Somatic and psychological effects of low-dose aromatase inhibition in men with obesity-related hypogonadotropic hypotestosteronemia

Article (PDF Available)inEuropean Journal of Endocrinology 169(5) · August 2013with25 Reads
DOI: 10.1530/EJE-13-0190 · Source: PubMed
Reduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor. To evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH). Double-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI > 35 kg/m2, and serum total testosterone levels < 10 nmol/L. All patients started on 1 tablet of 2.5 mg/week, with subsequent dose escalation every month until a serum total testosterone of 20 nmol/L was reached. Endpoints: psychological function, body composition, exercise capacity, and glucose, lipid and bone metabolism. 39 patients completed the study according to protocol. Letrozole decreased serum estradiol from 119.1 ± 10.1 to 59.2 ± 6.1 pmol/L (P < 0.001), increased serum LH from 3.3 ± 0.3 to 8.8 ± 0.9 U/L (P < 0.0001), and raised serum total testosterone from 8.6 ± 0.7 to 21.5 ± 1.3 nmol/L (P < 0.0001). Significant effects on the predefined endpoints were not observed. Despite a marked rise in serum testosterone, low dose aromatase inhibition had no somatic or psychological effects in men with OrHH.
Somatic and psychological effects of low-dose aromatase
inhibition in men with obesity-related hypogonadotropic
Sandra Loves
, Jos de Jong
, Adriaan van Sorge
, Darryl Telting
, Cees J Tack
, Ad Hermus
Klaas Westerterp
and Hans de Boer
Departments of
Internal Medicine,
Clinical Pharmacy and
Clinical Chemistry, Rijnstate Hospital, PO Box 9555, 6800 TA Arnhem,
The Netherlands, Departments of
General Internal Medicine and
Endocrinology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB
Nijmegen, The Netherlands and
Department of Human Biology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
(Correspondence should be addressed to S Loves; Email:
Introduction: Reduced testosterone levels are frequently observed in obese men. Increased aromatase
activity may be an etiological factor.
Objective: In this study, we evaluate the clinical effects of aromatase inhibition in obesity-related
hypogonadotropic hypotestosteronemia (OrHH).
Methods: Double-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI O35 kg/m
and a serum total testosterone !10 nmol/l. All patients started on one tablet of 2.5 mg/week, with
subsequent dose escalation every month until a serum total testosterone of 20 nmol/l was reached.
Endpoints: Psychological function, body composition, exercise capacity, and glucose, lipid, and bone
Results: Thirty-nine patients completed the study according to protocol. Letrozole decreased serum
estradiol from 119.1G10.1 to 59.2G6.1 pmol/l (P!0.001), and increased serum LH from 3.3G0.3
to 8.8G0.9 U/l (P!0.0001) and serum total testosterone from 8.6G0.7 to 21.5G1.3 nmol/l
(P!0.0001). Significant effects on the predefined endpoints were not observed.
Conclusion: Despite a marked rise in serum testosterone, low-dose aromatase inhibition had no somatic
or psychological effects in men with OrHH.
European Journal of Endocrinology 169 705–714
Reduced serum total testosterone levels are frequently
observed in obese men. Its prevalence increases in
proportion to BMI (1, 2, 3). Serum total testosterone
levels !10 nmol/l are found in about 60% of men with
aBMIO40 kg/m
, and reduced free-testosterone levels
(cut-off 225 pmol/l) in about 40% of these cases.
Obesity-related hypogonadotropic hypotestosteronemia
(OrHH) is characterized by the combination of a low
total testosterone, a marked decrease in sex hormone-
binding globulin (SHBG), a relatively high serum
estradiol (E
) and luteinizing hormone (LH) levels
within the normal range, but inappropriately low for
the degree of hypotestosteronemia (1, 2). The decrease
in total testosterone is explained by two mechanisms,
i.e. a decrease in SHBG levels and reduced LH secretion
(1, 2, 4). The latter gains in importance with increasing
degrees of obesity and this ultimately leads to reduced
levels of free testosterone in severely obese men (4).
Obesity-related suppression of LH secretion has been
related to excessive aromatase activity (5, 6). Increased
conversion of androgens to E
and estrone (E
) promotes
estrogen-mediated suppression of pituitary LH and
follicle-stimulating hormone (FSH) secretion and will
cause a secondary decrease in testosterone production.
Leptin- or cytokine-induced inhibition of LH secretion
and hypothalamic–pituitary dysfunction caused by
obstructive sleep apnea may also have a role in the
development of OrHH (7, 8).
Androgen deficiency is associated with increased fat
mass, decreased muscle and bone mass, diminished
muscle strength, insulin resistance, dyslipidemia, and
hypertension (9, 10). It may also affect brain function and
can lead to fatigue, depressive moods, loss of initiative
and drive, and docile behavior (11, 12, 13, 14).
This suggests that normalization of serum testosterone
in obese men might be a beneficial approach. However,
testosterone supplementation alone is unlikely to
normalize the gonadal status in OrHH. It may normalize
serum testosterone levels, but it will also fuel estrogen
synthesis and cause a major rise in serum E
that could have adverse effects. Partial inhibition of
aromatase activity is a more attractive approach, at
European Journal of Endocrinology (2013) 169 705–714 ISSN 0804-4643
q 2013 European Society of Endocrinology DOI: 10.1530/EJE-13-0190
Online version via
least in theory. So far, two open-label, uncontrolled pilot
studies have shown that the aromatase inhibitor letrozole
can normalize serum testosterone and E
levels in OrHH
(15). However, the clinical impact of this intervention is
currently not known.
The aim of the present study was to examine whether
normalization of serum androgens by aromatase
inhibition might improve body composition, glucose,
and lipid metabolism and induce favorable psycho-
logical changes.
Subjects and methods
Severely obese, but otherwise healthy men, 20–50 years
of age, with a BMI 35–50 kg/m
were recruited by
advertisement in local newspapers. All subjects under-
went a general physical and psychological examination
and laboratory screening, with blood samples taken
after an overnight fast, between 0800 and 1000 h.
OrHH was defined as a serum total testosterone level
!10 nmol/l, associated with a serum LH level !9 U/l,
and normal serum free thyroxine (FT
), thyroid-
stimulating hormone (TSH), prolactin, cortisol,
adrenocorticotrophic hormone (ACTH), and insulin-
like growth factor 1 (IGF1) levels. Additional inclusion
criteria were normal pubertal development, normal
testicular volume, intact sense of smell, and a stable
body weight for at least 3 months preceding the study.
Exclusion criteria were clinical or biochemical evidence
of pituitary or hypothalamic disease, serum E
!40 pmol/l, type 2 diabetes mellitus requiring insulin
to keep HbA1c below 7.0%, biochemical evidence of
hemochromatosis (transferrin saturation O45% and
serum ferritin O300 mg/l), symptomatic prostate
disease or elevated serum PSA levels, unstable cardiac
disease, liver disease, medication known to affect the
gonadal axis, psychiatric disease, and men who had
discontinued smoking within 6 months before the study.
The study protocol was approved by the Medical Ethical
Committee and was registered at
as NCT00138710. All study subjects gave their written
informed consent.
Study design
The patients were randomized to double-blind
treatment with placebo or letrozole (tablets of 2.5 mg).
All subjects started on one tablet per week. Each month,
the dose was increased by one tablet a week until the
total testosterone target level of 20 nmol/l was reached,
side effects occurred, or the maximum dose of seven
tablets (17.5 mg) per week was reached. The predefined
dose schedule was as follows: 1st month, tablet on
Monday; 2nd month, tablet on Monday and Friday; 3rd
month, tablet on Monday, Wednesday, and Friday; 4th
month, one tablet a day from Monday to Friday; 5th and
6th month, one tablet every day.
The dose was reduced by one tablet a week if total
testosterone was O30 nmol/l or E
was !40 pmol/l for
at least 4 weeks, or if severe side effects were reported
that were considered to be related to treatment. If the
decrease in dose did not result in normalization of serum
total testosterone or serum E
, the dose was further
reduced by another tablet a week, and so on, until the
total testosterone target of 20 nmol/l was reached or
serum E
had increased to a value O40 pmol/l.
A mild hypocaloric diet was prescribed, consisting of
75% of the amount required to maintain ideal body
weight. Patients were also advised to walk at least
30 min a day.
Outcome measures
Follow-up visits were scheduled every 4th week for
6 months. At each visit, body weight, waist circumfer-
ence, and blood pressure were measured, and blood
was collected between 0800 and 1000 h for measure-
ment of serum LH, FSH, E
, total testosterone, SHBG,
albumin, and PSA. Body composition, bone density,
exercise capacity, psychological characteristics, and
an extensive laboratory investigation including
whole blood count, serum creatinine, liver enzymes,
androstenedione, E
, a-subunits, FT
, TSH, total tri-
iodothyronine (T
), IGF1, cortisol, ACTH, HbA1c,
fasting glucose and C-peptide, glucose tolerance test
(measurement of glucose and insulin levels at baseline,
30, 60, 90, and 120 min, after ingestion of 75 g
glucose), fasting lipid profiles, and the bone markers
N-terminal propeptide of type 1 procollagen (PINP) and
C-terminal telopeptide of type 1 collagen (ICTP) were
measured at baseline and after 6 months.
Laboratory assays
LH, FSH, and total testosterone were measured by solid-
phase, two-site chemoluminescent immunometric assay
(CLIA) on the Immulite 2500 analyzer (Siemens,
Diagnostic Products Corporation, Los Angeles, CA,
USA; male reference ranges: LH 1–8 IU/l, FSH
1–11 IU/l, and total testosterone 10–30 nmol/l). Total
testosterone had an analytical sensitivity of 0.5 nmol/l,
validated against a commercial calibrator (Siemens,
Diagnostic Products Corporation).
, SHBG, and C-peptide were measured with an
ECLIA assay on an E170 analyzer (Roche Diagnostics
GmbH, male reference ranges: E
40–160 pmol/l, SHBG
14.5–48.4 nmol/l, and C-peptide 0.27–1.28 nmol/l). E
had a detection limit of 40 pmol/l and an analytical
sensitivity of 18.4 pmol/l, validated against isotopic
dilution gas chromatography–mass spectrometry. E
was measured with a competitive RIA (Immunotech,
Beckman Coulter (Prague, Czech Republic), male
reference range: 10–80 ng/l). Androstenedione was
measured with a competitive radiometric immunoassay
(Siemens, Diagnostic Products Corporation, male refer-
ence range: 2.8–10.5 nmol/l). IGF1 was measured with
a CLIA on an Immulite 2000 analyzer (Siemens,
Diagnostic Products Corporation, reference range age
dependent). Intact PINP and ICTP were measured by RIA
(Orion Diagnostica (Espoo, Finland), male reference
range: 22–87 and 2.1–5.0 mg/l respectively). Free
testosterone was calculated according to the equation
of Vermeulen et al. (16). Insulin sensitivity was
calculated using the homeostasis model assessment
index (17).
Calorie intake
A mild hypocaloric diet, consisting of 75% of the amount
needed to maintain ideal body weight, was prescribed
in both groups. The calculation was based on the
Harris–Benedict formula: ((66, 473)C(13.7516!BW)C
(5!S)K(6.755!A))!4.2 kJ, where BW, ideal body
weight (kg); S, stature (cm); and A, age (years). 1 kJZ
0.2390 kcal: 25% was added for physical activity (18).
Body composition and bone density
Body composition was measured by the deuterium
dilution method according to the technique described by
Westerterp et al. (19). Bone density of the lumbar spine
and both femoral necks was measured by dual-energy
X-ray absorptiometry (Lunar DXA, GE Healthcare,
Madison, WI, USA).
Exercise capacity
The excessive body weights precluded the use of a
standard bicycle test. Therefore, a staircase test was
more feasible. All patients were asked to climb a 60-step
staircase (equivalent to three levels) as fast as they
could. Time, pulse rate, blood pressure, and oxygen
saturation were measured at baseline, upon completion
of climbing the staircase, and after a 5-min rest.
Psychological testing was carried out with tests validated
for the Dutch population: Symptom Checklist-90
(SCL-90), Groninger Intelligence Test (GIT), and
the Dutch Personality Questionaire (DPQ). The SCL-90
measures anxiety, depression, somatization, insuffi-
ciency, distrust, hostility, and sleep disorders (20). The
DPQ measures inadequacy, social inadequacy, rigidity,
grievance, self-satisfaction, dominance, and self-esteem
(21). The GIT measures overall intelligence and is
included to investigate the patients’ ability to understand
and perform the psychometric tests (22). The reported
scores for a general Dutch population were used as
reference values.
Safety monitoring
Serum PSA levels were measured every 4 weeks. In case
of a rise in serum PSA or symptoms of obstructive
prostate disease, the study medication was discontinued
and the patient was referred to the urologist. Serum E
levels were measured every 4 weeks. Dose reduction was
carried out if serum E
decreased to a level !40 pmol/l.
Statistical analyses
A power analysis was performed to assess the number of
participating subjects to be able detect a 10 kg difference
in change of body weight between the two groups. With
aZ0.01 and bZ0.05, and a
subjects in each group are required. Results of the study
are shown as mean values and
S.E.M. In this proof-
of-concept study only patients who completed the
6-month study according to protocol were included in
the analysis. After confirmation of normal distribution,
differences in baseline characteristics between the
placebo and letrozole group were examined by t-test.
The results of treatment were analyzed by paired or
unpaired t-tests, where appropriate. Mann–Whitney or
Wilcoxon matched pair tests were used for variables
that did not follow a normal distribution. Fisher’s exact
test was used to compare categorical variables between
groups. A P value !0.05 was considered to represent
statistical significance. E
levels that fell below the
detection limit of 40 pmol/l were given a value of
20 pmol/l for statistical purposes.
Baseline characteristics
Forty-two men were included in the study. Three men
did not complete treatment for personal reasons not
related to the study. Thirty-nine men completed the
study according to protocol, 18 received letrozole and
21 were treated with placebo.
Age at inclusion was 44.6G1.6 years (range
29.8–56.4 years), with a BMI of 40.8G1.1 kg/m
(range 33.7–53.0 kg/m
). Serum total testosterone
ranged from 4.6–9.9 nmol/l, total E
51–210 pmol/l, and serum LH from 1–8.4 U/l. At
baseline, the two groups were well matched for all
outcome measures, except for a higher ICTP level in the
letrozole group (Tables 1 and 2). In the placebo group,
one man was treated with tolbutamide 250 mg once
daily and one used metformin 500 mg once daily. In the
letrozole group, four men used metformin in a stable
dose throughout the study (mean daily dose 1200G
374 mg). Decreased libido tended to occur more
frequently in the letrozole group (nine vs four men,
PZ0.09). Erectile dysfunction was reported equally in
both groups (four vs three men, PZ0.68). We did not
use a validated questionnaire.
Letrozole for obesity-related hypogonadism 707EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 169
The baseline scores of the psychological items are
summarized in Table 3. A higher score correlates with
more severe psychological dysfunction. The scores were
within the reference ranges and no statistical differences
between the two groups were observed. The advised
caloric intake was 1632G39 kcal/day in the placebo
group and 1639G40 kcal/day in the letrozole group
Table 1 Baseline characteristics (B) and changes (D) in body composition and serum hormone levels
after 6 months of treatment.
Placebo (nZ21) Letrozole (nZ18) P*
Body weight (kg)
B 132.2G4.6 136.1G4.9 0.57
D K5.1G1.9
BMI (kg/m
B 40.4G1.1 41.9G1.2 0.37
D K1.6G0.6
Waist (cm)
B 130.9G2.9 132.6G2.8 0.68
D K4.5G1.6
Fat mass (kg)
B 52.9G3.3 56.7G3.2 0.41
D K5.9G1.8
Fat-free mass (kg)
B 80.3G2.9 79.7G1.9 0.86
D C0.2G0.6 C1.3G0.9 0.32
LH (U/l)
B 2.9G0.4 3.3G0.3 0.13
D K0.1G0.3 C5.5G0.9
FSH (U/l)
B 4.8G0.5 5.1G0.6 0.72
D K0.2G0.2 6.3G0.8
a-Subunits (U/l)
B 0.3G0.0 0.3G0.0 0.84
D C0.1G0.1 C0.1G0.0
Total testosterone (nmol/l)
B 8.8G0.5 8.6G0.7 0.80
D C0.8G0.7 C12.9G0.8
Free testosterone (pmol/l)
B 244.3G14.1 243.7G19.4 0.98
D C17.4G18.8 C447.3G24.4
Androstenedione (ng/l)
B 7.8G0.5 7.5G0.5 0.37
D C0.1G0.4 C2.4G0.6
Estradiol (pmol/l)
B 124.3G9.3 119.1G10.1 0.70
D K18.9G6.1
Estrone (ng/l)
B 59.4G4.5 76.0G8.6 0.13
D K2.9G3.8 K36.6G6.5
Albumin (g/l)
B 41.2G0.6 41.6G0.5 0.59
D K0.6G0.5 K0.9G0.6 0.45
SHBG (nmol/l)
B 16.5G1.2 16.1G1.2 0.81
D C1.3G0.7 K0.1G0.7 0.21
PSA (U/l)
B 0.7G0.1 1.1G0.2 0.15
D C0.1G0.1 C0.3G0.0
Decreased libido
B 4 9 0.09
D 3 8 0.09
Erectile dysfunction
B 3 4 0.68
D 3 3 0.99
IGF1 (nmol/l)
B 23.5G4.2 18.4G1.3 0.48
D C2.3G1.1 K2.6G1.3 !0.01
*P significance level of differences between groups;
P!0.01, and
P!0.001, significance level of
changes within group. LH, luteinizing hormone; SHBG, sex hormone-binding globulin.
708 S Loves and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 169
Letrozole dose
At 6 months, all subjects in the placebo group reached
a dose of seven tablets per week. In the letrozole
group, the mean dose at 6 months was 1.9G0.4 tablets
per week (4.7G1.0 mg/week). Ten men reached the
total testosterone target level on one tablet per week,
four men needed two tablets per week, and two men
needed four tablets per week. Only one patient in the
letrozole group received a dose of seven tablets per week.
His total testosterone level did not rise above
15.5 nmol/l, despite a rise in serum LH from 3.3 to
9.4 U/l. One subject was treated with only 0.5 tablet per
week because serum E
decreased below 40 pmol/l on a
higher dose. After dose reduction, serum E
rose to
67 pmol/l with a total testosterone level of 29.6 nmol/l.
Changes in serum hormone levels
Letrozole therapy decreased serum E
from 119.1G
10.1 to 59.2G6.1 pmol/l (PZ0.0001), and E
from 76G8.5 to 31.9G2.9 ng/l (P!0.0001). After
6 months, serum E
levels were !40 pmol/l in three
men in the letrozole group, and in one of the men of the
placebo group (Fig. 1). Letrozole increased serum LH
from 3.3G0.3 to 8.8G0.9 U/l (P!0.0001), FSH from
5.1G0.6 to 11.4G0.2 (P!0.0001), total testosterone
from 8.6G0.7 to 21.5G1.3 nmol/l (P!0.0001), free
testosterone from 244G19 to 691G39 nmol/l
(P!0.0001), and androstenedione from 7.5G 0.5 to
9.9G0.6 nmol/l (PZ0.0013). Letrozole did not affect
serum albumin or SHBG levels. Free testosterone rose
to supra-physiological levels in 12 out of 18 men, with
levels ranging from 636 to 1005 pmol/l (Fig. 1).
In the placebo group, with the exception of a slight
but significant drop in serum E
level from 124G9.3 to
106G8.1 pmol/l (PZ0.006), there were no significant
changes in LH, FSH, total, or free testosterone,
androstenedione, E
, SHBG, or albumin levels (Table 1
and Fig. 2). Neither letrozole nor placebo had any effect
on TSH, free T
, prolactin, cortisol, or ACTH levels
(data not shown). Erectile dysfunction or libido did not
change significantly.
Table 2 Glucose homeostasis, lipid levels, bone markers, and
bone density at baseline (B) and the changes (D) after 6 months of
(nZ18) P*
Fasting glucose
B 6.0G0.1 6.0G0.2 0.68
D K0.0G0.2 K0.3G0.2 0.19
Fasting C-peptide
B 1.4G0.1 1.6G0.1 0.16
D K0.2G0.1
K0.3G0.1 0.84
HbA1c (%)
B 5.7G0.1 6.0G0.2 0.99
D C0.1G0.1 K0.2G0.1 0.18
AUC glucose
B 1068G49 1158G57 0.24
D K33G45 K6G47 0.68
AUC insulin
B 11 858G978 13 422G1353 0.24
D K2844G828
K2473G1403 0.81
B 1.1G0.4 0.9G0.2 0.45
D K0.4G0.3 K0.0G0.1 0.28
HDL (mmol/l)
B 1.1G0.0 1.2G0.0 0.64
D K0.0G0.0 K0.1G0.0
LDL (mmol/l)
B 3.3G0.2 3.1G0.2 0.57
D K0.4G0.1
K0.2G0.2 0.24
TG (mmol/l)
B 1.7G0.2 2.2G0.3 0.16
D K0.1G0.2 C0.1G0.2 0.45
PINP (mg/l)
B 36.7G2.4 38.2G3.5 0.83
D C7.2G4.7 C8.4G2.2
ICTP (mg/l)
B 3.5G0.2 4.2G0.2 0.02
D C0.2G0.3 C0.7G0.3
Lumbar spine
B 0.4G0.3 K0.0G0.4 0.39
D C0.1G0.6 K0.2G0.9 0.76
Left hip (T-score)
(DBMC (g/cm
B 0.9G0.3 0.9G0.3 0.97
D K0.3G0.3 C0.3G0.2 0.16
Right hip (T-score)
(DBMC (g/cm
B 0.6G0.3 0.9G0.3 0.54
D C0.1G0.3 C0.2G0.3 0.82
*P significance level of differences between groups.
significance level of changes within group. TG, triglycerides; HOMA-IR,
homeostasis model assessment of insulin sensitivity; DBMC/g, change in
bone mineral content.
Table 3 Baseline psychological characteristics.
(nZ18) P*
Anxiety 12–15 12.0G0.8 13.3G1.6 0.53
Depression 20–24 21.8G2.0 23.7G3.1 0.70
Somatization 15–19 17.0G1.4 17.6G1.3 0.76
11–15 12.7G1.0 14.9G1.7 0.29
Distrust 22–27 23.2G1.2 24.9G2.2 0.82
Hostility 7–9 7.4G0.6 6.9G0.3 0.93
4–6 5.3G0.6 5.7G0.7 0.45
Neuroticism 113–124 117.7G6.5 128.0G11.4 0.49
Inadequacy 7–14 6.6G1.8 9.6G1.9 0.05
7–13 6.9G1.5 8.3G1.7 0.53
Rigidity 24–32 22.6G1.9 24.7G1.7 0.44
Resentment 15–22 14.1G1.2 17.6G1.7 0.11
Self esteem 9–15 12.2G1.2 10.4G0.7 0.22
Dominance 13–20 18.9G1.5 18.5G2.0 0.88
Self sufficiency 25–32 31.1G1.2 27.3G1.4 0.048
*P significance level of differences between groups.
Letrozole for obesity-related hypogonadism 709EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 169
Changes in body composition and
exercise capacity
Body weight decreased significantly in both groups, but
the changes did not differ between the groups (letrozole
vs placebo: K5.1G1.5 vs K5.1G1.9 kg, PZ0.99).
Similarly, waist circumference decreased in both groups
but the changes did not differ between the groups
(K4.1G0.8 vs K4.5G1.6 cm, PZ0.45). Changes in
fat mass and fat-free mass did not differ between
groups (Table 1), and there also were no significant
differences between groups in exercise performance
(data not shown).
Changes in metabolic parameters
Compared with placebo, letrozole did not affect the
fasting glucose levels, HbA1c, or insulin sensitivity
(Table 2).
PSA levels increased in the letrozole group, but
symptomatic prostate disease did not occur (letrozole,
C0.3G0.0 U/l; placebo, C0.1G0.0 U/l, PZ0.03).
The letrozole group demonstrated a slight but signi-
ficant increase in hemoglobin levels (letrozole,
C0.2G0.1 mmol/l; placebo, K0.2G0.1 mmol/l,
PZ0.01). IGF1 levels showed a small but significant
decrease in the letrozole group (letrozole, K2.6G
1.3 nmol/l; placebo, C2.3G1.1 nmol/l, P!0.01).
HDL levels decreased marginally in the letrozole group
(letrozole, K0.1G0.0 mmol/l; placebo, 0.0G
0.0 mmol/l, PZ0.04).
Plasma alanine and aspartate aminotransferase
levels dropped slightly but significantly in both groups
to a similar extent. Letrozole treatment did not change
PINP and ICTP levels. Bone mineral content did not
change in either group.
Changes in psychological parameters
Letrozole treatment had no effect on any psychological
item that was tested (data not shown).
The main nding of this study is that low-dose
aromatase inhibition in men with OrHH can induce a
major rise in serum total testosterone but does not
induce beneficial effects on clinical endpoints. This lack
of effect cannot be explained by an overall lack of power
or poor matching. Although both groups contained
several men with low normal instead of subnormal free
testosterone levels, and this could have reduced the
chance to detect an effect, it is unlikely to explain the
negative ndings. A post hoc analysis of men with
P = 0.0001
P = 0.001
P < 0.0001
P = < 0.0001
Androstenedione (ng/l)
Estradiol (pmol/l)Estrone (ng/ml)
10 000
Free testosterone (pmol/l)
Figure 1 Changes in the levels of free serum total estradiol, estrone,
testosterone, and androstenedione in the letrozole-treated patients
before and after 6 months of treatment.
710 S Loves and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 169
baseline free testosterone levels !225 mol/l, with 90%
power to detect a 10 kg difference in weight at aZ0.05,
also did not reveal an effect. We therefore conclude
that we are looking at a true lack of effect. To explain
this unexpected nding, the following hypothesis is
proposed: the clinical effects normally associated with
testosterone replacement therapy in men are a result
of both testosterone and E
receptor activation. In case
of aromatase inhibition, these parallel and often
synergistic effects of testosterone and E
are uncoupled,
which could explain the lack of clinical effects. As this
study was not primarily designed to test this role of
estrogens in men, this hypothesis should be regarded as
a retrospective explanation of the findings; however, an
explanation that is also supported by direct and indirect
evidence from the literature.
Previous experience with aromatase inhibition
The lack of effect of aromatase inhibition is in
agreement with studies performed in other types of
patients. Aromatase inhibitors have been used in boys
with idiopathic short stature to promote linear growth
(24, 25), in eugonadal young adults to study metabolic
effects (26, 27), and in eugonadal and hypogonadal
elderly to examine the effect on frailty (26, 28, 29). The
only clinical effect shown thus far is an increase in body
height of about 6 cm in boys with idiopathic short
stature, i.e. an effect caused by the reduction of estrogen
levels below the normal range. Other major effects were
not observed.
Aromatase inhibition vs testosterone
The hormonal changes induced by letrozole are
fundamentally different from those seen during tes-
tosterone replacement therapy, and this may be the key
to understand the differences in clinical efficacy.
Testosterone replacement raises both serum testoster-
one and E
, whereas aromatase inhibitors induce a rise
in testosterone but a decrease in E
(15). It appears that
the expected beneficial effects of a rise in testosterone are
offset by the decrease in estrogens. It is likely that some
of the effects of testosterone replacement are not caused
by testosterone itself but are predominantly induced
by the rise in E
. The testosterone/E
–GH interaction
also needs to be considered. To some extent, the lack
of anabolic and lipolytic effects may also have been
caused by reduced GH/IGF1 secretion. Such a
mechanism is suggested by the small but statistically
significant decrease in serum IGF1 that was observed
in the letrozole group. Testosterone is known to
stimulate GH secretion, an effect that is mediated
by estrogens (30, 31). Letrozole may have uncoupled
this interaction.
Findings in animal studies
Animal studies support the hypothesis of testosterone
and E
synergism in males. Both androgen receptors
(AR) and estrogen receptors (ER) are omnipresent in
male animals, and activation of both receptors is crucial
to observe the full benefit of testosterone replacement
therapy. Dihydrotestosterone, a non-aromatizable andro-
gen that only activates the AR, does not change body
composition in orchidectomized rats. In contrast,
treatment with E
increases muscle mass, prevents the
post-orchidectomy increase in fat mass, and is more
effective in preventing bone loss (32). The importance of
has also been shown in models of males with estrogen
deficiency such as the ERa knockout (ERaKO) and the
aromatase-KO mice. The ERaKO mice demonstrate
adipocyte hypertrophy, glucose intolerance, insulin
resistance, and reduced energy expenditure (33).
Total testosterone (nmol/l)
LH (U/l)
Total estradiol (pmol/l)
Figure 2 Mean changes in serum estradiol, serum LH,
and testosterone levels during 6 months of treatment in patients
treated with placebo (open dots) or letrozole (black dots). The
dashed lines represent the lower and upper limits of normal.
Letrozole for obesity-related hypogonadism
Aromatase-KO mice have increased intra-abdominal
adipose tissue, decreased lean body mass, dyslipidemia,
and insulin resistance, and administration of estrogen
decreases their fat depots to the size of WT littermates
(34). All these observations support the notion that
/ERa signaling is of major importance for the
regulation of fat mass, lean body mass, and physical
activity in male mice (33, 34).ERa activation alone is
sufficient to reduce fat mass, but AR and ERa signaling
are both required to achieve an optimal muscle mass
deficiency (ArD) confirm the importance of estrogens in
men (36). ArD men have high LH levels, normal or
elevated serum levels of testosterone and androstene-
dione, and low or undetectable serum E
and E
Thus, they lack estrogen but not testosterone effects.
They are very tall because of non-fusion of the epiphyses,
and have excess abdominal fat, reduced bone mineral
density, elevated triglyceride levels, low HDL, hepatic
steatosis, and insulin resistance. E
treatment induces
epiphysial fusion, increases bone density, and improves
glucose and lipid metabolism in these men (37).
Potentially deleterious effects
Aromatase inhibitors can be expected to have deleter-
ious effects in men when doses are used that cause
estrogen deficiency. In this study with low-dose
letrozole, we did not detect adverse effects. Apparently,
the dose reduction performed when serum E
decreased below 40 pmol/l was sufficient to prevent
that. Trials using high-dose aromatase inhibition
reported deleterious effects. Mild vertebral deformities
were detected in 45% of the letrozole-treated boys (38).
In elderly men treated with anastrozole 1 mg daily for
a year, spinal BMD was significantly decreased (39).
Limitations of this study
Power analysis to detect an effect was only based on
changes in body weight, and therefore a type 2 error for
other clinical endpoints cannot be definitely excluded.
Addition of a testosterone-treated group as control
might have served to better understand the study results
by offering a background of combined testosterone and
effects. Fear of excessive E
effects was the main
reason to exclude this as an option.
Future research
The only potential indication for aromatase inhibition
in adult men that has arisen so far is the treatment of
obesity-related infertility. A relationship has been found
between increased BMI and decreased sperm concen-
trations, sperm motility, abnormal morphology, and
decreased fertility rates (40). Aromatase inhibition
raises serum FSH levels in hypo- and eugonadal men,
and this may have positive effects on fertility. Aromatase
inhibition in overweight and obese men with oligozoos-
permic infertility and a high E
:testosterone ratio as a
result of increased aromatase activity improved semen
quantity and quality and raised the frequency of
pregnancies (40).
Advised approach in men with OrHH
A recent meta-analysis has convincingly shown that
weight loss is associated with a substantial rise in total
and free testosterone levels and a decline in estrogen
levels (41). The decrease in BMI was the main
determinant of the rise in testosterone levels. Therefore,
induction of weight loss is recommended as the option of
first choice in men with OrHH.
In conclusion, a 6-month course of low-dose
letrozole-induced aromatase inhibition in men with
OrHH did not have beneficial somatic or psychological
effects. This lack of effect might be attributed to an
uncoupling of testosterone and estrogen effects. For
non-sexual functions in men, estrogens seem to be at
least as important as androgens. If this point of view
proves to be correct it may become necessary to include
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
This investigator-initiated study was supported by Novartis (Basel,
Switzerland). Novartis did not participate in the design, data analysis,
or writing of the manuscript.
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Received 7 March 2013
Revised version received 12 July 2013
Accepted 15 August 2013
714 S Loves and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 169
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