The primary objectives are to establish dose-response relationship for 2% transdermal testosterone (Tostran®) gel to achieve total testosterone serum concentrations between 1.5-2.5 nmol/l in transgender women after vaginoplasty and to assess side…
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Source
Brief title
Condition
- Endocrine disorders of gonadal function
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To establish dose-response relationship, the main study parameters are the
testosterone levels at different daily dosages of 2.5 mg (1/4th pump), 3.3 mg
(1/3rd pump) and 5 mg (1/2nd pump) at the short-term (minimum 2 weeks) and
after two months of continuous use. When testosterone levels between 1.5 and
2.5 nmol/l have been reached, the participants will continue on that dose for
two months in which testosterone levels are determined every month. At each
visit, changes in symptoms of androgenism are assessed which include facial and
bodily hair growth, alopecia, acne and application site symptoms.
Secondary outcome
Secondary endpoints include the evaluation of a clinical symptoms questionnaire
to assess the expected effects of changes in serum testosterone concentrations.
Finally, for participants who wish to participate in the elective part of the
study, feasibility of measuring changes in vaginal pulse amplitude (VPA) will
be assessed using photoplethysmography during different erotic stimuli.
Background summary
Transgender women have a female gender identity that does not match their
assigned male sex at birth. In order to induce secondary female
characteristics, transgender women may receive hormone therapy through
estradiol and anti-androgen therapy. Subsequently, transgender women may choose
to undergo a vaginoplasty where the testicles are removed and a neovagina is
created. After a vaginoplasty, testosterone levels are lower than those found
in ovulating cisgender women (female sex assigned at birth, female gender
identity), which may cause symptoms associated with hypogonadism such as
fatigue, depressed mood, cognitive decline, reduced sexual desire and
arousability. Low testosterone levels may also limit genital blood flow during
subjective sexual arousal. In postmenopausal cisgender women with low
testosterone levels and similar complaints, low-dose transdermal testosterone
therapy is recommended and has no severe side-effects. However, no adequate
testosterone formulation is available for use in women and dose-response
relationships differ after short-term and longer term serum analysis. One pilot
study in transgender women reported that low-dose testosterone supplementation
had a positive effect on symptoms of low sexual desire, but the dose to reach
physiological testosterone levels that are comparable to cisgender women, as
well as the prevalence of sides effects, currently remain unknown.
Study objective
The primary objectives are to establish dose-response relationship for 2%
transdermal testosterone (Tostran®) gel to achieve total testosterone serum
concentrations between 1.5-2.5 nmol/l in transgender women after vaginoplasty
and to assess side effects of androgenism at the different dosages. Secondary
objectives are to assess the feasibility and applicability of a clinical
symptoms questionnaire.
Finally, in a subgroup of participants who provide additional consent for an
elective part of the study, we aim to assess the feasibility of vaginal pulse
amplitude measurements using photoplethysmography.
Study design
This is a non-blinded pilot study with two phases: a step-wise dose-titration
phase and a dose-continuation phase.
Intervention
During the study, participants will receive 2% transdermal testosterone gel
(Tostran®) daily. During the dose-titration phase, participants will receive
daily doses of 2% transdermal testosterone gel (Tostran®) at 2.5 mg (1/4th
pump), optionally 3.3 mg (1/3rd pump) and optionally 5 mg (1/2nd pump) in a
step-up scheme in three to four week intervals. Considering the bioavailability
of 12% of Tostran®, this amounts to 300 ug/day for the first two weeks, 396
ug/day during the next four weeks and 600 ug/day during the final four weeks.
When a total testosterone serum concentration between 1.5 and 2.5 nmol/l has
been reached, no further dose-increase will take place and participants will
enter the dose-continuation phase where they continue on the established daily
dose for two months.
Study burden and risks
The dose-titration phase will include maximum four one-hour visits to the
clinic: at baseline and at two weeks for all participants and at six after
baseline for participants whose receive a first dose-increase and at ten weeks
after baseline for participants who receive a second dose-increase. When
participants have a serum total testosterone level between 1.5-2.5 nmol/l, they
will cease further dose-increase and remain on this dose for three months in
which they will visit the clinic every month for clinical evaluation where
side-effects are evaluated and blood is drawn. After signing informed consent,
participants will be asked to fill out a questionnaire to assess baseline
symptoms of adrogenism and clinical symptoms of hypogonadism. Afterwards, max
17.5 mL (4 tubes) blood will be drawn and weight, height, blood pressure and
heart rate will be measured. During the following visits in the dose-escalation
phase, blood will be drawn and side-effects of androgenism will be assessed. In
the two month dose-continuation phase, participants will visit the clinic
monthly and side-effects are assessed and blood is drawn. Additionally, at the
final visit, the clinical symptoms questionnaire will be filled in. During the
study, participants will continue their regular visits to the gender clinic if
these have been scheduled and we aim to schedule these on the same day as a
study visit. The risk associated with the investigational treatment are
expected to be limited and reversible. The mildly increased levels of
testosterone may cause slightly increased facial and body hair, slight weight
increase and mild acne. The application of the gel may cause dryness of the
skin at the application site. An uncommon side effect may be alopecia. A rarely
reported side effect in cisgender women is deep venous thrombosis, but it is
likely that this risk arises from the concurrent use of estrogens that
transgender women are already using before the study. Studies show no increased
risk of polycythemia and adverse lipid profiles when using transdermal
application at these low concentrations(1). There is no risk of voice changes
because the irreversible deepening of the voice associated with testosterone
has already taken place in transgender women who underwent physiological
puberty and initiated hormone therapy after 18 years of age. Available data
suggest that short-term transdermal testosterone therapy does not impact breast
cancer risk.
Boelelaan 1117
Amsterdam 1081 HV
NL
Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
- Start of gender affirming hormone therapy at or after 18 years of age
- Current use of estradiol therapy with good compliance for at least one year
- Underwent vaginoplasty
- Sufficient knowledge of the Dutch language
- BMI 18-30 kg/m2
- Testosterone levels <0.8 nmol/l measured since vaginoplasty
- To participant in optional vaginal pulse amplitude measurement: minimal
self-reported vaginal depth of five centimeters
Exclusion criteria
- No regular follow-up visits at the clinic for gender dysphoria
- Previous use of testosterone therapy
- Current treatment for depression
- Severe familial dyslipidemia (e.g. Familial Hypercholesterolemia)
- Serum estradiol concentration lower than 150 pmol/l or higher than 700
pmol/L the VUmc reference range (150-700 pmol/L) at last visit prior to
baseline.
- Mental health issues that prevent participation
- Hematocrit at last visit prior to baseline of >0.49 l/l
- Current use of anticoagulation treatment or corticosteroids
- Any of the following contraindications for the use of testosterone gel
(Tostran®): Known, past or suspected breast cancer; Known or suspected
estrogen-dependent malignant tumours (e.g genital tract carcinoma); Acute liver
disease, or a history of liver disease as long as liver function tests have
failed to return to normal (<2.5xULN); Porphyria; Cerebral hemorrhage; Known
hypersensitivity to the active substances or to any of the excipients
(Propylene glycol, Ethanol anhydrous, Isopropyl alcohol, Oleic acid, Carbomer
1382, Trolamine, Butylhydroxytoluene (E321), Hydrochloric acid (used for pH
adjustment)); Interfering medication (SPC).
Design
Recruitment
Medical products/devices used
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-005344-30-NL |
| CCMO | NL79312.029.22 |