2442

ORIGINAL RESEARCH—ENDOCRINOLOGY

Effects of Testosterone Undecanoate Administered Alone or

in Combination with Letrozole or Dutasteride in Female to
Male Transsexuals

Maria Cristina Meriggiola, MD, PhD,* Francesca Armillotta, MD,* Antonietta Costantino, PhD,*
Paola Altieri, MD,* Farid Saad, DVM,†‡ Thomas Kalhorn, PhD,§ Anna Myriam Perrone, MD,*
Tullio Ghi, MD,* Carlotta Pelusi, MD,* and Giuseppe Pelusi, MD*
*Center for Reproductive Health, Department of Obstetrics and Gynecology, S. Orsola Hospital, University of Bologna,
Bologna, Italy; †Scientific Affairs Men’s Healthcare, Bayer Schering Pharma, Berlin, Germany; ‡Gulf Medical University,
Ajman, United Arab Emirates; §Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA

DOI: 10.1111/j.1743-6109.2008.00909.x

ABSTRACT

Introduction. Testosterone undecanoate (TU) has potential as androgen therapy for ovariectomized female to male
(FtM) transsexual subjects; however, the long-term physiologic effects of TU treatment, the significance of tes-
tosterone (T), and the T metabolites dihydrotestosterone (DHT) and estradiol (E) on specific outcome parameters
are currently unknown.
Aim. The aim of this study was to investigate the long-term treatment of TU with regard to bone metabolism, body
composition, and lipid profile in FtM subjects, and to evaluate the relationship between observed effects and
circulating levels of T, E, and DHT.
Main Outcome Measures. Circulating follicle-stimulating hormone, luteinizing hormone, T, E, DHT, and lipid
concentrations were measured, as well as bone metabolism, body composition, and insulin resistance.
Methods. This was a 1-year, randomized treatment, open-label, uncontrolled safety study. Fifteen ovariectomized
FtM subjects from an outpatient clinic were divided into three groups to receive TU 1,000 mg alone or in
combination with oral administration of letrozole (L) 2.5 mg/die or dutasteride (D) 0.5 mg/die for a period of 54
weeks.
Results. TU alone and TU + D treatments were successful in terms of hormone adjustment, did not result in any
adverse effects, and were well-tolerated. Bone mineral density decreased by an average of 0.9 g/cm2 in the TU + L
group, and the addition of D resulted in a failure to gain lean mass.
Conclusions. This study confirmed that TU is a successful and safe treatment for FtM subjects. These data indicate
that E has an important role in bone metabolism and that DHT may play a role in muscle metabolism. Meriggiola
MC, Armillotta F, Costantino A, Altieri P, Saad F, Kalhorn T, Perrone AM, Ghi T, Pelusi C, and Pelusi G.
Effects of testosterone undecanoate administered alone or in combination with letrozole or dutasteride in
female to male transsexuals. J Sex Med 2008;5:2442–2453.
Key Words. Testosterone Undecanoate; Letrozole; Dutasteride; FtM Transsexual; Bone Metabolism; Muscle

Introduction or estradiol (E), respectively. In both men and

women, E is known to modulate bone density [1]

T estosterone (T), produced by the testes in

men and in small amounts by the ovaries in
women, is metabolized by 5a-reductase or aro-
matase to produce dihydrotestosterone (DHT)
and the feedback mechanism of follicle-
stimulating hormone (FSH) and luteinizing
hormone (LH) secretion [2,3]. T and DHT regu-
late many physiologic functions predominantly

J Sex Med 2008;5:2442–2453 © 2008 International Society for Sexual Medicine

TU Treatment in FtM Transsexuals
through direct and indirect activation of the
androgen receptor (AR) [4,5], including spermato-
genesis, muscle protein metabolism, plasma lipid
levels, and erythropoiesis. The presence of ARs
has been detected in a range of male and female
gonadal and nongonadal tissues [6–9], suggesting a
level of ubiquity for potential androgen sensitivity
that is not gender specific. For example, low levels
of T exert effects on female physiology and syn-
thetic T is administered in postmenopausal sub-
jects to alleviate symptoms of sexual dysfunction as
part of hormone replacement therapy [10,11].
Exogenous T can be used to restore physiologic
T levels in hypogonadal men and is also beneficial
in a range of other nongonadal diseases such as to
treat muscle wasting syndromes, hematologic dis-
orders, renal disease, and for male hormonal
contraception [12–16]. The pharmacologic and
pharmacokinetic profile of steroidal AR ligands is
limited by undesirable and potentially serious side
effects such as hepatotoxicity, while a lack of tissue
specificity leads to both anabolic and androgenic
effects [17]. The development of selective andro-
gen receptor modulators (SARMs) with strong
agonist activity in the pituitary, muscle, and bone,
but weak stimulation of prostate tissue is the
current focus of preclinical studies for treatments
targeting anabolic T replacement and osteoporosis
in men and women [18,19]. A greater understand-
ing of the specific physiologic functions targeted
by T, DHT, and E will aid the development of
SARM treatments and hormone replacement
therapies.
Testosterone undecanoate (TU) is available as a
relatively long-acting nonhepatotoxic oral steroid
therapy for the treatment of T deficiency. The
midchain undecanoate fatty acid molecule, present
at the 17b-position, enhances solubility in oil and,
therefore, TU bypasses the liver by entering the
lymphatic system. However, clinical regimens
have been shown to be most effective when pro-
vided as an intramuscular injection [20]. TU has a
favorable pharmacokinetic and safety profile as a
treatment for male androgen deficiency in
hypogonadal patients [20,21] and positive effects
have been observed on bone, muscle, and meta-
bolic parameters without any adverse effects [22].
Recent reports also indicated that TU treatment
was successful in the gender reassignment of
female to male (FtM) transsexual subjects [23,24],
providing levels of T, DHT, and E within the
normal range for men. Using a previously devised
protocol [21,25], two initial injections of TU were
administered with a 6-week interval, and subse-
2443
quent doses were injected at 12-week intervals.
Secondary male characteristics were attained, and
biochemical analysis showed significant decreases
in plasma cholesterol and low-density lipoprotein
(LDL) [23], LH, prolactin (PRL), sex hormone
binding globulin (SHBG), triglycerides, and
increases in hemoglobin and hematocrit [24]. Adi-
ponectin and leptin were significantly decreased in
FtM subjects after 6 months of treatment with a
different T ester, testosterone enanthate (TE) [26].
High-density lipoprotein (HDL) was significantly
lower [24,26] or unchanged [23] after treatment.
Certain cardiovascular risk factors were also iden-
tified following T ester treatment of FtMs [27,28],
although it was recently reported that HDL levels
following TU treatment of FtM subjects were
within a range that was not considered to represent
cardiovascular risk [23].
In this study, we administered TU injections
following previously reported schedules alone or in
combination with the 5a-reductase inhibitor
dutasteride (D) or with the aromatase inhibitor
letrozole (L) to ovariectomized FtM transsexuals.
The aim of this pilot study was to evaluate whether
ovariectomized FtM transsexuals would serve as a
model to understand the effects of T and its
metabolites DHT and E on the reproductive hor-
mones and relevant biochemical, bone, and anthro-
pometric parameters. The absence of gonads in
these subjects removes potentially confounding
effects of gonadal products allowing a more clear
separation of the effects of different steroids. These
data will provide important information that will
help both to optimize T replacement in FtM or
hypogonadal subjects, and develop specific and
selective androgen receptor modulators.
Study Design and Methods
Subjects
Study participants were healthy FtM volunteers
(N = 15), aged 18–45 years and a body mass index
(BMI) within the range of 20–29 kg/m2. All sub-
jects had previously experienced elective hysterec-
tomy and adnexectomy surgery and required T
therapy in order to attain and maintain secondary
male characteristics. All subjects received injec-
tions of Testoviron depot 100 mg (Bayer Schering
Pharma, Berlin, Germany) every 7–15 days (TE
110 mg + testosterone propionate 25 mg). The
length of previous T treatment was 71.4 ⫾ 30.5,
52.4 ⫾ 18.1, and 72.0 ⫾ 25.5 (months) in group
TU alone, TU + D, and TU + L, respectively
(mean ⫾ standard deviation [SD]), P = not signifi-
J Sex Med 2008;5:2442–2453
2444
cant (n.s.) among groups. All subjects had received
their last T injection at least 15 days before the
first visit (baseline). The subjects were informed of
the nature, aims, and objectives of the trial, and all
gave written consent before participation. The
study was approved by the Ethical Committee of
S. Orsola Hospital, Bologna.
Treatment
TU (Nebido, Bayer Schering Pharma) (generously
donated by the drug company), L (Femara, Novar-
tis Pharma, Varese, Italy), and D (Avodart, Glaxo-
SmithKline, Verona, Italy).
During a 3-week control period prior to the
start of the study, the subjects provided three
fasting blood samples and a single urine sample for
the determination of baseline measurements.
Thereafter, the subjects were randomly divided
into three groups to receive TU alone (1,000 mg/
injection) (group TU alone), TU (1,000 mg/
injection) plus L (2.5 mg/day, orally) (group
TU + L), or TU (1,000 mg/injection) plus D
(0.5 mg/day, orally) (group TU + D). TU injec-
tions were performed at weeks 0, 6, 18, 30, and 42.
All blood samples were withdrawn after 10
hours of fasting, in the morning between 8:00 and
10:00 am, immediately prior to each dose admin-
istration, and serum fractions were stored at -80°C
until required.
Anthropometric and Bone Parameters
At baseline and at week 54 of treatment, body
composition and bone mineral density ([BMD]
g/cm2) at the lumbar spine were measured by dual
X-ray absorptiometry using the Hologic 49159
densitometer and standard QDR body composi-
tion software (Model QDR4500W, Software Level
11.2, Hologic Spine, Hologic, Bedford, MA,
USA). Standardization of the densitometer was
performed daily using a body composition calibra-
tion phantom, and the same doctor (P.A.) and
densitometer were used throughout the study to
minimize errors due to the technique. The intra-
person coefficient of variation was 0.40% for L.M.
and 0.96% for total body fat. T and Z scores were
calculated using the female database provided by
the manufacturer.
Body weight and height measurements were
recorded to the nearest 0.1 kg and the nearest
0.5 cm, respectively. Waist and hip circumferences
were measured according to the World Health
Organization recommendations [29] at every visit,
by the same person (F.A.).
J Sex Med 2008;5:2442–2453
Meriggiola et al.
Serum levels of osteocalcin (OC) (ng/mL),
bone-specific alkaline phosphatase (BALP) (UI/
L), parathormone (PTH) (pg/mL), and calcium
(Ca) and phosphorous (P) (mg/dL) were also mea-
sured as previously described [30].
Levels of Circulating Hormones
Blood samples for hormone measurements were
stored at -80°C and assayed at the end of the study
period; all the samples were run in the same assay.
Serum levels of LH, FSH, and SHBG were
measured by highly specific time-resolved fluor-
oimmunoassays (DELFIA, Wallac Inc., Turku,
Finland).
T was measured by RIA (TKTT5, Diagnostic
Products Corporation, Los Angeles, CA, USA).
The lower limits of quantitation were 0.019 IU/L,
0.016 IU/L, 0.35 nmol/L, and 1.56 nmol/L for
LH, FSH, T, and SHBG, respectively. Mean intra-
assay coefficients of variation were 10.5% and 5%
for LH, 8.3% and 2.3% for FSH, 10% and 6.6%
for T, and 3.8% and 2.2% for SHBG in the low
and high parts of the standard curve, respectively.
Mean interassay coefficients of variation were
20.5% and 9.6% for LH, 16.8% and 4.3% for
FSH, 13.6% and 6.8% for T, and 3.1% and 6.8%
for SHBG in the low and high parts of the stan-
dard curve, respectively.
E was measured by RIA (DSL-39100, Diag-
nostic System Laboratories, Inc., Webster, TX,
USA). The lower limit of quantification was
5.5 pmol/L. Mean intra-assay coefficient of varia-
tions (CVs) in the low and high parts of the stan-
dard curve were 5.6% and 5.3%.
Serum DHT was analyzed as the oxime deriva-
tive by HPLC/MS/MS (PPD-Pharmaco, Rich-
mond, VA, USA). Intra- and interassay CVs were
11.6% and 19.2%, respectively. The detection
limit of the assay was between 1 and 10 pg/mL,
depending on the particular assay run. Calibration
curves resulted in correlation coefficients of
r ⱖ 0.99 over the standard concentration range of
10–1,000 pg/mL [31].
PRL was measured by immunochemilumines-
cent assay (ADVIA Centaur, Chiron Diagnostic,
Los Angeles, CA, USA). The lower limit of quan-
tification of the assay was 6.4 ng/mL. Mean intra-
assay CV was 5.0%.
Blood, Lipid, Glucose, and Insulin Profiles
Standard laboratory assays for hemoglobin, hema-
tocrit, total cholesterol, triglycerides, HDL cho-
lesterol, LDL cholesterol, glucose and insulin,
aspartate aminotransferase, alanine aminotrans-
TU Treatment in FtM Transsexuals
ferase, total bilirubin, blood urea nitrogen, and
creatinine were performed as previously reported
[32].
Skin Irritation and Safety Parameters
Acne was assessed by the modified Cook method
(score from 0 to 9 for diffusion of the lesions on
the face) [33].
Statistical Analysis
Many of the continuous variables were expressed
in terms of mean ⫾ SD of the mean. When the
distributions were strongly asymmetric, mean ⫾
SD of log transformed variables or median, and
75th–25th percentile were used.
The percentage of variations (used when basal
values were different from zero) was calculated
as follows: (values at different follow-up
times - values at basal time) ¥ 100/values at basal
time.
The percentage of logarithmic variations (used
when basal values could be close to zero) was cal-
culated as follows: 100 ¥ LOG (values at different
follow-up times/values at basal time).
The Wilcoxon test evaluated by the Monte
Carlo method for small samples was performed
to test the hypotheses of changes at different
follow-up times.
The Mann–Whitney test evaluated by the
Monte Carlo method for small samples was per-
formed to test the hypotheses about the differ-
ences between TU alone and TU + L or TU + D.
For all tests, P < 0.05 was considered significant.
Statistical analysis was carried out by means of
the Statistical Package for the Social Sciences soft-
ware version 14.0 (SPSS Inc., Chicago, IL, USA).
Results
All the 15 enrolled subjects completed the study.
There were no reports of adverse events during
the study, and the injections were well-tolerated.
Four subjects complained of discomfort and mild
pain after the injections and reported indurations
at the injection sites lasting for 2–3 days. Two
subjects in the TU + L treatment group developed
severe facial acne with a Cook score of >6, but the
subjects continued to receive treatment.
Hormones
Baseline levels and changes in serum reproductive
hormones throughout treatment are summarized
in Figures 1 and 2, and Tables 1 and 2. At baseline,
2445
no significant difference was found between
the TU-alone and TU + D or TU + L groups
(Table 1).
Mean serum total T levels tended to increase in
all three groups as compared with the baseline but
were statistically significantly increased only in
groups TU + D and TU + L (week 54 vs. baseline:
TU + D and TU + L [P = 0.043]; TU alone
[P = n.s.] Figure 1). At week 54, percentage change
from baseline did not differ among the three
groups (Table 2).
Mean serum E levels tended to increase in the
TU-alone and TU + D groups and remained
stable in the TU + L group. At week 54, percent-
age change from baseline was significantly differ-
ent in the TU + L group as compared with the
TU-alone group (Table 2).
Mean serum DHT levels were significantly
increased in the TU-alone and TU + L groups
(week 54 vs. baseline: TU alone [P = 0.047];
TU + L [P = 0.019]). Percentage DHT decrease
from baseline was significant in the TU + D
group as compared with the TU-alone group
(Table 2).
Plasma SHBG levels did not show any signifi-
cant changes in the TU-alone and TU + D groups
but significantly decreased in the TU + L group
(week 54 vs. baseline [P = 0.043]).
Percentage change of T/E was significantly
increased in the TU + L group as compared with
the TU-alone group (Table 2).
At week 54, FSH and LH levels significantly
decreased as compared with the baseline in the
TU-alone group (week 54 vs. baseline LH:
P = 0.043; FSH: P = 0.043), decreased without
achieving significance in the TU + D group, and
tended to be higher than the baseline in the
TU + L group (P = n.s.) (Figure 2).
No significant changes of PRL levels was
detected in any groups at any times.
Anthropometric and Bone Parameters
Changes in anthropometric parameters resulting
from the TU, TU + L, and TU + D treatment of
FtM subjects are presented in Tables 2 and 3. A
tendency toward an increase in mean body weight,
waist circumference, waist to hip ratio (WHR),
and lean mass in the TU-alone and TU + L
groups at the end of the study was observed, as
compared with the baseline data (Table 3). Mean
waist circumference and lean mass values were
unchanged in the TU + D group, while a tendency
toward a decrease in body weight and fat mass
J Sex Med 2008;5:2442–2453
 2446 Meriggiola et al.
1,6 2,5

A B
1,4 TU
TU + D
1,2 TU + L
2,0
log total T (nmol/L)

log E (pmol/L)
1,0

0,8
1,5
0,6

0,4

1,0
0,2

0,0 0,0
baseline wk 6 wk 18 wk 30 wk 42 wk 54 baseline wk 6 wk 18 wk 30 wk 42 wk 54

Time (weeks) Time (weeks)

2,5 1,0

C D

2,0
0,5
log SHBG (nmol/L)

log DHT (nmol/L)

1,5

0,0

1,0

-0,5
0,5

0,0 -1,0
baseline wk 6 wk 18 wk 30 wk 42 wk 54 baseline wk 6 wk 18 wk 30 wk 42 wk 54

Time (weeks) Time (weeks)

Figure 1 Mean (⫾standard deviation) nadir serum log total testosterone (T) (A), estradiol (E) (B), sex hormone binding
globulin (SHBG) (C), and dihydrotestosterone (DHT) (D) in the three groups of subjects. TU = testosterone undecanoate;
D = dutasteride; L = letrozole.

were observed at the end of the treatment period
in this group. The increase in WHR for TU + D
group was similar to changes recorded for TU and
TU + L groups. There were no statistically signifi-
cant differences in percentage changes of anthro-
pometric parameters between TU treatment
and TU + L. The only significant difference
between TU and TU + D occurred because of the
failure of D-treated subjects to gain lean mass
(Table 2).
Bone metabolism was significantly affected by
the addition of L to TU treatment; BMD, T score,
and Z score were significantly lower in the TU +
L group compared with the TU-alone group
(P = 0.008 for BMD, T score, and Z score; see
Table 2). BMD, T score, and Z score did not show
any statistically significant change in the TU-alone
and TU + D groups, although in the TU-alone
group, there was a tendency toward an increase of
these parameters at the end of the study period
(Table 3).
The effects of the addition of L were also
observed on serum markers of bone metabolism
including a relatively large, although not signifi-
cant, increase in mean end-point levels of osteo-
calcin compared with a small decrease in the
TU-alone group. PTH levels tended to increase in
the TU-alone and TU + D groups and slightly
decreased in the TU + L group. The effects of L
on the aforementioned markers were not reflected
in recorded serum levels of free calcium and potas-
sium, which were similar between the three patient
treatment groups.
Lab Tests
With regard to general biochemical parameters,
which are presented in Table 4, there was an
increase in mean hemoglobin and hematocrit
levels that was similar among subjects of all treat-
ment groups.
Fasting levels of total serum cholesterol, HDL
cholesterol, LDL cholesterol, and triglycerides did
not show any significant changes in any groups
throughout the study.

J Sex Med 2008;5:2442–2453

TU Treatment in FtM Transsexuals 2447

TU
20 TU + D
TU + L

LH (log% change from baseline)

0

-20

-40

-60

-80

-100
baseline wk 6 wk 18 wk 30 wk 42 wk 54

Time (weeks)

20
FSH (log% change from baseline)

-20

-40

-60

Figure 2 Mean log percentage

change from baseline of serum -80
luteinizing hormone (LH) and
follicle-stimulating hormone (FSH)
-100
in the three groups of subjects.
baseline wk 6 wk 18 wk 30 wk 42 wk 54
TU = testosterone undecanoate; D =
dutasteride; L = letrozole. Time (weeks)

Glucose, insulin, and Homeostasis Model Discussion

Assessment (HOMA) results for the three treat-
ment groups were not significantly different from The aim of this study was to determine whether
the baseline. ovariectomized FtM subjects represent a good
There were no changes in any other lab tests in model to evaluate the safety of long-term TU
any groups throughout the study period. administration and to collect information on the

Table 1 Mean ⫾ standard deviation (SD) parameters at baseline in the three groups of subjects
Mean ⫾ SD P

TU alone TU + D TU + L TU vs. TU + D TU vs. TU + L

Age (years) 34.4 ⫾ 4.39 36.0 ⫾ 4.58 36.6 ⫾ 5.86 0.42 0.69
BMI (kg/m2) 22.15 ⫾ 2.13 23.80 ⫾ 2.46 23.94 ⫾ 3.36 0.31 0.55
FSH (IU/L) 37.30 ⫾ 27.77 28.94 ⫾ 27.25 49.92 ⫾ 24.01 0.84 0.55
LH (IU/L) 24.64 ⫾ 22.26 24.02 ⫾ 22.08 32.98 ⫾ 18.44 0.84 0.69
TT (nmol/L) 7.91 ⫾ 6.04 7.12 ⫾ 6.31 4.76 ⫾ 4.83 1.00 0.55
E (pmol/L) 64.4 ⫾ 43.4 41.4 ⫾ 19.4 37.8 ⫾ 23.1 0.42 0.31
SHBG (nmol/L) 23.0 ⫾ 9.14 27.6 ⫾ 14.26 41.2 ⫾ 21.34 0.53 0.22
DHT (nmol/L) 1.29 ⫾ 1.2 0.94 ⫾ 0.7 0.88 ⫾ 0.8 0.69 0.42
PRL (ng/mL) 9.00 ⫾ 4.30 10.00 ⫾ 4.18 11.60 ⫾ 6.80 0.69 0.77
T/E (nmol/L/pmol/L) 0.12 ⫾ 0.08 0.21 ⫾ 0.13 0.10 ⫾ 0.12 0.27 0.73

TU = testosterone undecanoate; D = dutasteride; L = letrozole; BMI = body mass index; FSH = follicle-stimulating hormone; LH = luteinizing hormone; TT = total
testosterone; E = estradiol; SHBG = sex hormone binding globulin; DHT = dihydrotestosterone; PRL = prolactin; T/E = testosterone/estradiol.

J Sex Med 2008;5:2442–2453

2448 Meriggiola et al.

Table 2 Percentage of logarithmic variations (median, 75th–25th percentile) at week 54 as compared with the baseline
in the three groups of subjects
Groups P value
Parameters TU alone TU + D TU + L TU vs. TU + D TU vs. TU + L
FSH (IU/L) -25.4 (96.6) -30.4 (83.6) 3.7 (29.6) 0.225 0.055
LH (IU/L) -35.0 (127.0) -47.9 (106.3) -1.6 (47.5) 0.308 0.031
TT (nmol/L) 25.2 (10.3) 34.9 (55.3) 98.1 (89.5) 0.323 0.087
E (pmol/L) 28.3 (29.5) 21.5 (51.1) -19.4 (50.1) 1.000 0.012
SHBG (nmol/L) –7.0 (9.8) 25.0 (10.4) -22.3 (9.5) 0.096 0.150
DHT (nmol/L) 35.1 (40.8) -40.9 (50.7) 44.3 (43.5) 0.014 0.557
PRL (ng/mL) 0.0 (23.3) 0.0 (12.2) 72.1 (27.9) 0.833 0.222
T/E (nmol/L/pmol/L) 7.2 (66.0) 15.9 (35.0) 130.6 (69.2) 0.737 0.028
OC (ng/mL) -19.2 (30.5) 36.0 (57.3) 67.4 (101.6) 0.548 0.095
BALP (UI/L) -25.0 (55.4) -13.3 (51.9) 0.0 (13.6) 0.841 0.841
Ca (mg/dL) 0.0 (6.5) 2.2 (3.3) 6.5 (9.8) 1.000 0.841
P (mg/dL) 13.3 (26.8) 13.9 (26.3) 22.6 (31.2) 0.516 0.548
PTH (pg/mL) 60.0 (47.9) 55.9 (58.4) -6.3 (28.8) 1.000 0.151
BMD
Lumbar spine
Density (g/cm2) 2.1 (2.1) 0.1 (3.5) -7.6 (5.0) 0.310 0.008
Z score 0.2 (20.0) 0.1 (30.0) -0.7 (70.0) 0.310 0.008
T score 0.2 (20.0) 0.3 (40.0) -0.7 (80.0) 0.881 0.008
Body weight (kg) 4.4 (2.6) -2.3 (2.7) 8.7 (10.9) 0.095 0.690
Waist circumference (cm) -3.3 (11.8) 0.0 (2.2) 3.8 (6.2) 1.000 0.310
WHR 1.0 (1.1) 4.8 (10.3) 4.7 (7.0) 0.841 0.310
Lean mass (kg) 5.0 (3.3) 2.3 (4.5) 4.7 (5.3) 0.016 0.548
Fat mass (kg) -4.2 (10.6) -13.4 (17.1) 13.4 (44.2) 0.421 0.841

TU = testosterone undecanoate; D = dutasteride; L = letrozole; FSH = follicle-stimulating hormone; LH = luteinizing hormone; TT = total testosterone; E = estradiol;
SHBG = sex hormone binding globulin; DHT = dihydrotestosterone; PRL = prolactin; T/E = testosterone/estradiol; OC = osteocalcin; BALP = bone-specific alkaline
phosphatase; Ca = calcium; P = phosphorus; BMD = bone mineral density; PTH = parathormone; WHR = waist–hip ratio. Bold text indicates P < 0.05.

effects of T and its metabolites E and DHT on treatment in ovariectomized FtM transsexuals.
different physiologic end points [23,24]. Our The inhibition of aromatization clearly shows to
results confirm that long-acting intramuscular TU negatively affect bone metabolism, while the inhi-
injection is an effective, safe, and well-tolerated bition of the 5a-reduction of T to DHT did not

Table 3 Mean ⫾ standard deviation (SD) bone and anthropometric variables at baseline and week 54 in the three
groups of subjects
Mean ⫾ SD
TU TU + D TU + L
Baseline Week 54 P Baseline Week 54 P Baseline Week 54 P
OC (ng/mL) 27.4 ⫾ 10.2 24.7 ⫾ 13.2 0.625 23.1 ⫾ 15.4 21.4 ⫾ 6.6 0.813 24.7 ⫾ 12.7 38.2 ⫾ 12.1 0.125
BALP (UI/L) 27.4 ⫾ 6.23 24.4 ⫾ 9.79 0.500 19.6 ⫾ 9.58 13.0 ⫾ 3.24 0.375 18.2 ⫾ 5.76 18.4 ⫾ 5.08 1.000
Ca (mg/dL) 9.32 ⫾ 0.47 9.56 ⫾ 0.18 0.625 9.06 ⫾ 0.23 9.18 ⫾ 0.20 0.375 9.40 ⫾ 0.45 9.76 ⫾ 0.37 0.375
P (mg/dL) 3.40 ⫾ 0.96 3.50 ⫾ 0.63 0.875 3.36 ⫾ 0.56 3.84 ⫾ 0.62 0.250 3.36 ⫾ 0.38 4.02 ⫾ 0.36 0.125
PTH (pg/mL) 50.8 ⫾ 24.97 69.6 ⫾ 34.92 0.188 47.0 ⫾ 18.14 70.4 ⫾ 26.13 0.188 40.8 ⫾ 12.31 35.8 ⫾ 8.76 1.000
BMD
Lumbar spine
Density (g/cm2) 0.98 ⫾ 0.06 1.01 ⫾ 0.08 0.063 1.01 ⫾ 0.15 1.01 ⫾ 0.13 1.000 1.02 ⫾ 0.95 0.93 ⫾ 0.10 0.063
Z score -0.50 ⫾ 0.54 -0.20 ⫾ 0.72 0.063 -0.28 ⫾ 1.23 -0.22 ⫾ 1.02 0.875 -0.18 ⫾ 0.79 -1.00 ⫾ 0.70 0.063
T score -0.58 ⫾ 0.57 -0.30 ⫾ 0.69 0.063 -0.40 ⫾ 1.27 -0.14 ⫾ 1.31 0.250 -0.28 ⫾ 0.86 -1.12 ⫾ 0.79 0.063
Body weight (kg) 60.33 ⫾ 6.20 62.87 ⫾ 6.75 0.063 63.51 ⫾ 9.18 62.27 ⫾ 8.84 0.438 63.14 ⫾ 12.09 65.64 ⫾ 9.85 0.313
Waist circumference 86.2 ⫾ 4.82 87.6 ⫾ 4.28 0.750 83.6 ⫾ 7.50 83.4 ⫾ 6.50 1.000 84.4 ⫾ 9.10 89.4 ⫾ 6.88 0.125
(cm)
WHR 0.91 ⫾ 0.03 0.93 ⫾ 0.05 0.438 0.86 ⫾ 0.06 0.88 ⫾ 0.03 0.438 0.88 ⫾ 0.06 0.92 ⫾ 0.04 0.063
Lean mass (kg) 42.90 ⫾ 3.31 45.60 ⫾ 4.16 0.063 45.14 ⫾ 4.61 45.20 ⫾ 4.83 0.813 45.52 ⫾ 6.99 47.26 ⫾ 7.35 0.188
Fat mass (kg) 15.28 ⫾ 4.23 15.10 ⫾ 3.67 1.000 16.74 ⫾ 6.62 15.27 ⫾ 4.79 0.438 16.22 ⫾ 4.72 16.30 ⫾ 4.06 1.000

TU = testosterone undecanoate; D = dutasteride; L = letrozole; OC = osteocalcin; BALP = bone-specific alkaline phosphatase; Ca = calcium; P = phosphorus;
PTH = parathormone; BMD = bone mineral density; WHR = waist–hip ratio.

J Sex Med 2008;5:2442–2453

TU Treatment in FtM Transsexuals 2449

Table 4 Mean ⫾ standard deviation (SD) biochemical and hematologic variables at baseline and week 54 in the three
groups of subjects
Mean ⫾ SD
TU alone TU + D TU + L
Baseline Week 54 P Baseline Week 54 P Baseline Week 54 P
Tot chol (mmol/L) 4.86 ⫾ 0.92 4.64 ⫾ 0.83 0.813 4.82 ⫾ 0.70 5.23 ⫾ 0.99 0.625 4.84 ⫾ 0.68 5.09 ⫾ 0.74 0.750
HDL (mmol/L) 1.55 ⫾ 0.46 1.48 ⫾ 0.18 1.000 1.46 ⫾ 0.39 1.58 ⫾ 0.24 0.438 1.60 ⫾ 0.29 1.36 ⫾ 0.23 0.250
Triglycerides (mmol/L) 1.41 ⫾ 0.84 1.33 ⫾ 0.74 0.625 0.87 ⫾ 0.48 1.28 ⫾ 0.98 0.188 1.04 ⫾ 0.53 1.32 ⫾ 0.69 0.063
LDL (mmol/L) 2.67 ⫾ 0.78 2.54 ⫾ 0.59 0.813 2.96 ⫾ 0.55 3.06 ⫾ 0.93 0.813 2.77 ⫾ 0.72 3.13 ⫾ 0.62 0.188
AST (U/L) 22.4 ⫾ 5.32 20.0 ⫾ 7.31 0.125 20.0 ⫾ 4.18 21.6 ⫾ 5.18 0.625 23.2 ⫾ 2.95 22.8 ⫾ 4.27 0.875
ALT (U/L) 19.0 ⫾ 3.39 19.4 ⫾ 8.05 1.000 13.8 ⫾ 3.96 21.8 ⫾ 13.01 0.125 25.8 ⫾ 8.67 26.4 ⫾ 9.18 1.000
Total bilirubin 0.89 ⫾ 0.67 0.68 ⫾ 0.40 0.313 0.57 ⫾ 0.20 0.56 ⫾ 0.28 1.000 1.18 ⫾ 1.35 1.20 ⫾ 1.30 1.000
Urea 0.30 ⫾ 0.08 0.32 ⫾ 0.04 0.500 0.30 ⫾ 0.05 0.28 ⫾ 0.05 0.500 0.30 ⫾ 0.07 0.38 ⫾ 0.05 0.125
Creatinine 0.99 ⫾ 0.16 1.02 ⫾ 0.15 0.438 0.94 ⫾ 0.08 1.03 ⫾ 0.19 0.188 1.00 ⫾ 0.08 1.12 ⫾ 0.05 0.063
Total proteins 7.56 ⫾ 0.34 7.32 ⫾ 0.29 0.125 7.24 ⫾ 0.36 7.20 ⫾ 0.48 0.500 7.72 ⫾ 0.29 7.52 ⫾ 0.18 0.438
Insulin (mU/mL) 6.4 ⫾ 2.07 8.6 ⫾ 3.36 0.313 4.4 ⫾ 1.34 7.4 ⫾ 4.62 0.125 7.8 ⫾ 2.86 7.5 ⫾ 1.73 0.750
Glucose (mmol/L) 4.52 ⫾ 0.40 4.52 ⫾ 0.48 1.000 4.35 ⫾ 0.34 4.37 ⫾ 0.29 0.625 4.70 ⫾ 0.31 4.35 ⫾ 0.49 0.250
HOMA 1.26 ⫾ 0.33 1.73 ⫾ 0.73 0.313 0.84 ⫾ 0.24 1.43 ⫾ 0.90 0.063 1.65 ⫾ 0.67 1.47 ⫾ 0.46 0.625
Hb (g/dL) 14.8 ⫾ 1.42 15.9 ⫾ 1.06 0.125 13.2 ⫾ 1.35 14.6 ⫾ 1.08 0.188 13.9 ⫾ 2.14 15.6 ⫾ 1.30 0.125
Hct (%) 42.7 ⫾ 2.84 45.7 ⫾ 3.07 0.063 40.8 ⫾ 4.94 44.4 ⫾ 2.03 0.313 40.9 ⫾ 4.75 44.6 ⫾ 2.79 0.313

TU = testosterone undecanoate; D = dutasteride; L = letrozole; Tot chol = total cholesterol; HDL = high-density lipoprotein; LDL = low-density lipoprotein;
AST = aspartate aminotransferase; ALT = alanine aminotransferase; HOMA = Homeostasis Model Assessment; Hb = hemoglobin; Hct = hematocrit.

seem to induce major effects except for an impair-
ment in gain of muscle mass that certainly deserves
further investigation.
This study confirms the safety of TU treatment,
and good levels of tolerance and compliance asso-
ciated with the successful outcome of TU therapy
[23,24]. Although a limited number of subjects
were treated, and a control group was not included
for ethical reasons, this model of gonadectomized
subjects allows for the detection of the beneficial
effects of exogenous T on muscle and bone in the
absence of endogenously produced steroids. All
subjects had previously received T injections, and
the length of previous T treatment and type of
treatment did not differ among the three groups of
subjects. This would suggest that the observed
effects of the different regimens used in the study
cannot be ascribed to previous treatments.
Through serum T levels measured just before the
next injection were above baseline in all subjects
(4.41–4.98 ng/mL) throughout the treatment
period. Although peak T levels were not measured
in this study, none of the subjects complained of
any androgen-excess symptoms, and hemoglobin
and hematocrit increased but remained within the
normal range at all time points in all subjects. At
the end of the study period, there was a tendency
toward an increase in body weight, which is
accounted for by the concomitant increase in lean
mass among subjects, and the mean end point and
BMD values were raised. There were no major
effects of TU treatment on liver markers, lipid
profile, or insulin resistance.
The individual physiologic effects of T and T
metabolites were investigated by manipulating TU
treatment regimens to inhibit the aromatase-
mediated conversion of T to E through the addi-
tion of L, or to inhibit the reduction of T to DHT
by 5a-reductase with D. Results from the TU + L
group showed that levels of circulating E were
significantly lower compared with the TU alone-
treated subjects; the mean end-point serum con-
centration of E was 80% and 94% higher in
TU-alone and TU + D groups, respectively, but
reduced by 28% in the TU + L group, which com-
pares well with other studies using aromatase
inhibitors in postmenopausal women, FtM trans-
sexuals, or in men [34–36]. Further effects of aro-
matase inhibition observed during this study
included the maintenance of baseline FSH and LH
levels compared with a significant drop in the
serum concentrations of these hormones in the
TU-alone subjects, suggesting that E played an
active regulatory role at the hypothamic/pituitary
level in agreement with previously published data
[35,37,38]. TU + L subjects also exhibited reduced
levels of SHBG, a factor that has been correlated
with a protective effect on cardiovascular risk, pos-
sibly through the interaction of sex steroid hor-
mones and lipid profiles [39].
The addition of L had no significant effects on
biochemical parameters, but there was a significant
negative impact on BMD, which dropped by an
average of 0.09 g/cm2 from the baseline measure-
ments in the TU + L group. Changes in serum
bone markers were also observed, including a ten-

J Sex Med 2008;5:2442–2453

2450
dency toward increased osteocalcin levels and
maintenance of baseline PTH levels in contrast
with increased end-point PTH concentration in
the TU-alone group. E has important effects on
bone metabolism because of the presence of aro-
matase and E receptors [40]. The inhibition of
aromatase by L has been shown to negate the
effects of E on pubertal epiphysial fusion, resulting
in increased adult growth height [41,42], and
although rare, cases of aromatase deficiency in
men are linked with low BMD and persistent
linear growth [43,44]. In women, bone mineral
loss and the associated risk of osteoporosis is a
well-documented consequence of the postmeno-
pausal decrease in E. Furthermore, L and anastro-
zole monotherapies are associated with an increase
in bone loss problems when administered as aro-
matase inhibitory breast cancer treatments [45,46].
In contrast, there was no report of changes in bone
metabolism in a previous study that tested the
effects of the aromatase inhibitor anastrozole
(1 mg/day) during TU treatment of FtM subjects
over a 3-month period [34]. It is thought that the
effects of L on BMD observed in the present study
may be because of the long-term nature of the
treatment regimen (2.5 mg/day for 54 weeks),
although it is also possible that L is more potent
than anastrozole in terms of targeting bone aro-
matase, as suggested by a previous report that L
was more effective than anastrozole in the suppres-
sion of estrone and estrone sulfate, but not E. The
addition of L to TU treatment did not signifi-
cantly affect the lipid profile or insulin resistance
of subjects, confirming the findings in a previous
trial of anastrozole treatment in mildly hypogo-
nadal elderly men [47].
The 5a-reductase inhibition obtained with the
administration of D led to a significant decrease in
serum DHT in TU + D group compared with the
TU-alone treatment group. The LH and FSH
suppression tended to be less profound in the
TU + D group as compared with the TU-alone
group. This observation may confirm previous
data suggesting a role of DHT in the regulation of
gonadotropin secretion [48–51]. TU + D subjects
did not gain lean mass, which was a significant side
effect compared with TU alone. The effects of
5a-reductase inhibitors on body weight and com-
position has never been thoroughly investigated.
In one study, the administration of finasteride led
to a decrease of BMI in the treatment group as
compared with the placebo [52]. In another more
recent study, the concomitant administration of
finasteride with TE led to a slightly lower body
J Sex Med 2008;5:2442–2453
Meriggiola et al.
weight gain, lean mass, and handgrip strength as
compared with the group of men treated with only
TE [53]. Muscle strength and power was not an
outcome measure in this study, but the results
from D treatment indicate that the specific role of
DHT in muscle mass deserves further investiga-
tion. There were no significant effects on liver,
lipid, or bone metabolism following TU + D
treatment.
The results of this study have confirmed the
safety of TU as a therapy for the maintenance of
T-dependent physiologic functions in FtM trans-
sexuals. In view of ongoing developments in the
field of SARMs, this study has also shown that
these subjects may represent a useful model to gain
information regarding the specific physiologic
targets and interactions of T, E, and DHT on
human physiology that will contribute toward suc-
cessful therapeutic indications in the future.
Acknowledgements
We gratefully acknowledge MS Dorothy McGuinness
in Dr. Bremner’s lab, for her excellent assistance in
the hormone assay performance. We thank Dr. WJ
Bremner for his advice and critical revision of the manu-
script. The authors would also like to thank Bayer-
Schering Pharma, Berlin, Germany for their generous
donation of TU (Nebido®).
Corresponding Author: Maria Cristina Meriggiola,
MD, PhD, Center for Reproductive Health, Gynecol-
ogy and Obstetrics Unit, University of Bologna, S.
Orsola Hospital, Via Massarenti 13––Bologna, Italy
40138. Tel: (39) 051-6363716; Fax: (39) 051-6363716;
E-mail: cristina.meriggiola@unibo.it
Conflict of Interest: None declared.
Statement of Authorship
Category 1
(a) Conception and Design
Farid Saad; Maria Cristina Meriggiola; Giuseppe
Pelusi
(b) Acquisition of Data
Francesca Armillotta; Paola Altieri; Antonietta
Costantino; Thomas Kalhorn
(c) Analysis and Interpretation of Data
Antonietta Costantino; Tullio Ghi; Anna Myriam
Perrone; Carlotta Pelusi; Maria Cristina Meriggiola
Category 2
(a) Drafting the Article
Antonietta Costantino; Maria Cristina Meriggiola
(b) Revising It for Intellectual Content
Farid Saad; Maria Cristina Meriggiola
TU Treatment in FtM Transsexuals
Category 3
(a) Final Approval of the Completed Article
Maria Cristina Meriggiola; Farid Saad; Carlotta
Pelusi; Francesca Armillotta; Thomas Kalhorn;
Giuseppe Pelusi; Antonietta Costantino; Anna
Myriam Perrone; Paola Altieri; Tullio Ghi
References
1 Napoli N, Faccio R, Shrestha V, Bucchieri S, Rini
GB, Armamento-Villareal R. Estrogen metabolism
modulates bone density in men. Calcified Tissue Int
2007;80:227–32. Epub April 4, 2007.
2 Finkelstein JS, Whitcomb RW, O’Dea LS, Long-
cope C, Schoenfeld DA, Crowley WF Jr. Sex steroid
control of gonadotropin secretion in the human
male. I. Effect of testosterone administration
in normal and gonadotropin-releasing hormone-
deficient men. J Clin Endocrinol Metab 1991;73:
609–20.
3 Finkelstein JS, O’Dea LS, Whitcomb RW, Crowley
WF. Sex steroid control of gonadotropin secretion
in the human male. II. Effect of E administration
in normal and gonadotropin-releasing hormone-
deficient men. J Clin Endocrinol Metab 1991;
73:621–8.
4 Hiort O, Zitzmann M. Androgen receptor: Patho-
physiology. In: Nieschlag E, Behre HM, eds. Tes-
tosterone action, deficiency and substitution. New
York: Cambridge University Press; 2004:93–124.
5 Brett MA, Roberts LF, Johnson TW, Wassersug RJ.
Eunuchs in contemporary society: Expectations,
consequences, and adjustments to castration (part
II). J Sex Med 2007;4:946–55.
6 Janssen PJ, Brinkmann AO, Boersma WJ, Van der
Kwast TH. Immunohistochemical detection of the
androgen receptor with monoclonal antibody F39.4
in routinely processed, paraffin-embedded human
tissues after microwave pre-treatment. J Histochem
Cytochem 1994;42:1169–75.
7 Guay A, Jacobson J. The relationship between tes-
tosterone levels, the metabolic syndrome (by two
criteria), and insulin resistance in a population of
men with organic erectile dysfunction. J Sex Med
2007;4:1046–55.
8 Vignozzi L, Morelli A, Filippi S, Ambrosini S,
Mancina R, Luconi M, Mungai S, Vannelli GB,
Zhang XH, Forti G, Maggi M. Testosterone regu-
lates RhoA/Rho-kinase signaling in two distinct
animal models of chemical diabetes. J Sex Med
2007;4:620–30; discussion 631–2.E.
9 Maggi M, Schulman C, Quinton R, Langham S,
Uhl-Hochgraeber K. The burden of testosterone
deficiency syndrome in adult men: Economic and
quality-of-life impact. J Sex Med 2007;4:1056–
69.
10 Kingsberg S. Testosterone treatment for hypoactive
sexual desire disorder in postmenopausal women. J
Sex Med 2007;4(3 suppl):227–34.
2451
11 Bolour S, Braunstein G. Testosterone therapy in
women: A review. Int J Impot Res 2005;17:399–408.
12 Nieschlag E, Behre HM. Clinical use of testoster-
one in hypogonadism and other conditions. In:
Nieschlag E, Behre HM, eds. Testosterone action,
deficiency and substitution. New York: Cambridge
University Press; 2004:375–403.
13 Yassin AA, Saad F. Improvement of sexual function
in men with late-onset hypogonadism treated with
testosterone only. J Sex Med 2007;4:497–501.
14 Corona G, Mannucci E, Petrone L, Balercia G,
Paggi F, Fisher AD, Lotti F, Chiarini V, Fedele D,
Forti G, Maggi M. NCEP-ATPIII-defined meta-
bolic syndrome, type 2 diabetes mellitus, and preva-
lence of hypogonadism in male patients with sexual
dysfunction. J Sex Med 2007;4:1038–45.
15 Corona G, Mannucci E, Petrone L, Schulman C,
Balercia G, Fisher AD, Chiarini V, Forti G, Maggi
M. A comparison of NCEP-ATPIII and IDF meta-
bolic syndrome definitions with relation to meta-
bolic syndrome-associated sexual dysfunction. J Sex
Med 2007;4:789–96.
16 Yassin AA, Saad F, Traish A. Testosterone unde-
canoate restores erectile function in a subset of
patients with venous leakage: A series of case
reports. J Sex Med 2006;3:727–35.
17 Gao W, Kim J, Dalton JT. Pharmacokinetics
and pharmacodynamics of nonsteroidal andro-
gen receptor ligands. Pharm Res 2006;23:1641–
58.
18 Kilbourne EJ, Moore WJ, Freedman LP, Nagpal S.
Selective androgen receptor modulators for frailty
and osteoporosis. Curr Opin Investig Drug 2007;
8:821–29.
19 Gao W, Dalton JT. Expanding the therapeutic use
of androgens via selective androgen receptor modu-
lators (SARMs). Drug Discov Today 2007;12:241–8.
Epub February 7, 2007.
20 Zhang GY, Gu YQ, Wang XH, Cui YG, Bremner
WJ. A pharmacokinetic study of injectable testoster-
one undecanoate in hypogonadal men. J Androl
1998;19:761–8.
21 Schubert M, Minnemann T, Hubler D, Rouskova
D, Christoph A, Oettel M, Ernst M, Mellinger U,
Krone W, Jockenhovel F. Intramuscular testoster-
one undecanoate: Pharmacokinetic aspects of a
novel testosterone formulation during long-term
treatment of men with hypogonadism. J Clin Endo-
crinol Metab 2004;89:5429–34.
22 Saad F, Kamischke A, Yassin A, Zitzmann M, Schu-
bert M, Jockenhel F, Behre HM, Gooren L,
Nieschlag E. More than eight years’ hands-on expe-
rience with the novel long-acting parenteral tes-
tosterone undecanoate. Asian J Androl 2007;9:291–
7.
23 Jacobeit JW, Gooren LJ, Schulte HM. Long-acting
intramuscular testosterone undecanoate for treat-
ment of female-to-male transgender individuals. J
Sex Med 2007;4:1479–84.
J Sex Med 2008;5:2442–2453
2452
24 Mueller A, Kiesewetter F, Binder H, Beckmann
MW, Dittrich R. Long-term administration of
testosterone undecanoate every 3 months for tes-
tosterone supplementation in female-to-male trans-
sexuals. J Clin Endocrinol Metab 2007;92:3470–5.
Epub June 19, 2007.
25 Harle L, Basaria S, Dobs AS. Nebido: A long-acting
injectable testosterone for the treatment of male
hypogonadism. Expert Opin Pharmacother 2005;
6:1751–9.
26 Berra M, Armillotta F, D’Emidio L, Costantino A,
Martorana G, Pelusi G, Meriggiola MC. Testoster-
one decreases adiponectin levels in female to male
transsexuals. Asian J Androl 2006;8:725–9. Epub
July 11, 2006.
27 Elbers JM, Giltay EJ, Teerlink T, Scheffer PG, Ass-
cheman H, Seidell JC, Gooren LJ. Effects of sex
steroids on components of the insulin resistance
syndrome in transsexual subjects. Clin Endocrinol
(Oxf) 2003;58:562–71.
28 Giltay EJ, Toorians AW, Sarabdjitsingh AR, de
Vries NA, Gooren LJ. Established risk factors for
coronary heart disease are unrelated to androgen-
induced baldness in female-to-male transsexuals. J
Endocrinol 2004;180:107–12.
29 World Health Organization. Physical status: The
use and interpretation of anthropometry. Report of
a WHO Expert Committee. World Health Organ
Tech Rep Ser 1995;854:1–452.
30 Caudarella R, Vescini F, Buffa A, Sinicropi G,
Rizzoli E, La Manna G, Stefoni S. Bone mass loss in
calcium stone disease: Focus on hypercalciuria and
metabolic factors. J Nephrol 2003;16:260–6.
31 Kalhorn TF, Page ST, Howald WN, Mostaghel
EA, Nelson PS. Analysis of testosterone and dihy-
drotestosterone from biological fluids as the
oxime derivatives using high-performance liquid
chromatography/tandem mass spectrometry. Rapid
Commun Mass Spectrom 2007;21:3200–6.
32 Meriggiola MC, Bremner WJ, Paulsen CA, Valdis-
erri A, Incorvaia L, Motta R, Pavani A, Capelli M,
Flamigni C. A combined regimen of cyproterone
acetate and testosterone enanthate as a potentially
highly effective male contraceptive. J Clin Endo-
crinol Metab 1996;81:3018–23.
33 Carmina E, Lobo RA. Comparison of the relative
efficacy of antiandrogens for the treatment of acne
in hyperandrogenic women. Clin Endocrinol 2002;
57:231–4.
34 Bunck MC, Toorians AW, Lips P, Gooren LJ. The
effects of the aromatase inhibitor anastrozole on
bone metabolism and cardiovascular risk indices in
ovariectomized, androgen-treated female-to-male
transsexuals. Eur J Endocrinol 2006;154:569–75.
35 Hayes FJ, Seminara SB, Decruz S, Boepple PA,
Crowley WF Jr. Aromatase inhibition in the human
male reveals a hypothalamic site of estrogen feed-
back. J Clin Endocrinol Metab 2000;85:3027–
35.
J Sex Med 2008;5:2442–2453
Meriggiola et al.
36 Richardson D, Goldmeier D, Frize G, Lamba H,
De Souza C, Kocsis A, Scullard G. Letrozole versus
testosterone. A single-center pilot study of HIV-
infected men who have sex with men on highly
active anti-retroviral therapy (HAART) with hypo-
active sexual desire disorder and raised estradiol
levels. J Sex Med 2007;4:502–8.
37 Bagatell CJ, Dahl KD, Bremner WJ. The direct
pituitary effect of testosterone to inhibit gonado-
tropin secretion in men is partially mediated by
aromatization to estradiol. J Androl 1994;15:15–
21.
38 Schnorr JA, Bray MJ, Veldhuis JD. Aromatization
mediates testosterone’s short-term feedback
restraint of 24-hour endogenously driven and
acute exogenous gonadotropin-releasing hormone-
stimulated luteinizing hormone and follicle-
stimulating hormone secretion in young men. J Clin
Endocrinol Metab 2001;86:2600–6.
39 Pugeat M, Moulin P, Cousin P, Fimbel S, Nicolas
MH, Crave JC, Lejeune H. Interrelations between
sex hormone-binding globulin (SHBG), plasma
lipoproteins and cardiovascular risk. J Steroid
Biochem Mol Biol 1995;53:567–72.
40 Nilsson O, Chrysis D, Pajulo O, Boman A, Holst M,
Rubinstein J, Martin Ritzén E, Sävendahl L. Local-
ization of estrogen receptors-alpha and -beta and
androgen receptor in the human growth plate at
different pubertal stages. J Endocrinol 2003;177:
319–26.
41 Wickman S, Sipilä I, Ankarberg-Lindgren C, Nor-
javaara E, Dunkel L. A specific aromatase inhibitor
and potential increase in adult height in boys with
delayed puberty: A randomised controlled trial.
Lancet 2001;357:1743–8.
42 Dunkel L, Wickman S. Novel treatment of delayed
male puberty with aromatase inhibitors. Horm Res
2002;57(2 suppl):44–52.
43 Rochira V, Faustini-Fustini M, Balestrieri A, Carani
C. Estrogen replacement therapy in a man with con-
genital aromatase deficiency: Effects of different
doses of transdermal estradiol on bone mineral
density and hormonal parameters. J Clin Endo-
crinol Metab 2000;85:1841–5.
44 Herrmann BL, Saller B, Janssen OE, Gocke P,
Bockisch A, Sperling H, Mann K, Broecker M.
Impact of estrogen replacement therapy in a male
with congenital aromatase deficiency caused by a
novel mutation in the CYP19 gene. J Clin Endo-
crinol Metab 2002;87:5476–84.
45 Miki Y, Suzuki T, Sasano H. Aromatase inhibitor
and bone. Biomed Pharmacother 2007;61:540–2.
Epub September 14, 2007.
46 Jonat W, Hilpert F, Kaufmann M. Aromatase
inhibitors: A safety comparison. Expert Opin Drug
Saf 2007;6:165–74.
47 Dougherty RH, Rohrer JL, Hayden D, Rubin SD,
Leder BZ. Effect of aromatase inhibition on lipids
and inflammatory markers of cardiovascular disease
TU Treatment in FtM Transsexuals
in elderly men with low testosterone levels. Clin
Endocrinol (Oxf) 2005;62:228–35.
48 Cailleux-Bounacer A, Rohmer V, Lahlou N,
Lefebvre H, Roger M, Kuhn JM. Impact level
of dihydrotestosterone on the hypothalamic-
pituitary-leydig cell axis in men. Int J Androl 2007
[Epub ahead of print].
49 Kuhn JM, Rieu M, Laudat MH, Forest MG, Pugeat
M, Bricaire H, Luton JP. Effects of 10 days admin-
istration of percutaneous dihydrotestosterone on
the pituitary-testicular axis in normal men. J Clin
Endocrinol Metab 1984;58:231–5.
50 Santen RJ. Is aromatization of testosterone to estra-
diol required for inhibition of luteinizing hormone
secretion in men? J Clin Invest 1975;56:1555–
63.
2453
51 Veldhuis JD, Rogol AD, Samojlik E, Ertel NH. Role
of endogenous opiates in the expression of negative
feedback actions of androgen and estrogen on pul-
satile properties of luteinizing hormone secretion in
man. J Clin Invest 1984;74:47–55.
52 Roehrborn CG, Lee M, Meehan A, Waldstreicher J.
Effects of finasteride on serum testosterone and
body mass index in men with benign prostatic
hyperplasia. Urology 2003;62:894–9.
53 Page ST, Amory JK, Bowman FD, Anawalt BD,
Matsumoto AM, Bremner WJ, Tenover JL. Exog-
enous testosterone (T) alone or with finasteride
increases physical performance, grip strength, and
lean body mass in older men with low serum T. J
Clin Endocrinol Metab 2005;90:1502–10. Epub
November 30, 2004.
J Sex Med 2008;5:2442–2453