 
Responsibility in the study 
 
Sponsor 
David Nathansson 
ME Endokrinologi 
Karolinska Universitetssjukhuset 
C2:94 Karolinska Universitetssjukhuset 
Huddinge 
141 86 Stockholm, Sweden 
david.nathansson@regionstockholm.se 
Principal investigator 
Mats Holmberg 
ANOVA, Karolinska Universitetssjukhuset 
Norra Stationsgatan 69 
17176 Stockholm 
+46705266365 
mats.holmberg@regionstockholm.se 
 
 
 
 

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List of used acronyms and abbreviations 
Förkortning 
Förklaring 
AE 
Adverse Event 
AR 
Adverse Reaction  
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
ICH 
International Council for Harmonisation 
ITT 
Intention-to-treat 
LVFS 
Läkemedelverkets författningssamling (the Swedish medicial agency) 
PP 
Per Protocol analysis 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TCS 
Transgender Congruence Scale 
SDI 
Sexual Desire Inventory 
BPAQ 
Buss-Perry Aggression Questionnaire 
BBQ 
Brunnsviken Brief Quality of life scale 
PERS-S 
Perth Emotional reactivity Scale-Short Form 
BIS-11 
Baratt Impulsiveness Scale 
MADRS 
Montgomery–Åsberg Depression Rating Scale 
Rosenberg 
Rosenberg Self Esteem Scale 
 
 

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1. Synopsis 
EudraCT number:  
2019004349-34 
Title:  
Early mental response to hormonal treatment in 
transgender men – The EMRE Study 
Brief 
background/Rationale/Purpose: 
Gender dysphoria is a condition characterized by a 
perceived incongruence between the body and identity. 
For several decades now, this condition has been 
treated with cross-sex hormone therapy and surgery in 
order to change the body to be more congruent with the 
perceived gender identity. Patient satisfaction with this 
treatment is very high where an overwhelming majority 
of patients live the rest of their lives according to their 
perceived gender. A clinical observation, however, is 
that most patients experience that the congruence 
between the perceived gender and the assigned one 
improves very quickly on hormonal treatment. Long 
before any changes in the body have taken place. This 
may be partly due to a relief from having finally started 
treatment (i.e. a psychological / social explanation) but 
an alternative (and much more likely) explanation is that 
the hormonal treatment directly affects the brain. Since 
the cause of gender dysphoria is unknown today, this 
study is therefore a step in trying to clarify the 
mechanism. In addition, it is of value to be able to 
demonstrate the benefits of hormonal treatment in these 
patients. Finally, there is a basic research motive for this 
study. The effect of sex hormones on the brain is very 
well known from a clinical perspective but all the more 
unknown from a research perspective. This study will 
contribute knowledge in this area.  
Aim: 
Primary question: Does transsexual mens’ experience of 
gender incongruence improve within 6 weeks of 
hormonal treatment? Long before any bodily changes 
occur. 
Secondary issue: Does transmens’ experience of self-
confidence, aggression, depression, anxiety, emotional 
reactivity, quality of life, impulsiveness and sexual desire 
change during 6 weeks of sex-hormone replacement 
therapy compared to placebo. 

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Study design: 
Prospective, randomized, placebo controlled, double 
blind study 
Study population: 
Individuals assigned female sex at birth who have 
received the diagnosis transsexualism but who have not 
yet started hormonal therapy (transmen) 
Number of studypersons 
70 
Inclusion criteria: 
• 
Given written consent to participate in the study. 
• 
Transman diagnosed with transsexualism, as 
defined in ICD-10. 
• 
A desire for complete sex-confirming hormonal 
treatment 
• 
Approved for Nebido treatment by a clinically 
responsible Endocrinologist 
Exclusion criteria:  
   
• 
Concomitant hormonal condition affecting the gonadal axis (e.g. CAH, PCOS, 
CAIS, PAIS, untreated thyroid disease, untreated hypercortisolism, etc.) 
• 
Disability that prevents the patient from fully participating in the study. 
• 
Treatment with steroid hormones (androgens, estrogens, progestogens or 
continuous treatment with per oral corticosteroids within the last three months. 
Previous use of hormone preparations without a doctor's prescription. 
• 
Laboratory samples which, according to responsible endocrinologist, fall 
significantly outside the normal reference range. 
• 
Anamnestic or investigational suspicion of breast cancer or existing or previous 
liver tumours. 
• 
Levels of P-ASAT, P-ALAT or P-GT at the screening time which is > 2 times the 
reference range 
• 
Hypersensitivity to the active substance or to any of the excipients 
• 
Ongoing pregnancy or wishes for an early pregnancy 
Test drug, dosage, 
administration: 
Nebido 4 ml/1000mg administered intramuscularly. One 
single dose included in the study. 

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Effect evaluation: 
Primary variable: Difference in score in Transgender 
Congruence Scale between inclusion and 6 weeks of 
treatment with testosterone or placebo 
Secondary variable: Difference in score in Rosenbergs 
Self-confidence Scale, Sexual Desire Inventory, 
Montgomery Åsberg Depression Rating Scale, Perth 
Emotional reactivity Scale-Short Form, Buss-Perry 
Aggression Questionnaire, Baratt Impulsivness Scale 
and Brunnsviken Brief Quality of life scale between 
inclusion, 2 weeks of treatment and after 6 weeks of 
treatment with testosterone or placebo 
Study period: 
Q 3 2022 – Q4 2025 
2. Background information and rationale 
2.1 Gender dysphoria is currently a psychiatric diagnosis in Sweden (8). To meet the criteria 
of the DSM-5 Diagnostic Manual, the patient must demonstrate an incongruity between their 
gender identity and their assigned gender that causes significant distress or impairment (1). 
The patient must also express a strong desire to be seen and treated as a member of a 
gender other than that assigned at birth and / or a strong desire to change their primary or 
secondary gender characteristics. The diagnostic criteria in ICD-10 are less specific but state 
that the patient must wish to live and be accepted as "the opposite sex" (i.e. opposite to that 
assigned at birth); and that this desire is usually accompanied by a desire to make the body 
more congruent with its gender identity, through hormone therapy and surgery (2). ICD-10 
uses the term "transsexualism" rather than "gender dysphoria". 
There is currently much debate in both the medical and LGBTQ communities about whether 
gender dysphoria should be depatologized and the term "transgender" used by the LGBTQ 
community contains a wider range of gender identities and behaviours than the diagnostic 
criteria for DSM-5 and ICD-10 (9). In fact, a large proportion of self-identified transgender 
people defines their gender as non-binary, and often do not seek gender-confirming 
healthcare either (10,11). For the purpose of this study, however, we limit ourselves to binary 
transgender people, by defining gender dysphoria (transsexualism) in accordance with the 
diagnostic criteria for ICD-10. Diagnostic criteria for gender dysphoria in children and 
adolescents differ from the criteria for adults (1,2). This study only concerns gender 
dysphoria in adults. And for practical reasons only trans gender men. 
A meta-analysis conducted by Collin et al 2016 found that studies aimed at determining the 
prevalence of gender dysphoria have yielded very different results (11). Trans-related 
diagnoses as well as surgical and hormonal gender correction are rare, with an estimated 
incidence of 6.8 and 9.2 / 100,000 individuals, respectively. However, self-reported trans 
identity is much more common, with an estimated prevalence of 871/100 000 individuals. 
Gender dysphoria is associated with significant suffering, reduced quality of life and high self-
reported disabilities (3,10). Comorbidity with other psychiatric diagnoses is high (12), 

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although part of the comorbidity is probably due to what stems from the dysphoria itself, in 
combination with minority stress and discrimination (3.12). E.g. Unemployment as a result of 
discrimination can lead to poverty and reduced access to care, which increases the risk of 
mental or physical health problems (12). 
2.2 Gender-confirming hormone therapy 
Hormone therapy (HB) is in most cases an important part of gender-confirming care of binary 
trans people (13,14). In transwomen (assigned men at birth), hormone therapy usually 
consists of estrogen - usually estradiol - in combination with an anti-androgen (5). Treatment 
regimens in the world differ depending on local tradition and legislation (5). In Europe, 
cyproterone acetate - a progestogen that also has antiandrogenic properties - is widely used 
(5,15). Other treatment options are spironolactone - a diuretic that has antiandrogenic 
properties - and GnRH agonists. In transgender men (assigned women at birth), treatment 
usually consists of testosterone alone (5). Method of administration is either topical gel or 
intramuscular injection. This study includes only transgender men, assigned female sex at 
birth and are consequently treated with testosterone. 
 
2.3 Effects of estradiol on the brain 
There are three main forms of estrogens in humans: estrone, estradiol and estriol (17). 
Estradiol is the predominant endogenous form, and the one commonly used as part of HB in 
trans women (5,17,18). In trans men, the total levels of estradiol are lowered to levels 
equivalent to those of testosterone administration, although estradiol is also a natural 
metabolite of testosterone. This lowering of estradiol levels also affects the brain. Estradiol is 
a steroid hormone that diffuses easily across the cell membrane (17). In the cell cytoplasm or 
nucleus, it binds to and activates estrogen receptors, which in turn regulate the expression of 
a large number of genes (19). There are also non-genomic pathways, which are less well 
understood (20). Estradiol also diffuses easily across the blood-brain barrier (BBB), in a 
process that is not saturable, so the estradiol levels in the central nervous system (CNS) 
mainly reflect the concentration in the blood (21). The effects of estrogens in the brain are 
significant, complex and incompletely understood. Cyr et al. (2000) states in their review 
article on drugs with estrogen-like effect and activity: "Changes in dopaminergic, cholinergic, 
GABAergic, glutamatergic and serotonergic neurotransmission through estrogen-mediated 
mechanisms have been clearly demonstrated." (22) 
Estradiol and testosterone are both mood boosters (18). Fluctuating levels of estradiol, 
sudden falls in estradiol concentrations and persistent estradiol deficiency are all linked to 
mood swings. A proposed mechanism for the effect of estradiol on mood is that it increases 
the rate of degradation of monoamine oxidase. It also increases intraneuronal serotonin 
transport. Both measures increase the availability of serotonin and other monoamines in the 
synapses, thus affecting mood. Estradiol has also been shown to increase the availability of 
5-hydroxytryptamine (serotonin) 3A binding sites in areas of the brain relevant to mood and 
cognition (18), and to increase binding to the serotonin 2A receptor - the most common 
serotonin receptor in the brain ( 23). This may explain the synergistic effect seen in some 
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reuptake inhibitors (SSRIs) (18). Estradiol also acts as an anti-inflammatory and antioxidant 
and has positive effects on cognitive function. It stimulates regeneration of damaged neurons 
and production of neurotransmitters. 
In cis women, estradiol levels fluctuate depending on the menstrual cycle and the period of 
their life they are in (18). Periods during which estradiol fluctuates more drastically - puberty, 
pregnancy (especially the postpartum period) and perimenopause - are associated with an 
increased incidence of mood swings. A remarkably high percentage (50-80%) of women 
experience a certain degree of "postpartum blues". It has been suggested that this is caused 
by the sudden decrease in estrogen that follows postpartum. 
The perimenopausal period has been clearly linked to depressive symptoms (18). This 
period is characterized by high estrogen variation with estrogen levels that are higher on 
average, but even more irregular than during other periods of life. Estradiol in the form of 
HRT is often prescribed during this period, mainly to relieve physical symptoms such as hot 
flashes and fatigue, but there is also evidence to support a positive effect of estradiol 
supplementation in the treatment of depression during perimenopause. 
There is conflicting evidence for postmenopausal depression, when estradiol levels are low 
but stable, and estrone becomes the main form of estrogen. There are some studies that 
suggest that estradiol replacement therapy may relieve symptoms of depression in 
postmenopausal patients and that it may also increase the effect of fluoxetine - an SSRI 
antidepressant. 
In a review of the last 30 years of estrogen and affective disorder research, Douma et al 
conclude: "Although other factors may be involved, there is a link between estrogen activity 
(whether it is determined by the actual level, rate of change, or cascades of subsequent 
events) and affective symptoms in women well established in the literature reviewed. "(18) 
2.4 Effects of testosterone on the brain 
Like estradiol, testosterone is a steroid hormone that diffuses easily across the BBB, as well 
as across the cell membrane (24). Its effects are mediated mainly via the androgen receptor 
(AR). There are also non-genomic pathways of androgenic activity, although they are less 
well known (20). AR is a nuclear receptor and acts as a transcription factor. 
Testosterone can affect target cells directly or through conversion to the more potent form of 
dihydrotestosterone (DHT), or via conversion to estradiol (25). Both testosterone and DHT 
act directly on the androgen receptor, but DHT has a higher affinity for it. The relative 
concentrations of the enzymes that mediate the conversion of testosterone to DHT or 
estradiol (5-alpha-reductase and aromatase, respectively) vary between different tissues. In 
the central nervous system, aromatase is abundant in some nuclei, suggesting that the 
effects of testosterone can be mediated through conversion to estradiol there.  
Serotonin plays a central role in mood, stress regulation and cognition (23). Testosterone 
affects serotonin signalling, although serotonergic neurons do not express androgen 
receptors. A PET study has shown that serum testosterone levels correlate with a proxy 

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measure of serotonin tone in healthy men, suggesting that men with high serum testosterone 
have a higher serotonergic tone. However, the clinical relevance of this is unclear. 
Much of the research has focused on testosterone in relation to sexual behaviour and 
function (25). Several studies have found that testosterone plays an important role in sexual 
desire, sexual thoughts and sexual activity in men. The positive effects on male sexual 
function appear to be more pronounced in men with deficiency / hypogonadal men. Positive 
effects of exogenously administered testosterone on sexual function have also been shown 
in women who are androgen deficient due to natural or surgical menopause. 
The correlation between testosterone and aggression has been thoroughly studied (25). 
Physically and verbally aggressive behavior has been suggested to correlate with high levels 
of plasma testosterone in men. However, the correlation seems to be more pronounced in 
young men and in men with very high levels of testosterone, while moderate 
supraphysiological levels of testosterone have not been linked to increased aggression. 
As previously mentioned, both estradiol and testosterone are mood boosters (18). The 
symptoms of depression are very similar to the symptoms of hypogonadism in men, which 
can make it difficult to distinguish between these conditions (25). They share symptoms such 
as depression, fatigue, decreased libido, energy and general joy in life. While each condition 
has properties that the other lacks, many studies suggest a link between depression and 
hypogonadism in men. Lower testosterone levels have been found in depressed men 
compared to healthy controls, especially in cases of severe or treatment-resistant 
depression. The correlation between testosterone and depression in women has not been 
studied extensively, but low serum testosterone and other androgens have been associated 
with depression in women, especially in older women, and there are studies showing 
improvement in depressive symptoms with testosterone treatment. However, a study has 
shown that both high and low plasma concentrations of testosterone correlate with 
depression in women (26). In addition to depression, the correlations between several other 
mental illnesses and abnormal levels of testosterone have been studied (25). Low levels 
have been found in schizophrenia and chronic sleep disorders. High levels have been found 
in post-traumatic stress and have been associated with low stress tolerance in young men. 
Improvement of obsessive-compulsive disorder with antiandrogen therapy has been reported 
in some studies, as well as increased severity of Tourette-related symptoms with 
testosterone therapy.  
2.5 Mental effects of hormonal therapy in trans men 
Specifically in the trans-male group, increased sexual desire after HB has been reported in a 
number of publications. Whether these changes are due to hormone therapy or the fact that 
starting treatment is seen as a period of joy after an often long investigation period is not 
known. Decreased sensitivity / sensitivity after hormone insertion has also been reported. 
3. Risk-benefit evaluation 
The cause of gender dysphoria is today basically unknown. The condition is mainly 
considered congenital where abnormal development of the brain during the time gender 

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identity and phenotype develops is a theory. Clinically, this condition has been treated for 
several decades with adaptation of the body to the perceived identity with the help of e.g. 
gender-opposite hormone therapy and surgery. Patient satisfaction with this treatment is high 
and an overwhelming majority of these patients live the rest of their lives as the perceived 
gender. 
After patients have been investigated and found to meet the diagnostic criteria for 
transsexualism (F64.0, ICD-10), they are referred to an endocrinologist for initiation of sex-
opposite hormone therapy. In trans men, this treatment of testosterone consists either in the 
form of a daily supply of gel or in the form of long-acting injections (Nebido). An 
overwhelming majority are treated with Nebido. 
A clinical observation is that patients experience a marked improvement in their gender 
incongruence already after a short period of gender-opposite treatment. I.e. long before any 
changes in the body occurred. The most likely explanation for this is a direct hormonal effect 
on the brain. 
This issue is very important from a variety of perspectives. Partly regarding the question of 
what causes the actual condition of gender incongruence: Partly regarding which treatment 
works and finally partly from a basic research perspective where many of the sex hormones' 
effect on the brain are well known in clinics with poor research. 
The benefit is thus very great with this study. Performing randomized, placebo-controlled 
studies on the trans group has long been considered impossible. However, thanks to the fact 
that this study has been planned in consultation with transgender people, a design has been 
constructed that enables comparison with placebo.  
In terms of risks, patients receive an injection of Nebido (4 ml / 1000mg) or placebo. This is 
standard clinical treatment and when it is time for syringe no. 2 (after 6 weeks), the study is 
broken for the individual participant. For those receiving placebo, the study is also 
discontinued after 6 weeks of treatment and then they also receive Nebido according to 
clinical routine. 
Risks with the injection are local tenderness at the injection site and transient cough 
associated with the injection. These risks are well known and transient. 
No increased risks arise through participation in the study compared with standard clinical 
treatment. 
4. Objectives 
The aim of this study is to capture and describe the early effects on the brain of sex-opposite 
hormone therapy of trans men. 
Primary variable: The difference in points on the Transgender Congruence Scale between 
inclusion, 2 weeks after treatment and 6 weeks after treatment with testosterone or placebo 

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Secondary variable: The difference in points on Rosenberg's self-confidence scale, Sexual 
Desire Inventory, Montgomery Åsberg Depression Rating Scale, Perth Emotional reactivity 
Scale-Short Form, Buss-Perry Aggression Questionnaire, Baratt Impulsivness Scale and 
Brunnsviken Brief Quality of life Scale between inclusion, 2 weeks of treatment and after 6 
weeks of treatment with testosterone or placebo.  
4.1. 
Primary aim 
The primary purpose of this study is to study whether treatment with testosterone provides 
greater improvement in the experience of gender incongruence compared to placebo in trans 
men. 
4.2. 
Secondary aim 
The secondary purpose of this study is to describe changes in self-esteem, aggression, 
sexual desire, emotion, quality of life, impulsiveness and anxiety and depression during the 
first 6 weeks of hormonal treatment. 
4.3. 
Primary variabel 
Difference in points on the Transgender Congruence Scale between inclusion, after 2 weeks 
of treatment and after 6 weeks of treatment with testosterone or placebo. 
4.4. 
Secondary variabel  
Difference in points on Rosenberg's self-confidence scale, Sexual Desire Inventory, 
Montgomery Åsberg Depression Rating Scale, Perth Emotional reactivity Scale-Short Form, 
Buss-Perry Aggression Questionnaire and Brunnsviken Brief Quality of life Scale between 
inclusion, after 2 weeks of treatment and after 6 weeks of treatment with testosterone or 
placebo. 
 
 
 
5. Study design and Procedures 
5.1. 
Overall study design  
This is a prospective, randomized, double-blind placebo-controlled study of 50 individuals 
with assigned female sex at birth and recently diagnosed with transsexualism (F64.0)  
The diagnosis of transsexualism is made by a psychiatrist, after which the patient is referred 
to an endocrinologist who makes his own assessment of the suitability of hormonal 
treatment.  
There is a long, well-established clinical treatment of these patients with testosterone.  

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In the study, participants are treated with testosterone (Nebido) in standard dosage 
according to SmPC or placebo, both in injection form. Nebido treatment is started with two 
injections 6 weeks apart and every 12 weeks thereafter. To minimize deviations from clinical 
routine, the study length has therefore been set at 6 weeks, after which all patients are 
offered continued treatment according to clinical routine.  
 
 
 
 
Figure 1 
 
Visit 
1 
2 
 
online 
3 
Nebido 
N=35 
Placebo 
N=35 
 
 
 
 
 
Week: 
 
-1 
 
0 
 
 
 
2 
 
6 
 
 
 
 
 
 
 
 
 
 
Screening 
 
Blood samples 
Doctor visit 
Inclusion 
Randomization 
Questionnaire 
Treatment 
 
Questionnaire Questionnaire 
Blood samples 
Return to 
clinical routine 
 
R 

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5.2. 
Procedures and flow chart 
 
Table 1 
Flow chart 
Procedures 
 
Visit 1 
Visit 2  
Inclusion 
Online 
Week 2 (+- 3 
days) 
Visit 3 
Week 6 (+- 3 
days) 
Incl/exclusion criteria 
√ 
 
 
 
Informed consent 
√ 
 
 
 
Medical history/current 
medication 
√ 
 
 
 
Blood samples 
√ 
 
 
√ 
Randomization 
 
√* 
 
 
Injection Nebido or 
placebo 
 
√ 
 
 
Filling form CRF 
 
√ 
 
√ 
Filling of all scales (8 in 
total) 
 
√ 
√ 
√ 
Unwanted events (AE & 
SAE) 
 
√ 
√ 
√ 
Study ends 
 
 
 
√ 
 
5.3. 
Biological sampling procedures 
5.3.1. Handling, storage and destruction of biological samples 
Sampling for safety and efficacy monitoring is performed according to standard at ANOVA 
before inclusion (before drug administration). The following assays include S-Testosterone, 
S-Estradiol, S-LH, S-FSH, S-SHBG, P-ASAT, P-ALAT, S-25-OH-Vitamin D, B-Hb, B-EVF, B- 
MCH, B-MCHC, B-LPK, B-TPK, P-Ca, P-CRP, P-Phosphate, fS-Insulin, P-Glucose, P-GT, B-
HbA1c, P-HDL, fP-LDL, fP-Cholesterol, fP-Triglyceride, P-Na, S-Prolactin, S-fT3, S-fT4 and 
S-TSH. After 6 weeks of treatment, S-Testosterone, S-Estradiol, S-LH, S-FSH, S-SHBG are 
checked. All samples are analyzed at Karolinska University Hospital Laboratory. No samples 
are saved.  

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5.3.2. Total volume blood per study subject 
The total volume of blood taken from each study subject during the study is a maximum of 40 
ml. 
5.4. 
Study end 
The study ends when the last researcher has completed the last follow-up (LSLV). 
The study may be terminated prematurely if it turns out that the treatment causes a large 
number of unwanted serious events or if the recruitment of research personnel cannot be 
fulfilled within a reasonable time limit. If the study is terminated prematurely, or temporarily 
stopped, the investigator shall immediately inform the researchers of this and ensure 
appropriate treatment and follow-up. The regulatory authority should be informed as soon as 
possible, but no later than within 15 days. 
Decision on early termination of the study is made by the sponsor.    
6. Selection of study subjects 
6.1. 
Inclusion criteria 
To be included in the study, the participant must meet the following criteria: 
• The subject has given their written consent to participate in the study. 
• Transgender people diagnosed with transsexualism, as defined in ICD-10. 
• A desire for complete sex-confirming hormonal treatment 
• Approved for Nebido treatment by a clinically responsible Endocrinologist 
 
6.2. 
Exclusion criteria 
Participants may not be included in the study if any of the following criteria are met: 
• Concomitant hormonal condition affecting the gonadal axis (e.g. CAH, PCOS, CAIS, 
PAIS, untreated thyroid disease, untreated hypercortisolism, etc.) 
• Disability that prevents the patient from fully participating in the study. 
• Treated with steroid hormones (androgens, estrogens, progestogens or continuous 
treatment with per oral corticosteroids within the last three months. Previous use of 
hormone preparations without a doctor's prescription. 
• Laboratory samples which, according to testers, fall significantly outside the normal 
reference range. 

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• Anamnestic or investigational suspicion of breast cancer or existing or previous liver 
tumors. 
• Levels of P-ASAT, P-ALAT or P-GT at the screening time which is> 2 times the 
reference range Hypersensitivity to the active substance or to any of the excipients. 
• Hypersensitivity to the active substance or to any of the excipients. 
• Ongoing pregnancy or wishes for an early pregnancy. 
 
6.3. 
Management of pregnancy 
Nebido is contraindicated during pregnancy. For those participants who do not have penetrative sex 
with men and who do not plan any assisted reproduction within 9 months from the start of the 
study, this anamnestic task is sufficient. For those study participants who have penetrative sex with 
men, pregnancy tests are checked before inclusion if pregnancy is possible. An absolute requirement 
during the study period for these is also the use of a barrier method. Barrier method is not a 
requirement for a male partner who is vasectomized or if the included trans male has ligated the 
fallopian tubes. 
6.4. 
Screening 
That subjects meet all inclusion criteria and have no exclusion criteria is determined before 
inclusion, treatment or randomization takes place. 
6.5. 
Discontinuation criteria 
 
Subjects can terminate their participation in the study at any time without this having any 
consequences for the participant's continued treatment. The examiner / sponsor can at any 
time terminate the study for a researcher due to for example, unacceptable side effects or 
that the researcher does not follow the procedures in the study protocol. If the researcher 
interrupts the study, follow-up of the person will be performed according to the clinic's 
routine. 
6.6. 
Handling of other medication during the study period 
Permitted or prohibited medication during the study. Stable treatment with antidepressants, 
anxiety relievers, sleep medications, central stimulants, statins and blood pressure therapy is 
allowed during the study. Pain medication or antipyretics if needed are allowed within the 
study. New or discontinuation of psychoactive substances such as antidepressants, central 
stimulants or antipsychotics is noted but does not lead to exclusion. Drugs that affect the 
gonad axis as aromatase inhibitors or androgen receptor inhibitors are not allowed during the 
study. Cortisol synthesis inhibitors are also not allowed. Ongoing use of drugs (cannabis, 
central stimulants, opioids) is not permitted. 

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6.7. 
Management of possible interactions 
Ongoing treatment with drugs that may interact with testosterone such as warfarin or, if 
necessary, medication or inhalation medication of corticosteroids does not lead to exclusion 
but is followed by special consideration of the possible consequences of interaction. New 
introduction of the above-mentioned substances also leads to increased vigilance with regard 
to possible interactions. 
 
 
 
7. Trial drugs 
7.1. 
Description of trial drug 
Nebido 4 ml / 1000mg. Manufactured by Bayer AB. Each vial / vial of 4 ml solution for 
injection contains 1000 mg testosterone undecanoate equivalent to 631.5 mg testosterone.  
 
Excipient with known effect: 2000 mg benzyl benzoate per ampoule / vial. Castor oil, refined. 
 
Control consists of placebo. 
 
Medicines and placebos are provided by Bayer AB 
 
7.2. 
Dosage and route of administration 
The drug is delivered by Bayer to Tamro AB, which labels and delivers to ANOVA. The drug 
can be stored at room temperature. 
7.3. 
Packing, labeling, and handling 
Läkemedlet levereras av Bayer till Tamro AB som märker och levererar till ANOVA. 
Läkemedlet kan förvaras i rumstemperatur.  
7.4. 
Traceability and adherence to the treatment of the trial drug 
Not applicable. Injection is given by a nurse. 
7.5. 
Randomization 
The subjects are included / randomized consecutively as they are found suitable to be 
included in the study. If a researcher interrupts their study participation, the researcher code 
will not be reused, and the researcher will not be allowed to be included in the study again. 
Randomization will be performed by Karolinska Trial Alliance (KTA). 

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7.6. 
Blinding 
All participating research staff will be blinded to the treatment the patient is receiving. The 
drug and placebo will be labeled by Tamro AB, which will ensure that Nebido and placebo 
cannot be separated. 
7.7. 
Breaking code 
In connection with inclusion in the study, all participants will receive a card stating that they 
are part of a clinical drug trial with Nebido or placebo. This card contains contact information 
for ANOVA for contact during office hours Monday to Friday and for the principal examiner 
responsible for contact in the evenings / nights and weekends when the reception at ANOVA 
is closed. Code-breaking list for code-breaking is stored on ANOVA. If a situation requiring 
code breach arises, the sponsor will be contacted by the responsible principal examiner.  
7.8. 
Treatment after the end of the study 
Continued treatment according to clinical routine.  
8. Assessment of efficacy and safety 
8.1. 
Primary variable 
The primary variable is the delta value in points on the Transgender Congruence Scale. 
Clarified expressed the difference in points on TCS at inclusion, after 2 weeks of treatment 
and after 6 weeks of treatment. 
8.2. 
Secondary variable 
Difference in points on Rosenberg's self-confidence scale, Sexual Desire Inventory, 
Montgomery Åsberg Depression Rating Scale, Perth Emotional reactivity Scale-Short Form, 
Buss-Perry Aggression Questionnaire, Baratt Impulsivness Scale and Brunnsviken Brief 
Quality of life Scale between inclusion, after two weeks of treatment and after 6 weeks of 
treatment with testosterone or placebo. 
9. Management of adverse medical events 
9.1. 
Definitions 
9.1.1. Adverse Event (AE) 
AE: Any adverse medical event or deterioration of an existing medical condition in a 
researcher who has received a trial drug, whether or not it is causally related to treatment, 
i.e. may be an unfavorable and undesirable sign (including an abnormal laboratory finding), 
symptom or disease that is temporally associated with the use of a trial drug, whether or not 
it is related to the trial drug. 
9.1.2. Adverse Drug Reaction (ADR) 
In clinical use before a new drug is approved or before its new uses are approved, and 
especially when the therapeutic dose cannot be determined, any adverse and unintended 

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response to a drug, regardless of dose, should be considered adverse drug reactions ADR 
(Adverse Drug Reactions). The phrase "response" to a drug means that a causal link 
between a drug and a side effect is at least a reasonable possibility, i.e. that the relationship 
cannot be ruled out. 
9.1.3. Serious Adverse Event (SAE) 
Any adverse event occurring at any dose: 
• 
results in death 
• 
is life threatening 
• 
causes hospitalization or extended hospitalization 
• 
causes permanent or significant disability or impairment 
• 
results in a congenital injury / malformation 
Medical and scientific assessment should be performed to determine if an event is "serious" 
and if it would lead to reporting in other situations, such as important medical events that 
may not be directly life-threatening or result in death or hospitalization, but may endanger the 
researcher or may require intervention to prevent one of the other results given in the 
definition above. These should also normally be considered as SAEs. 
9.1.4. Suspected, unexpected, serious adverse reaction (SUSAR) 
SUSAR: A reaction / event that is unexpected, serious and suspected to be caused by the 
treatment, i.e. side effects not included in the Summary of Product Characteristics (SmPC). 
9.2. 
Assessment of adverse medical events 
9.2.1. Assessment of causation 
The investigator is responsible for determining whether there is a causal link between AE / 
SAE and the use of a trial drug. 
The AEs that are suspected of having a connection with the investigational medicinal product 
will be followed up until the researcher has recovered or been well cared for and is well on 
his way to recovery (see also section 9.4). 
All AEs should be categorized as probably related, possibly related or not related as defined 
below: 
Probably related: Clinical event, including abnormal responses from laboratory tests, 
occurring within a reasonable time after administration of the intervention / trial drug. It is 
unlikely that the event can be attributed to an underlying disease or other drug, but it is most 
likely caused by the trial drug and the occurrence is reasonable in connection with the use of 
the trial drug. 
Possibly related: Clinical event, including abnormal responses from laboratory analyzes, 
occurring within a reasonable time after administration of the intervention / trial drug. The 
event can be explained by the trial drug and the occurrence is reasonable in connection with 
the use of the trial drug, but there is not sufficient information to establish the relationship. 
The event can be explained by the underlying disease or other drugs. 

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Not related: Clinical event, including abnormal responses from laboratory tests, but which is 
not reasonable in relation to the use of the intervention / trial drug. The event is unlikely to be 
related to the intervention / trial drug and may be explained by other drugs or underlying 
disease. 
9.2.2. Assessment of intensity 
Any adverse medical event should be classified by the examiner as mild, moderate or 
pronounced. 
Mild: The event is relatively mild and transient in nature but does not affect the researcher's 
normal life. 
Moderate: The event causes deterioration of function but does not affect health. The event 
may be unpleasant enough and interfere with normal activities but does not completely 
hinder them. 
Pronounced: The event causes impairment of function or ability to work or poses a health 
risk to the researcher. 
9.3. 
Reporting and recording of adverse medical events 
 
During the study visit after six weeks, undesirable events (AE) are registered. All AEs that 
occur during the study and that are observed by the investigator / research nurse or reported 
by the researcher will be registered in the CRF regardless of whether they are related to the 
investigational medicinal product or not. Assessment of causation, intensity and whether AE 
is judged to be an SAE or not is done by the examiner directly in CRF. As a minimum, a 
description of the event is registered for each AE / SAE (diagnosis / symptoms if there is no 
diagnosis), start and stop dates, causal relationship, intensity, whether AE is judged to be an 
SAE or not, measures and outcome. 
9.3.1. Reporting of adverse medical events (AE)  
All AEs must be registered in the CRF within 3 days as above (paragraph 9.3). 
 
9.3.2. Reporting of serious adverse medical events (SAE)  
Serious adverse medical events (SAEs) are reported to the sponsor on a special SAE form within 24 
hours of the examiner becoming aware of SAEs. 
 
9.3.3. Reporting of suspicious, unexpected, serious adverse reactions 
(SUSAR) 
The SAEs that are assessed by the sponsor as SUSAR are reported on a CIOMS form to the 
Norwegian Medicines Agency (Eudra Vigilance database) according to the specified time 
frames. 
As the sponsor does not have the opportunity to report directly in the EudraVigilance 
database, the Medical Products Agency is asked to help with this when a SUSAR occurs in 

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Sweden. Reporting then takes place on a CIOMS form which is sent to the Medical Products 
Agency by post. As these reports contain personal data, they should not be sent to the 
Medical Products Agency by regular e-mail. SUSARs that are reported should, if possible, be 
reported blinded, i.e. with an indication of which trial drug the subject experienced side 
effects. Placebo should only be reported if it is suspected that some component of the 
placebo preparation has caused the side effect. 
SUSARs that are fatal or life-threatening are reported as soon as possible and no later than 
within 7 days after the occurrence has become known to the sponsor. Relevant follow-up 
information is then submitted within a further 8 days. Other SUSARs are reported as soon as 
possible and no later than within 15 days after they have come to the sponsor's notice. 
9.4. 
Follow-up of incidents (AE / SAE) 
Patients are treated with only one injection. That is, discontinuation of treatment is not 
possible. Should the patient suffer a serious event after the first injection, it will primarily be 
handled by a doctor at ANOVA, and secondarily by a doctor at the nearest emergency 
department. All AEs will be followed up by the responsible examiner until the patient has 
stabilized or recovered. AE will be reported after patient safety is ensured. 
9.5. 
Annual Safety Report (DSUR)  
The annual safety report to the Medical Products Agency will be submitted by the sponsor. 
9.6. 
Reference safety information 
As reference safety information, the product summary comes from Fass dated: First 
approval: 2004-10-15; Renewed approval: 2008-11-25 to be used. 
9.7. 
Analysis population 
The study will include 70 individuals with assigned female sex (trans men) who have recently 
been diagnosed with transsexualism (F640) and who have a desire for sex-opposite 
hormone therapy in the form of Nebido injections. 
9.8. 
Statistical analysis 
9.8.1. Statistical method 
Patients with active substance and placebo will be compared with the Mann-Whitney U test. 
Associations between variables will be analyzed with Spearman's rank test Spearmans rank 
test. 
 
Significance test is two-sided and the significance level is 0.05. Study results will be reported 
as differences in median values with associated interquartile range and p-values. 
 

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 All patients who underwent randomization and received a dose (1000mg / 4ml) of Nebido 
are included in the ITT population. All patients who received a dose are included in the safe 
population. 
 
 
9.8.2. Loss 
With good knowledge of the population, we expect a very low dropout rate. 
 
9.9. 
Dimension calculation 
Based on the publication Owen-Smith AA et al, 2018 “Association between Gender 
Confirmation Treatments and Perceived Gender Congruence, Body Image satisfaction, and 
Mental Health in a Cohort of Transgender Individuals. J Sex Med 15:591-600” and other 
consumptions, the hormonal treatment arm’s average increase during six weeks of treatment 
is estimated to six steps in the Transgender Congruence Scale from 30 to 36 with a standard 
deviation of 4,5. The placebo arm is estimated to have an average increase of 2 steps with a 
standard deviation of 6,5. If you test the following with a Mann-Whitney U-test and a power of 
0,8 it will result in a total of 66 patients (33 Hormonal treatment and 33 Placebo). With a drop 
out of 5% 70 patients will be recruited to the study.  
A clinical assessment is that a rapid change in the experience of gender dysphoria is very 
common. Long before any changes have taken place in the body. 
As the study design follows clinical routine, we expect very little dropout. 
9.10. 
Monitoring 
To ensure that the study is conducted according to the protocol, that data is collected, 
documented and reported according to ICH-GCP and current ethical and regulatory 
requirements, the study will be monitored by an independent monitor before the study 
begins, during the study and after the study ends. . The monitoring is performed according to 
the study's monitoring plan and aims to ensure that the researchers' rights, safety and well-
being are met and that the data in CRF are filled in, correct and in accordance with the 
source data. Monitoring will take place by Karolinska Trial Alliance (KTA). 
9.11. 
Source data 
The examiner must keep source documents for each researcher in the study. A document on 
what is classified as source data in the study must be in the investigator's file (Investigator 
Site File, ISF). The tester must ensure that all source documents are available for monitoring 
and other quality control. 
9.12. 
Deviations or serious violations 
Violations and deviations from trial protocols, GCP and other regulations that in a significant 
way directly affect, or in all probability would affect, researchers in Sweden or the scientific 

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value of the trial must be reported immediately within 7 days (from knowledge) to LV. It is the 
sponsor's responsibility to assess the consequences of deviations that have occurred, and 
thus also decide whether LV should be informed. 
Minor deviations that do not affect the integrity or safety of the researchers, or significantly 
affect the scientific value of the trial are documented in the trial documentation of the main 
investigator and the sponsor. 
9.13. 
Audit and inspections 
Authorized representatives of the sponsor and competent authorities may perform audits or 
inspections at the test site, including source data verification. The examiner must ensure that 
all source documents are available for audit and inspection. The purpose of an audit or 
inspection is to systematically and independently review all study-related activities and 
documents, to determine if these activities were performed, registered, analyzed and 
reported correctly according to the protocol, Good Clinical Practice (GCP) and applicable 
regulations. 
 
10. Ethics 
10.1. 
Compliance with the protocol, GCP and regulations 
The study will be conducted in accordance with the study protocol, ICH-GCP E6 (R2), the 
latest version of the Declaration of Helsinki and applicable regulatory requirements. This is to 
ensure the safety and integrity of the researchers as well as the quality of the data collected. 
10.2. 
Ethical review of the study 
The final study protocol, including the final version of the informed consent form and other 
information provided to the researchers, has been approved by the ethics review authority 
(Dnr 2022-03016-1). The Ethics Review Authority shall be informed of any amendments to 
the Protocol in accordance with applicable requirements. 
10.3. 
Procedure for obtaining informed consent 
The principal examiner (or the person who has been delegated the task) must at each 
examination site ensure that the researcher is given full and adequate oral and written 
information about the study, its purpose, possible risks and benefits as well as inclusion / 
exclusion criteria. Researchers must also be informed that they are free to cancel their 
participation in the study at any time without having to state the reason. The researcher must 
be given the opportunity to ask questions and be allowed time to consider the information 
provided. If the person chooses to participate, the researcher and the investigator sign the 
consent. A copy of the research person's information and the signed consent is provided to 
the research person. The researcher's signed and dated informed consent must be obtained 
before performing any study-specific activity in the study. Each researcher who participates 
in the study will be identified by a researcher number on a research person identification list. 
The researcher agrees that monitors and inspectors have access to their medical records. If 

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new information is added to the study, the researcher has the right to decide again whether 
he / she want to continue his / her participation. 
10.4. 
Data protection 
If any part of the data processing is performed by any other organization, within or outside 
the EU, appropriate agreements and / or other documentation will be established, to ensure 
that the processing is carried out in accordance with the provisions of the Data Protection 
Regulation and other relevant legislation, before any data transfer. 
The content of the informed consent form complies with relevant privacy and data protection 
legislation. In the research person's information and the informed consent form, the research 
people will be given complete information on how the collection, use and publication of their 
study data will take place. The research person's information and the informed consent form 
will explain how study data is stored in order to maintain confidentiality in accordance with 
national data legislation. All information processed by the sponsor will be “pseudonymized” 
and identified with the Study Code. 
The informed consent form will also explain that for verification of data, authorized 
representatives of the sponsor, as well as the relevant authority, may require access to parts 
of hospital or study records relevant to the study, including the researcher's medical history.  
10.5. 
Insurance 
All participants are insured by Stockholm County Council having taken out a patient injury 
insurance with the County Council's Mutual Insurance Company, Löf. 
11. 
Significant change to the study 
Significant changes to the signed protocol are only possible through approved protocol 
amendments and by agreement of all responsible persons. Details of non-material changes 
shall be clearly noted in the amended minutes. 
In the event that significant changes to the protocol (e.g. change of main purpose, primary or 
secondary variables, method of measuring primary variable, change of investigational 
medicinal product or dosage) will be made during the study, approval from the Ethical 
Review Authority and the Medical Products Agency must be obtained before implementing 
the amendments. A change that concerns a new review site, new reviewer and / or a new 
research person information shall only be approved by the Ethical Review Authority. 
Non-significant changes must be registered and entered in the documentation when it is then 
submitted, for example in any subsequent notification of a significant change or in connection 
with the reporting of End of Trial. 
12. 
Collection, handling and archiving of data 
Researchers participating in the study are coded with specific researcher numbers. All 
research persons are registered on a research person identification list (subject enrollment 

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and identification list) which links the research person's name and social security number 
with a research “personal number”. 
All data must be registered, managed and stored in a way that enables correct reporting, 
interpretation and verification. Complete sample folder, as well as source documents will be 
archived for at least 10 years after the study is completed. Source data in patient record 
systems are stored and archived in accordance with the regulations of each hospital region. 
12.1. Case Report Form (Researcher Form) 
A paper Case Report Form (CRF) is used for data collection. The examiner must ensure that 
the information is registered and that any corrections in CRF are made in accordance with 
what is stated in the study protocol and in accordance with the instructions. The examiner 
must ensure that the registered information is correct, complete and that reporting takes 
place according to the timelines predetermined. The tester signs the completed CRF. A copy 
of the completed CRF will be filed at the trial site. 
If an examination / test has not been performed and the task does not exist, select ND (Not 
done) or NK (Not known). If the question is irrelevant, write NA (Not applicable). Correction in 
paper CRF is done by drawing a line over the incorrect information. Then write the correct 
information next to the incorrectly filled in information, sign and date the correction. 
13. 
Notice that the study has been completed, reporting 
and publication 
No later than 90 days after the end of the study, the Medical Products Agency must be 
informed by submitting a "Declaration of End of Trial Notification". 
Within one year after completion of the study, the results are analyzed, a clinical study report 
with individual data is prepared and the study results are also reported to the EudraCT 
database. 
 
14. References 
1.  
American Psychiatric association. Diagnostic and statistical manual of mental 
disorders, 5th edition (DSM-5). Arlington VA; 2013.  
2.  
World Health Organization. International statistical classification of diseases 
and related health problems, 10th revision (ICD-10). Geneva; 1992.  
3.  
World Professional Association for Transgender Health (WPATH). Standards of 
Care for the Health of Transsexual, Transgender, and Gender Nonconforming People (7th 
version). 2009.  
4.  
Socialstyrelsen. God vård av vuxna med könsdysfori. 2015.  

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5.  
Hembree WC, Cohen-kettenis P, Waal HAD De, Gooren LJ, Iii WJM, Spack 
NP, et al. Endocrine Treatment of Transsexual Persons : An Endocrine Society Clinical 
Practice Guideline. J Clin Endocrinol Metab. 2009;94(September):3132–54. 
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6.  
Gijs L, Brewaeys A. Surgical Treatment of Gender Dysphoria in Adults and 
Adolescents: Recent Developments, Effectiveness, and Challenges. Annu Rev Sex Res. 
Taylor & Francis; 2007 Mar 1;18(1):178–224.  
7.  
Smith YLS, Van Goozen SHM, Kuiper AJ, Cohen-Kettenis PT. Sex 
reassignment: outcomes and predictors of treatment for adolescent and adult transsexuals. 
Psychol Med. England; 2005 Jan;35(1):89–99.  
8.  
Frisen L, Söder O, Rydelius P-A. Kraftig ökning av könsdysfori bland barn och 
unga. Lakartidningen. 2017;114(EFMY).  
9.  
Davy Z. The DSM-5 and the Politics of Diagnosing Transpeople. Arch Sex 
Behav. United States; 2015 Jul;44(5):1165–76.  
10.  
Zeluf G, Dhejne C, Orre C, Nilunger Mannheimer L, Deogan C, Hoijer J, et al. 
Health, disability and quality of life among trans people in Sweden-a web-based survey. BMC 
Public Health. England; 2016 Aug;16:903.  
11.  
Collin L, Reisner SL, Tangpricha V, Goodman M. Prevalence of Transgender 
Depends on the “Case” Definition: A Systematic Review. J Sex Med. Netherlands; 2016 
Apr;13(4):613–26.  
12.  
Bockting W, Knudson G, Goldberg JM, Goldberg J, Lindenberg D, Hunt R, et al. 
Counselling and Mental Health Care of Transgender Adults and Loved Ones. 2006.  
13.  
Newfield E, Hart S, Dibble S, Kohler L. Female-to-male transgender quality of 
life. Qual Life Res. Netherlands; 2006 Nov;15(9):1447–57.  
14.  
Pfäfflin F, Junge A. Thirty years of international follow-up studies after sex 
reassignment surgery: a comprehensive review 1961-1991. 1998.  
15.  
Läkemedelsindustriföreningen. Androcur [Internet]. Fass. 2018. Available from: 
https://www.fass.se/LIF/product?userType=0&nplId=19780414000015 
16.  
McEwen BS, Alves SE. Estrogen Actions in the Central Nervous System 1. 
Endocr Rev. 1999;20(3):279–307.  
17.  
Kuhl H. Pharmacology of estrogens and progestogens: influence of different 
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15. Appendix 
a) Transgender Congruence  Scale (TCS) – svensk översättning 
b) Perth Emotional Reactivity Scale-Short Form (PERS-S) – svensk översättning 
c) Sexual Desire Inventory (SDI) – svensk översättning 
d) Buss-Perry Agression Questionnaire (BPAQ) – svensk översättning 
e) Rosenberg Self Esteem Scale (RSES)– svensk översättning 
f) Montgomery Åsberg Depression Rating Scale (MADRS-S) 
g) Brunnsviken Brief Quality of life Scale (BBQ) 
h) Baratt Impulsiveness Scale (BIS-11)