Testosterone and Its Metabolites in GID
Condition: Transsexualism
Study type: Interventional
Phase: Phase 3

Summary: 
      The purposes of this study are:

        -  to determine the role of testosterone versus dihydrotestosterone with respect to the
           following physiological functions: bone metabolism, body composition, insulin resistance
           and lipid profile

        -  to determine the role of testosterone and dihydrotestosterone versus estradiol with
           respect to the following physiological functions: bone metabolism, body composition,
           insulin resistance and lipid profile
    

Detailed description: 
      BACKGROUND GID is a psychic disorder in which an otherwise normal person feels like he/she is
      a member of the opposite sex to which she/he belongs biologically. These patients require
      hormonal treatment to suppress the somatic characteristics of their own sex and to develop
      the somatic characteristics of the other sex. After psychotherapy and a period of hormonal
      treatment, they undergo surgical sex reassignment which, in the case of FtM subjects,
      consists of hystero-adnexectomy, reductive mastoplasty and possibly penile reconstruction.
      Thereafter, and for their entire life, they must be treated with testosterone (T) to maintain
      androgen-dependent physiological functions.

      RATIONALE After sex-reassignment surgery, FtM subjects must be treated with T for their
      entire life in order to maintain androgen-estrogen dependent physiological functions.

      These subjects represent an interesting model for the study of the effects of testosterone
      and its metabolites on different physiological functions. As of now, there is no information
      that the androgen receptors differ in males and females. Therefore, induction of the androgen
      effects in the FtM subjects can be considered similar to those in hypogonadal men and FtM
      subjects can serve as a model of the hypogonadal male.

      Therefore, the aim of this trial is to evaluate the effects of selective steroid replacement
      on different physiological functions. In particular in this study we will evaluate the
      relative role of testosterone, DHT and estradiol on the different physiological functions.
      For these purposes, we will administer testosterone undecanoate alone (Group A) or in
      combination with letrozole, an aromatase inhibitor (Group B). A third group of FtM subjects
      will be treated with TU plus dutasteride (Group C).

      In view of the development of selective androgen receptor modulators, the understanding of
      the relative role of each steroid on different physiological functions will provide useful
      information for future therapeutic indications. The information collected in this study will
      greatly help to optimize the long-term treatment of FtM subjects.

      In particular, in this study, we will test the following questions:

        -  what is the role of testosterone vs. DHT on the physiological functions evaluated in
           this study i.e. bone metabolism, body composition, insulin resistance and lipid profile
           (Group B vs. Group C)

        -  what is the role of testosterone and DHT vs estradiol on the physiological functions
           evaluated in this study i.e. bone metabolism, body composition, insulin resistance and
           lipid profile (Group C vs. Group A)

      DESIGN

      For this purpose, in this study we will treat FtM castrated, subjects for 54 weeks with:

        -  testosterone undecanoate 1000 mg 6-12 weeks (injection at week 0, 6, 18, 30, 42 and
           54)(n=5) (Group A)

        -  testosterone undecanoate 1000 mg 6-12 weeks (injection at week 0, 6, 18, 30, 42 and 54)
           mg/day plus letrozole 2.5 mg/day (n=5) (Group B)

        -  testosterone undecanoate 1000 mg 6-12 weeks (injection at week 0, 6, 18, 30, 42 and 54)
           plus dutasteride 0.5 mg/day (n=5) (Group C)

      Overall study design and plan-description Prospective, phase III, randomized study design
      will be used. The study consists of a control phase lasting 3 weeks and a 54-week treatment
      period.

      Control phase: (will last 3 weeks: In this period, subjects will provide three fasting (at
      least 10 hours) blood samples and one urine sample. Subjects will undergo 2 visits to ensure
      fulfillment of inclusion criteria and, absence of exclusion criteria, to determine state of
      health and to be informed about the purposes of the study. During the two visits, they will
      undergo:

        -  blood drawings for measurements of: LH, FSH, estradiol, testosterone DHEAS, total
           cholesterol, HDL cholesterol, triglycerides, insulin, glucose, leptin, adiponectin, uric
           acid, urea, creatinine, Na, K, Ca, P, Mg, Cl, total protein, bone alkaline phosphate,
           PTH, osteocalcin, crosslaps, 25(OH) vit D, H RANKL, osteoprotegerin.

        -  anthropometry: weight, measures

        -  DEXA for bone mass determination and body composition

        -  physical examination

        -  a sexual and behavioral questionnaire

        -  a pain questionnaire

      Treatment phase All injections will be administered by the investigator or co-investigators
      for the entire study. Fasting (10 hours) blood samples will be taken (immediately before
      giving the injections) every time subjects come for injections (week 0, 6, 18, 30 and 42) and
      at the end of the treatment phase. On these occasions, a physical examination including
      weight, blood pressure and pulse rate checks will be performed. Volunteers will be asked to
      complete a sexual and behavioral questionnaire and a pain questionnaire during these visits.

      At week 6, 18, 30 and 42 the following tests will be performed:

        -  blood drawings for measurements of: LH, FSH, estradiol, testosterone, DHT, total
           cholesterol, HDL cholesterol, triglycerides, insulin, glucose, leptin, adiponectin, uric
           acid, urea, creatinine, Na, K, Ca, P, Mg, Cl, total protein.

        -  anthropometry: weight, measures

        -  physical examination

        -  sexual and behavioral questionnaire

        -  pain questionnaire

      At week 54 the following tests will be performed:

        -  blood drawings for measurements of: LH, FSH, estradiol, testosterone, DHT, DHEAS, total
           cholesterol, HDL cholesterol, triglycerides, insulin, glucose, leptin, adiponectin, uric
           acid, urea, creatinine, Na, K, Ca, P, Mg, Cl, total protein, bone alkaline phosphate,
           PTH, osteocalcin, crosslaps, 25(OH) vit D, H RANKL, osteoprotegerin.

        -  anthropometry: weight, measures

        -  DEXA for bone mass determination and body composition

        -  physical examination

        -  sexual and behavioral questionnaire

        -  pain questionnaire

      Measurements:

      Blood samples(10 hours from last food intake). Blood collections will be carried out by
      venipuncture. After resting at room temperature for 30 min, the sample will be centrifuged at
      3000 rpm for 10 min. Serum samples (about 10 ml) from each blood sample will be stored at
      -20°C for analysis.

      Physical examinations:

      They will include inspection of external genitalia (clitorides) and a visit to detect
      appearance of acne and gynecomastia.

      Sexual function and behavior questionnaire:

      In the sexual and behavior questionnaire the subjects will judge their sexual activity and
      behavior in the period between visits. The subjects have the possibility to making additional
      comments about important events and disturbances.

      SELECTION OF STUDY POPULATION:

      Healthy female FtM subjects, who have undergone SR surgery (hystero-adnexectomy) will be
      recruited to participate in this study. Healthy female subjects between 18 to 45 years of age
      will be enrolled in the study according to Inclusion/Exclusion Criteria listed below. They
      will be informed about the nature, aim and objectives of the study and will be required to
      give their written consent to participate in the study. The presence of the inclusion
      criteria and the absence of the exclusion criteria will be documented in the Case Report
      Forms (CRF).
    

Intervention name(s): testosterone undecanoate alone; testosterone undecanoate plus letrozole; testosterone undecanoate plus dutasteride
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 1000 mg/12 weeks; TU 1000 mg/12 weeks Letrozole 2.5 mg/day; TU 1000 mg/12weeks Dutasteride 0.5 mg/day
Other intervention name(s): Nebid; Nebid; Nebid; Avodart
Intervention MeSH terms: Letrozole; Methyltestosterone; Dutasteride; Testosterone; Testosterone undecanoate; Testosterone enanthate; Testosterone 17 beta-cypionate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: transsexualism; testosterone; dihydrotestosterone; estradiol